Binding to ACE2

PR:000003622

PR angiotensin-converting enzyme 2

CL:0000129

CL microglial cell

CL:0000127

CL astrocyte

GO:0005102

GO receptor binding

MP:0001847

MP brain inflammation

MP:0002229

MP neurodegeneration

WIKI occurrence

WIKI pathological

WIKI increased

Sars-CoV-2 Virus from the coronaviridae family related to SARS-CoV, 229E, NL63, OC43, HKU1 and MERS.

Transmitted by aerosols

2021-02-23T04:50:40

2022-09-09T05:09:36

Virus

2018-05-29T07:10:01

bacteria

2021-02-23T05:15:41

SARS-CoV

2020-03-01T10:42:46

Chemical

2017-02-07T13:22:42

fungi

2021-02-23T05:23:45

9606

NCBI Homo sapiens

10090

NCBI mouse

9666

NCBI Mustela lutreola

9685

NCBI Felis catus

9694

NCBI Panthera tigris

9615

NCBI Canis familiaris

10116

NCBI rat

WCS_9606

common toxicological species human

WCS_7955

common ecological species zebrafish

9541

NCBI Macaca fascicularis

Binding to ACE2

Molecular

Angiotensin-converting enzyme 2 (<a href="https://www.genecards.org/cgi-bin/carddisp.pl?gene=ACE2">ACE2</a>) is an enzyme that can be found either attached to the membrane of the cells (mACE2) in many tissues and in a soluble form form (sACE2). A table on ACE2 expression levels according to tissues (Kim et al.) <table cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:medium none; height:806px; width:1049px"> <tbody> <tr> <td style="background-color:#a6a6a6; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:146px">   </td> <td style="background-color:#a6a6a6; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:146px"> Sample size </td> <td style="background-color:#a6a6a6; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:147px"> ACE2 mean expression </td> <td style="background-color:#a6a6a6; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; vertical-align:top; width:147px"> Standard deviation of expression </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Intestine </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 51 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 9.50 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.183 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Kidney </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 129 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 9.20 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 2.410 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Stomach </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 35 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 8.25 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 3.715 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Bile duct </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 9 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 7.23 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.163 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Liver </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 50 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 6.86 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.351 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Oral cavity </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 32 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 6.23 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.271 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Lung </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 110 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 5.83 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 0.710 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Thyroid </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 59 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 5.65 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 0.646 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Esophagus </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 11 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 5.31 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.552 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Bladder </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 19 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 5.10 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.809 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Breast </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 113 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 4.61 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 0.961 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Uterus </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 25 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 4.37 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.125 </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> Protaste </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:146px"> 52 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 4.35 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; vertical-align:top; width:147px"> 1.905 </td> </tr> </tbody> </table> ACE2 receptors in the brain (endothelial, neuronal and glial cells): The highest ACE2 expression level in the brain was found in the pons and medulla oblongata in the human brainstem, containing the medullary respiratory centers (Lukiw et al., 2020). High ACE2 receptor expression was also found in the amygdala, cerebral cortex and in the regions involved in cardiovascular function and central regulation of blood pressure including the sub-fornical organ, nucleus of the tractus solitarius, paraventricular nucleus, and rostral ventrolateral medulla (Gowrisankar and Clark 2016; Xia and Lazartigues 2010). The neurons and glial cells, like astrocytes and microglia also express ACE-2. In the brain, ACE2 is expressed in endothelium and vascular smooth muscle cells (Hamming et al., 2004), as well as in neurons and glia (Gallagher et al., 2006; Matsushita et al., 2010; Gowrisankar and Clark, 2016; Xu et al., 2017; de Morais et al., 2018) (from Murta et al., 2020). Astrocytes are the main source of angiotensinogen and express ATR1 and MasR; neurons express ATR1, ACE2, and MasR, and microglia respond to ATR1 activation (Shi et al., 2014; de Morais et al., 2018). ACE2 receptors in the intestines The highest levels of ACE2 are found at the luminal surface of the enterocytes, the differentiated epithelial cells in the small intestine, lower levels in the crypt cells and in the colon (Liang et al, 2020; Hashimoto et al., 2012, Fairweather et al. 2012; Kowalczuk et al. 2008).

In vitro methods supporting interaction between ACE2 and SARS-CoV-2 spike protein Several reports using surface plasmon resonance (SPR) or biolayer interferometry binding (BLI) approaches. to study the interaction between recombinant ACE2 and S proteins have determined a dissociation constant (Kd) for SARS-CoV S and SARS-CoV-2 S as follow, <table cellspacing="0" class="Table" style="border-collapse:collapse; width:568px"> <tbody> <tr> <td style="background-color:#f7f7f7; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:28px; width:176px"> Reference </td> <td style="background-color:#f7f7f7; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:28px; width:102px"> ACE2 protein </td> <td style="background-color:#f7f7f7; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:28px; width:140px"> SARS-CoV S </td> <td style="background-color:#f7f7f7; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:28px; width:151px"> SARS-CoV2 S </td> <td style="background-color:#f7f7f7; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:28px; width:128px"> Method </td> <td style="background-color:#f7f7f7; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:28px; width:156px"> Measured Kd </td> </tr> <tr> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; width:176px"> doi:<a class="id-link" href="https://doi.org/10.1126/science.abb2507" rel="noopener" target="_blank">10.1126/science.abb2507</a> </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:102px"> 1–615 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px"> 306–577 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px">   </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:128px"> SPR </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 325.8 nM </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px">   </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px"> 1–1208 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 14.7 nM </td> </tr> <tr> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; width:176px"> doi:<a class="id-link" href="https://doi.org/10.1001/jama.2020.3786" rel="noopener" target="_blank">10.1001/jama.2020.3786</a> </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:102px"> 19–615 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px"> 306–527 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px">   </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:128px"> SPR </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 408.7 nM </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px">   </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px"> 319–541 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 133.3 nM </td> </tr> <tr> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; width:176px"> <a href="https://elifesciences.org/articles/61390#bib67" style="color:blue; text-decoration:underline">Lan et al., 2020</a> </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:102px"> 19–615 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px"> 306–527 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px">   </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:128px"> SPR </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 31.6 nM </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px">   </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px"> 319–541 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 4.7 nM </td> </tr> <tr> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; width:176px"> doi:<a class="id-link" href="https://doi.org/10.1016/j.cell.2020.02.058" rel="noopener" target="_blank">10.1016/j.cell.2020.02.058</a> </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:102px"> 1–614 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px"> 306–575 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px">   </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:128px"> BLI </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 1.2 nM </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px">   </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px"> 328–533 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 5 nM </td> </tr> <tr> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; width:176px"> doi:<a class="id-link" href="https://doi.org/10.1126/science.abb2507" rel="noopener" target="_blank">10.1126/science.abb2507</a> </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:102px"> 1–615 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px"> 306–577 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px">   </td> <td rowspan="2" style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:128px"> BLI </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 13.7 nM </td> </tr> <tr> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:140px">   </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:151px"> 319–591 aa </td> <td style="background-color:white; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; width:156px"> 34.6 nM </td> </tr> </tbody> </table> Pseudo typed vesicular stomatitis virus expressing SARS-CoV-2 S (VSV-SARS-S2) expression system can be used efficiently infects cell lines, with Calu-3 human lung adenocarcinoma epithelial cell line, CaCo-2 human colorectal adenocarcinoma colon epithelial cell line and Vero African grey monkey kidney epithelial cell line being the most permissive (Hoffmann et al., 2020; Ou et al., 2020).  It can be measured using a wide variety of assays targeting different biological phases of infection and altered cell membrane permeability and cell organelle signaling pathway. Other assay measured alteration in the levels of permissive cell lines all express ACE2 or hACE2-expressing 293T cell (e.g. pNUO1-hACE2, pFUSE-hIgG1-Fc2), as previously demonstrated by indirect immunofluorescence (IF) or by immunoblotting are associated with ELISA(W Tai et al., nature 2020). To prioritize the identified potential KEs for selection and to select a KE to serve as a case study, further in-silico data that ACE2 binds to SARS-CoV-2 S is necessary for virus entry. The above analysis outlined can be used evidence-based assessment of molecular evidence as a MIE.

The KE is applicable to broad species/life stage/sex. The binding of ACE2 occurs in the cells which express ACE2.

UBERON:0000062

UBERON organ

CL:0000000

CL cell

High Mixed

High

Adult, reproductively mature

High

During development and at adulthood

High High High Moderate Moderate Low

de Morais SDB, et al. Integrative Physiological Aspects of Brain RAS in Hypertension. Curr Hypertens Rep. 2018 Feb 26; 20(2):10. Gallagher PE, et al. Distinct roles for ANG II and ANG-(1-7) in the regulation of angiotensin-converting enzyme 2 in rat astrocytes. Am J Physiol Cell Physiol. 2006 Feb; 290(2):C420-6. Gowrisankar YV, Clark MA. Angiotensin II regulation of angiotensin-converting enzymes in spontaneously hypertensive rat primary astrocyte cultures. J Neurochem. 2016 Jul; 138(1):74-85. Hamming I et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004 Jun;203(2):631-7. Jakhmola S, et al. SARS-CoV-2, an Underestimated Pathogen of the Nervous System. SN Compr Clin Med. 2020. Lukiw WJ et al. SARS-CoV-2 Infectivity and Neurological Targets in the Brain. Cell Mol Neurobiol. 2020 Aug 25;1-8. Matsushita T, et al. CSF angiotensin II and angiotensin-converting enzyme levels in anti-aquaporin-4 autoimmunity. J Neurol Sci. 2010 Aug 15; 295(1-2):41-5. Murta et al. Severe Acute Respiratory Syndrome Coronavirus 2 Impact on the Central Nervous System: Are Astrocytes and Microglia Main Players or Merely Bystanders? ASN Neuro. 2020. PMID: 32878468 Shi A, et al. Isolation, purification and molecular mechanism of a peanut protein-derived ACE-inhibitory peptide. PLoS One. 2014; 9(10):e111188. Xia, H. and Lazartigues, E.  Angiotensin-Converting Enzyme 2: Central Regulator for Cardiovascular Function. Curr. Hypertens. 2010  Rep. 12 (3), 170– 175 AOPWiki 2020-03-02T03:18:47

2024-10-21T02:25:03

Neuroinflammation

Tissue

Neuroinflammation or brain inflammation differs from peripheral inflammation in that the vascular response and the role of peripheral bone marrow-derived cells are less conspicuous. The most easily detectable feature of neuroinflammation is activation of microglial cells and astrocytes. It is evidenced by changes in shape, increased expression of certain antigens, and accumulation and proliferation of the glial cells in affected regions (Aschner, 1998; Graeber & Streit, 1990; Monnet-Tschudi et al, 2007; Streit et al, 1999; Kraft and Harry, 2011; Claycomb et al., 2013). Upon stimulation by cytokines or inflammogens (e.g. from pathogens or from damaged neurons), both glial cell types activate inflammatory signalling pathways, which result in increased expression and/or release of inflammatory mediators such as cytokines, eicosanoids, and metalloproteinases (Dong & Benveniste, 2001), as well as in the production of reactive oxygen (ROS) and nitrogen species (RNS) (Brown & Bal-Price, 2003). Different types of activation states are possible for microglia and astrocytes, resulting in pro-inflammatory or anti-inflammatory signalling and other cellular functions (such as phagocytosis) (Streit et al., 1999; Nakajima and Kohsaka, 2004). Therefore, neuroinflammation can have both neuroprotective/neuroreparative and neurodegenerative consequences (Carson et al., 2006 ; Monnet-Tschudi et al, 2007; Aguzzi et al., 2013 ; Glass et al., 2010). Under normal physiological conditions, microglial cells scan the nervous system for neuronal integrity (Nimmerjahn et al, 2005) and for invading pathogens (Aloisi, 2001; Kreutzberg, 1995; Kreutzberg, 1996; Rivest, 2009). They are the first type of cell activated (first line of defence), and can subsequently induce astrocyte activation (Falsig, 2008). Two distinct states of microglial activation have been described (Gordon, 2003; Kigerl et al, 2009; Maresz et al, 2008; Mosser & Edwards, 2008; Perego et al; Ponomarev et al, 2005; Moehle and West, 2015): The M1 state is classically triggered by interferon-gamma and/or other pro-inflammatory cytokines, and this state is characterized by increased expression of integrin alpha M (Itgam) and CD86, as well as the release of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6), and it is mostly associated with neurodegeneration. The M2 state is triggered by IL-4 and IL-13 (Maresz et al, 2008; Perego et al, 2011; Ponomarev et al, 2007) and induces the expression of mannose receptor 1 (MRC1), arginase1 (Arg 1) and Ym1/2; it is involved in repair processes. The activation of astrocytes by microglia-derived cytokines or TLR agonists resembles the microglial M1 state (Falsig 2006). Although classification of the M1/M2 polarization of microglial cells may be considered as a simplification of authentic microglial reaction states (Ransohoff, 2016), a similar polarization of reactive astrocytes has been descibed recently Liddlelow et al., 2017): Interleukin-1 alpha (IL-1alpha), TNF and subcomponent q (C1q) released by activated microglial cells induce A1-reactive astrocytes, which lose the ability to promote neuronal survival, outgrowth, synaptogenesis and phagocytosis and induce the death of neurons and oligodendrocytes.   Neuroinflammation and Brain development During brain development, microglia are known to play a critical role as shapers of neural circuits, by providing trophic factors and by remodeling and pruning synapses (Rajendran and Paolicelli, 2018). In addition to playing a role in synaptic management, microglia are important for the pruning of dying neurons and in the clearance of debris (<a href="#_ENREF_43" title="Harry, 2013 #5042">Harry, 2013</a>). Microglia seem to affect also processes associated with neuronal proliferation and differentiation (Harry and Kraft, 2012). Similarly to microglia, astrocytes have instructive roles in neurogenesis, gliogenesis, angiogenesis, axonal outgrowth, synaptogenesis, and synaptic pruning (Reemst et al., 2016). The development-dependent reactivity of microglial cells and astrocytes is not well known. Ischemic insult appears to elicit similar microglial reactivity both during brain development and in adulthood (<a href="#_ENREF_3" title="Baburamani, 2014 #6737">Baburamani et al, 2014</a>; <a href="#_ENREF_54" title="Leonardo, 2009 #6879">Leonardo & Pennypacker, 2009</a>). In contrast, treatment with lead acetate was previously shown to result in a more pronounced microglial and astrocyte reactivity in immature 3D rat brain cell cultures as compared to mature ones (<a href="#_ENREF_101" title="Zurich, 2002 #3368">Zurich et al, 2002</a>). Astrocyte reactivity was also more pronounced in immature 3D rat brain cell cultures following paraquat exposure, whereas development-dependent differences in the phenotype of reactive microglia were observed (Sandström et al., 2017). This suggests that neuroinflammation is occurring during brain development and may express a different phenotype than in adulthood, and that dysfunction of microglia and astrocyte during brain development could contribute to neurodevelopmental disorders and potentially to late-onset neuropathology (Reemst et al., 2016).   Neuroinflammation in relation to COVID19 SARS-CoV-2 patients with moderate and severe COVID-19 presented an elevated plasma levels of glial fibrillary acidic protein (GFAP), which is known as biochemical indicator of glial activation (Kanberg et al., 2020).

Neuroinflammation, i.e. the activation of glial cells can be measured by quantification of cellular markers (most commonly), or of released mediators (less common). As multiple activation states exist for the two main cell types involved, it is necessary to measure several markers of neuroinflammation: <ul> <li>Microglial activation can be detected based on the increased numbers of labeled microglia per volume element of brain tissue (due to increase of binding sites, proliferation, and immigration of cells) or on morphological changes. A specific microglial marker, used across different species, is CD11b. Alternatively various specific carbohydrate structures can be stained by lectins (e.g. IB4). Beyond that, various well-established antibodies are available to detect microglia in mouse tissue (F4/80), phagocytic microglia in rat tissue (ED1) or more generally microglia across species (Iba1). Transgenic mice are available with fluorescent proteins under the control of the CD11b promoter to easily quantify microglia without the need for specific stains.</li> <li>The most frequently used astrocyte marker is GFAP (99% of all studies) (Eng et al., 2000). This protein is highly specific for astrocytes in the brain, and antibodies are available for immunocytochemical detection. In neuroinflammatory brain regions, the stain becomes more prominent, due to an upregulation of the protein, a shape change/proliferation of the cells, and/or better accessibility of the antibody. Various histological quantification approaches can be used. Occasionally, alternative astrocytic markers, such as vimentin of the S100beta protein, have been used for staining of astrocytes (Struzynska et al., 2007). Antibodies for complement component 3 (C3), the most characteristic and highly upregulated marker of A1 neurotoxic reactive astrocytes are commercially available.</li> <li>All immunocytochemical methods can also be applied to cell culture models.</li> <li>In patients, microglial accumulation can be monitored by PET imaging, using [11C]-PK 11195 as a microglial marker (Banati et al., 2002).</li> <li>Activation of glial cells can be assessed in tissue or cell culture models also by quantification of sets of activation markers. This can for instance be done by PCR quantification of inflammatory factors, by measurement of the respective mediators, e.g. by ELISA-related immuno-quantification. Such markers include:</li> <li>Pro- and anti-inflammatory cytokine expression (IL-1β; TNF-α, Il-6, IL-4); or expression of immunostimmulatory proteins (e.g. MHC-II)</li> <li>Itgam, CD86 expression as markers of M1 microglial phenotype</li> <li>Arg1, MRC1, as markers of M2 microglial phenotype</li> </ul> For descriptions of techniques, see Falsig 2004; Lund 2006 ; Kuegler 2010; Monnet-Tschudi et al., 2011; Sandström et al., 2014; von Tobel et al.,  2014   Regulatory example using the KE Measurement of glial fibrillary acidic protein (GFAP) in brain tissue, whose increase is a marker of astrocyte reactivity, is required by the US EPA in rodent toxicity studies for fuel additives (40 CFR 79.67). It has been used on rare occasions for other toxicant evaluations.

Neuroinflammation is observed in human, monkey, rat, mouse, and zebrafish, in association with neurodegeneration or following toxicant exposure, or SARS-CoV-2 and other coronavirus infection. Some references (non-exhaustive list) are given below for illustration: Human: Vennetti et al., 2006 Monkey (Macaca fascicularis): Charleston et al., 1994, 1996 Rat: Little et al., 2012; Zurich et al., 2002; Eskes et al., 2002 Mouse: Liu et al., 2012 Zebrafish: Xu et al., 2014.

UBERON:0000955

UBERON brain

High Mixed

High

During brain development, adulthood and aging

High High Moderate Low Moderate

Aguzzi, A., Barres, B.A., Bennett, M.L., 2013. Microglia: scapegoat, saboteur, or something else? Science 339(6116), 156-161. Aloisi, F., 2001. Immune function of microglia. Glia 36, 165-179. Aschner M (1998) Immune and inflammatory responses in the CNS: modulation by astrocytes. ToxicolLett 103: 283-287 Banati, R. B. (2002). "Visualising microglial activation in vivo." Glia 40: 206-217.    Baburamani AA, Supramaniam VG, Hagberg H, Mallard C (2014) Microglia toxicity in preterm brain injury. Reprod Toxicol 48: 106-112 Brown GC, Bal-Price A (2003) Inflammatory neurodegeneration mediated by nitric oxide, glutamate, and mitochondria. Mol Neurobiol 27: 325-355 Carson, M.J., Thrash, J.C., Walter, B., 2006. The cellular response in neuroinflammation: The role of leukocytes, microglia and astrocytes in neuronal death and survival. Clin Neurosci Res 6(5), 237-245. Charleston JS, Body RL, Bolender RP, Mottet NK, Vahter ME, Burbacher TM. 1996. Changes in the number of astrocytes and microglia in the thalamus of the monkey Macaca fascicularis following long-term subclinical methylmercury exposure. NeuroToxicology 17: 127-138. Charleston JS, Bolender RP, Mottet NK, Body RL, Vahter ME, Burbacher TM. 1994. Increases in the number of reactive glia in the visual cortex of Macaca fascicularis following subclinical long-term methyl mercury exposure. ToxicolApplPharmacol 129: 196-206. Claycomb, K.I., Johnson, K.M., Winokur, P.N., Sacino, A.V., Crocker, S.J., 2013. Astrocyte regulation of CNS inflammation and remyelination. Brain Sci 3(3), 1109-1127. Dong Y, Benveniste EN (2001) Immune Function of Astrocytes. Glia 36: 180-190 Eng LF, Ghirnikar RS, Lee YL (2000) Glial Fibrillary Acidic Protein: GFAP-Thirty-One Years (1969-2000). NeurochemRes 25: 1439-1451 Eskes C, Honegger P, Juillerat-Jeanneret L, Monnet-Tschudi F. 2002. Microglial reaction induced by noncytotoxic methylmercury treatment leads to neuroprotection via interactions with astrocytes and IL-6 release. Glia 37(1): 43-52. Falsig J, Latta M, Leist M. Defined inflammatory states in astrocyte cultures correlation with susceptibility towards CD95-driven apoptosis. J Neurochem. 2004  Jan;88(1):181-93. Falsig J, Pörzgen P, Lund S, Schrattenholz A, Leist M. The inflammatory transcriptome of reactive murine astrocytes and implications for their innate immune function. J Neurochem. 2006 Feb;96(3):893-907. Falsig J, van Beek J, Hermann C, Leist M. Molecular basis for detection of invading pathogens in the brain. J Neurosci Res. 2008 May 15;86(7):1434-47. Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH (2010). Mechanisms underlying inflammation in neurodegeneration. Cell. 2010 Mar 19;140(6):918-34. Gordon S (2003) Alternative activation of macrophages. Nat Rev Immunol 3: 23-35 Graeber MB, Streit WJ (1990) Microglia: immune network in the CNS. Brain Pathol 1: 2-5 Harry GJ and Kraft AD (2012) Microglia in the developing brain: apotential target with lifetime effects. <a href="https://www.ncbi.nlm.nih.gov/pubmed/22322212" title="Neurotoxicology.">Neurotoxicology.</a> 33(2):191-206. Harry GJ (2013) Microglia during development and aging. Pharmacology & therapeutics 139: 313-326 Kanberg N, et al. Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19. Neurology. 2020 Sep 22;95(12):e1754-e1759 Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29: 13435-13444 Kraft AD, Harry GJ., Features of microglia and neuroinflammation relevant to environmental exposure and neurotoxicity. International Journal of Environmental research and Public Health., 2011, 8(7): 2980-3018. Kreutzberg GW (1995) Microglia, the first line of defence in brain pathologies. Arzneimttelforsch 45: 357-360 Kreutzberg GW (1996) Microglia : a sensor for pathological events in the CNS. Trends Neurosci 19: 312-318 Kuegler PB, Zimmer B, Waldmann T, Baudis B, Ilmjärv S, Hescheler J, Gaughwin P, Brundin P, Mundy W, Bal-Price AK, Schrattenholz A, Krause KH, van Thriel C, Rao MS, Kadereit S, Leist M. Markers of murine embryonic and neural stem cells, neurons and astrocytes: reference points for developmental neurotoxicity testing. ALTEX. 2010;27(1):17-42 Leonardo CC, Pennypacker KR (2009) Neuroinflammation and MMPs: potential therapeutic targets in neonatal hypoxic-ischemic injury. J Neuroinflammation 6: 13 Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, et al. 2017. Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638): 481-487. Little AR, Miller DB, Li S, Kashon ML, O'Callaghan JP. 2012. Trimethyltin-induced neurotoxicity: gene expression pathway analysis, q-RT-PCR and immunoblotting reveal early effects associated with hippocampal damage and gliosis. Neurotoxicol Teratol 34(1): 72-82. Liu Y, Hu J, Wu J, Zhu C, Hui Y, Han Y, et al. 2012. alpha7 nicotinic acetylcholine receptor-mediated neuroprotection against dopaminergic neuron loss in an MPTP mouse model via inhibition of astrocyte activation. J Neuroinflammation 9: 98. Lund S, Christensen KV, Hedtjärn M, Mortensen AL, Hagberg H, Falsig J, Hasseldam H, Schrattenholz A, Pörzgen P, Leist M. The dynamics of the LPS triggered inflammatory response of murine microglia under different culture and in vivo conditions. J Neuroimmunol. 2006 Nov;180(1-2):71-87. Maresz K, Ponomarev ED, Barteneva N, Tan Y, Mann MK, Dittel BN (2008) IL-13 induces the expression of the alternative activation marker Ym1 in a subset of testicular macrophages. J Reprod Immunol 78: 140-148 Moehle MS, West AB (2015) M1 and M2 immune activation in Parkinson's Disease: Foe and ally? Neuroscience 302:59-73 doi:10.1016/j.neuroscience.2014.11.018 Monnet-Tschudi F, Zurich MG, Honegger P (2007) Neurotoxicant-induced inflammatory response in three-dimensional brain cell cultures. Hum Exp Toxicol 26: 339-346 Monnet-Tschudi, F., A. Defaux, et al. (2011). "Methods to assess neuroinflammation." Curr Protoc Toxicol Chapter 12: Unit12 19.          Mosser DM, Edwards JP (2008) Exploring the full spectrum of macrophage activation. Nat Rev Immunol 8: 958-969 Nakajima K, Kohsaka S. 2004. Microglia: Neuroprotective and neurotrophic cells in the central nervous system. Current Drug Targets-Cardiovasc & Haematol Disorders 4: 65-84. Perego C, Fumagalli S, De Simoni MG (2011) Temporal pattern of expression and colocalization of microglia/macrophage phenotype markers following brain ischemic injury in mice. J Neuroinflammation 8: 174 Ponomarev ED, Maresz K, Tan Y, Dittel BN (2007) CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J Neurosci 27: 10714-10721 Ponomarev ED, Shriver LP, Maresz K, Dittel BN (2005) Microglial cell activation and proliferation precedes the onset of CNS autoimmunity. J Neurosci Res 81: 374-389 <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Rajendran%20L%5BAuthor%5D&cauthor=true&cauthor_uid=29563239">Rajendran L</a>1, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Paolicelli%20RC%5BAuthor%5D&cauthor=true&cauthor_uid=29563239">Paolicelli RC</a> (2018). Microglia-Mediated Synapse Loss in Alzheimer's Disease. <a href="https://www.ncbi.nlm.nih.gov/pubmed/29563239" title="The Journal of neuroscience : the official journal of the Society for Neuroscience.">J Neurosci.</a>  38:2911-2919. Ransohoff RM. 2016. A polarizing question: do M1 and M2 microglia exist? Nat Neurosci 19(8): 987-991. <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Reemst%20K%5BAuthor%5D&cauthor=true&cauthor_uid=27877121">Reemst K</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Noctor%20SC%5BAuthor%5D&cauthor=true&cauthor_uid=27877121">Noctor SC</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Lucassen%20PJ%5BAuthor%5D&cauthor=true&cauthor_uid=27877121">Lucassen PJ</a>, <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=Hol%20EM%5BAuthor%5D&cauthor=true&cauthor_uid=27877121">Hol EM</a>. (2016) The Indispensable Roles of Microglia and Astrocytes during Brain Development. <a href="https://www.ncbi.nlm.nih.gov/pubmed/27877121" title="Frontiers in human neuroscience.">Front Hum Neurosci.</a>  10:566. DOI:10.3389/fnhum.2016.00566 Rivest, S., 2009. Regulation of innate immune responses in the brain. Nat Rev Immunol 9(6), 429-439. Sandstrom von Tobel, J., D. Zoia, et al. (2014). "Immediate and delayed effects of subchronic Paraquat exposure during an early differentiation stage in 3D-rat brain cell cultures." Toxicol Lett. DOI : 10.1016/j.toxlet.2014.02.001 Sandstrom J, Broyer A, Zoia D, et al. (2017a) Potential mechanisms of development-dependent adverse effects of the herbicide paraquat in 3D rat brain cell cultures. Neurotoxicology 60:116-124 doi:10.1016/j.neuro.2017.04.010 Sandstrom J, Eggermann E, Charvet I, et al. (2017b) Development and characterization of a human embryonic stem cell-derived 3D neural tissue model for neurotoxicity testing. Toxicol In Vitro 38:124-135 doi:10.1016/j.tiv.2016.10.001 Streit, W.J., Walter, S.A., Pennell, N.A., 1999. Reactive microgliosis. Progress in Neurobiol. 57, 563-581. Struzynska L, Dabrowska-Bouta B, Koza K, Sulkowski G (2007) Inflammation-Like Glial Response in Lead-Exposed Immature Rat Brain. Toxicol Sc 95:156-162 Venneti S, Lopresti BJ, Wiley CA. 2006. The peripheral benzodiazepine receptor (Translocator protein 18kDa) in microglia: from pathology to imaging. Prog Neurobiol 80(6): 308-322. von Tobel, J. S., P. Antinori, et al. (2014). "Repeated exposure to Ochratoxin A generates a neuroinflammatory response, characterized by neurodegenerative M1 microglial phenotype." Neurotoxicology 44C: 61-70. Xu DP, Zhang K, Zhang ZJ, Sun YW, Guo BJ, Wang YQ, et al. 2014. A novel tetramethylpyrazine bis-nitrone (TN-2) protects against 6-hydroxyldopamine-induced neurotoxicity via modulation of the NF-kappaB and the PKCalpha/PI3-K/Akt pathways. Neurochem Int 78: 76-85. Zurich M-G, Eskes C, Honegger P, Bérode M, Monnet-Tschudi F. 2002. Maturation-dependent neurotoxicity of lead aceate in vitro: Implication of glial reactions. J Neurosc Res 70: 108-116. AOPWiki 2016-11-29T18:41:23

2022-07-15T09:54:27

N/A, Neurodegeneration

Tissue

The term neurodegeneration is a combination of two words - "neuro," referring to nerve cells and "degeneration," referring to progressive damage. The term "neurodegeneration" can be applied to several conditions that result in the loss of nerve structure and function, and neuronal loss by necrosis and/or apoptosis Neurodegeneration is a key aspect of a large number of diseases that come under the umbrella of “neurodegenerative diseases" including Huntington's, Alzheimer’s and Parkinson’s disease. All of these conditions lead to progressive brain damage and neurodegeneration. Alzheimer's disease is characterised by loss of neurons and synapses in the cerebral cortex and certain subcortical regions, with gross atrophy of the affected regions; symptoms include memory loss. Parkinson's disease (PD) results from the death of dopaminergic neurons in the midbrain substantia nigra pars compacta; symptoms include bradykinesia, rigidity, and resting tremor. Several observations suggest correlative links between environmental exposure and neurodegenerative diseases, but only few suggest causative links: Only an extremely small proportion (less than 5%) of neurodegenerative diseases are caused by genetic mutations (Narayan and Dragounov, 2017). The remainders are thought to be caused by the following: ·      A build up of toxic proteins in the brain (Evin et al., 2006) ·      A loss of mitochondrial function that leads to the oxidative stress and creation of neurotoxic molecules that trigger cell death (apoptotic, necrotic or autophagy) (Cobley et al., 2018) ·      Changes in the levels and activities of neurotrophic factors (Kazim and Iqbal, 2016; Machado et al., 2016; Rodriguez et al., 2014) ·      Variations in the activity of neural networks (Greicius and Kimmel, 2012) Protein aggregation: the correlation between neurodegenerative disease and protein aggregation in the brain has long been recognised, but a causal relationship has not been unequivocally established (Lansbury et al., 2006; Kumar et al., 2016). The dynamic nature of protein aggregation mean that, despite progress in understanding its mechanisms, its relationship to disease is difficult to determine in the laboratory. Nevertheless, drug candidates that inhibit aggregation are now being tested in the clinic. These have the potential to slow the progression of Alzheimer's disease, Parkinson's disease and related disorders and could, if administered pre-symptomatically, drastically reduce the incidence of these diseases. Loss of mitochondrial function: many lines of evidence suggest that mitochondria have a central role in neurodegenerative diseases (Lin and Beal, 2006). Mitochondria are critical regulators of cell death, a key feature of neurodegeneration. Dysfunction of mitochondria induces oxidative stress, production of free radicals, calcium overload, and mutations in mitochondrial DNA that contribute to neurodegenerative diseases. In all major examples of these diseases there is strong evidence that mitochondrial dysfunction occurs early and acts causally in disease pathogenesis. Moreover, an impressive number of disease- specific proteins interact with mitochondria. Thus, therapies targeting basic mitochondrial processes, such as energy metabolism or free-radical generation, or specific interactions of disease-related proteins with mitochondria, hold great promise. Decreased level of neurotrophic factors: decreased levels and activities of neurotrophic factors, such as brain-derived neurotrophic factor (BDNF), have been described in a number of neurodegenerative disorders, including Huntington's disease, Alzheimer disease and Parkinson disease (Zuccato and Cattaneo, 2009). These studies have led to the development of experimental strategies aimed at increasing BDNF levels in the brains of animals that have been genetically altered to mimic the aforementioned human diseases, with a view to ultimately influencing the clinical treatment of these conditions. Therefore BDNF treatment is being considered as a beneficial and feasible therapeutic approach in the clinic. Variations in the activity of neural networks: Patients with various neurodegenerative disorders show remarkable fluctuations in neurological functions, even during the same day (Palop et al., 2006). These fluctuations cannot be caused by sudden loss or gain of nerve cells. Instead, it is likely that they reflect variations in the activity of neural networks and, perhaps, chronic intoxication by abnormal proteins that the brain is only temporarily able to overcome. Neurodegeneration in relation to COVID19 SARS-CoV-2 patients present elevated plasma levels of neurofilament light chain protein (NfL), which is a well-known biochemical indicator of neuronal injury (Kanberg et al., 2020). Postmortem brain autopsies demonstrate virus invasion to different brain regions, including the hypothalamus and olfactory bulb, accompanied by neural death and demyelination (Archie and Cucullo 2020; Heneka et al. 2020). Autopsy results of patients with SARS showed ischemic neuronal damage and demyelination; viral RNA was detected in brain tissue, particularly accumulating in and around the hippocampus (Gu et al. 2005). Brain magnetic resonance imaging (MRI) investigations in SARS-CoV-2 patients show multifocal hyperintense white matter lesions and cortical signal abnormalities (particularly in the medial temporal lobe) on fluid-attenuated inversion recovery (FLAIR), along with intracerebral hemorrhagic and microhemorrhagic lesions, and leptomeningeal enhancement (Kandemirli et al. 2020; Kremer et al. 2020; Mohammadi et al., 2020). Moreover, eight COVID-19 patients with signs of encephalopathy had anti–SARS-CoV-2 antibodies in their CSF, and 4 patients had CSF positive for 14-3-3-protein suggesting ongoing neurodegeneration (Alexopoulos et al. 2020).

The assays for measurements of necrotic or apoptotic cell death are described in the Key Event: Cell injury/Cell death Recent neuropathological studies have shown that Fluoro-Jade, an anionic fluorescent dye, is a good marker of degenerating neurons. Fluoro-Jade and Fluoro-Jade B were found to stain all degenerating neurons, regardless of specific insult or mechanism of cell death (Schmued et al., 2005). More recently, Fluoro-Jade C was shown to be highly resistant to fading and compatible with virtually all histological processing and staining protocols (Schmued et al., 2005). In addition, Fluoro-Jade C is a good tool for detecting acutely and chronically degenerating neurons (Ehara and Ueda, 2009).

The necrotic and apoptotic cell death pathways are quite well conserved throughout taxa (Blackstone and Green, 1999, Aravind et al., 2001). It has been widely suggested that apoptosis is also conserved in metazoans, although despite conservation of Bcl-2 proteins, APAF-1, and caspases there is no biochemical evidence of the existence of the mitochondrial pathway in either C. elegans or Drosophila apoptosis (Baum et al., 2007; Blackstone and Green, 1999).

UBERON:0000955

UBERON brain

High Mixed

High

During brain development, adulthood and aging

High High Moderate

Aravind, L., Dixit, V. M., and Koonin, E. V. (2001). Apoptotic Molecular Machinery: Vastly Increased Complexity in Vertebrates Revealed by Genome Comparisons. Science 291, 1279-1284. Baum, J. S., Arama, E., Steller, H., and McCall, K. (2007). The Drosophila caspases Strica and Dronc function redundantly in programmed cell death during oogenesis. Cell Death Differ 14, 1508-1517. Blackstone, N. W., and Green, D. R. (1999). The evolution of a mechanism of cell suicide. Bioessays 21, 84-88. Cobley JN, Fiorello ML, Bailey DM (2018) 13 reasons why the brain is susceptible to oxidative stress. Redox Biol 15: 490-503 Ehara A, Ueda S. 2009. Application of Fluoro-Jade C in acute and chronic neurodegeneration models: utilities and staining differences. Acta histochemica et cytochemica 42(6): 171-179. Evin G, Sernee MF, Masters CL (2006) Inhibition of gamma-secretase as a therapeutic intervention for Alzheimer's disease: prospects, limitations and strategies. CNS Drugs 20: 351-72 Greicius MD, Kimmel DL (2012) Neuroimaging insights into network-based neurodegeneration. Curr Opin Neurol 25: 727-34 Kazim SF, Iqbal K (2016) Neurotrophic factor small-molecule mimetics mediated neuroregeneration and synaptic repair: emerging therapeutic modality for Alzheimer's disease. Mol Neurodegener 11: 50 Kumar V, Sami N, Kashav T, Islam A, Ahmad F, Hassan MI (2016) Protein aggregation and neurodegenerative diseases: From theory to therapy. Eur J Med Chem 124: 1105-1120 Lansbury1 PT & Lashuel HA (2006) A century-old debate on protein aggregation and neurodegeneration enters the clinic. Nature 443, 774-779. Lin1 MT & Beal MF (2006) Mitochondrial dysfunction and oxidative stress in neurodegenerative diseases. Nature 443, 787-795 Machado V, Zoller T, Attaai A, Spittau B (2016) Microglia-Mediated Neuroinflammation and Neurotrophic Factor-Induced Protection in the MPTP Mouse Model of Parkinson's Disease-Lessons from Transgenic Mice. Int J Mol Sci 17 Narayan P, Dragunow M (2017) Alzheimer's Disease and Histone Code Alterations. Adv Exp Med Biol 978: 321-336 Palop JJ, Chin1 J & Mucke L, Review Article A network dysfunction perspective on neurodegenerative diseases. 2006, Nature 443, 768-773 Rodrigues TM, Jeronimo-Santos A, Outeiro TF, Sebastiao AM, Diogenes MJ (2014) Challenges and promises in the development of neurotrophic factor-based therapies for Parkinson's disease. Drugs Aging 31: 239-61 Schmued LC, Stowers CC, Scallet AC, Xu L. 2005. Fluoro-Jade C results in ultra high resolution and contrast labeling of degenerating neurons. Brain Res 1035(1): 24-31. Zuccato C & Cattaneo E, Brain-derived neurotrophic factor in neurodegenerative diseases.2009, Nature Reviews Neurology 5, 311-3 COVID19-related references relevant to KE Neurodegeneration: Alexopoulos et al. Anti-SARS-CoV-2 antibodies in the CSF, blood-brain barrier dysfunction, and neurological outcome: Studies in 8 stuporous and comatose patients. Neurol Neuroimmunol Neuroinflamm. 2020 Sep 25;7(6):e893. Archie SR, Cucullo L. Cerebrovascular and neurological dysfunction under the threat of COVID-19: is there a comorbid role for smoking and vaping? Int J Mol Sci. 2020 21(11):3916 12. Gu J et al. Multiple organ infection and the pathogenesis of SARS. J Exp Med. 2005;202:415–424. Heneka MT, et al. Immediate and long-term consequences of COVID-19 infections for the development of neurological disease. Alzheimers Res Ther. 2020 12(1):1–3. Kandemirli SG, et al. Brain MRI findings in patients in the intensive care unit with COVID-19 infection. Radiology. 2020 Oct;297(1):E232-E235. Kanberg N, et al. Neurochemical evidence of astrocytic and neuronal injury commonly found in COVID-19. Neurology. 2020 Sep 22;95(12):e1754-e1759. Kremer S, et al. Brain MRI findings in severe COVID-19: a retrospective observational study. Radiology. 2020 Nov;297(2):E242-E251. Mohammadi S. et al. Understanding the Immunologic Characteristics of Neurologic Manifestations of SARS-CoV-2 and Potential Immunological Mechanisms. Mol Neurobiol. 2020 Dec;57(12):5263-5275. AOPWiki 2016-11-29T18:41:24

2021-02-23T05:07:07

Encephalitis

Organ

Encephalitis by definition is an inflammation of the brain tissue, most commonly caused by viral infections, and in some rare cases it can be caused by bacteria or even fungi. There are two main types of encephalitis: primary and secondary, with primary occurring when a virus directly infects the brain and the spinal cord. On the other hand, secondary encephalitis as a consequence of an infection occurring elsewhere in the body that then spread to the brain (Johnson, 2018). Several causes may cause encephalitis, but the most common is a viral infection, and can be characterized by mild or severe flu-like symptoms, possibly causing confused thinking, seizures, or problems with movement or with senses, such as sight or hearing. In some cases, encephalitis can be life-threatening, and for this reason timely diagnosis and treatment are essential (Mayo, 2021). Viral encephalitis refers to inflammatory lesions in the brain parenchyma caused by pathogens, including neuronal damage and nerve tissue lesions. It is characterized by acute onset, and common symptoms include headache, fever (mainly high fever), vomiting, convulsions, and consciousness disorders (Ellul and Solomon, 2018). Encephalitis in the context of COVID19 Among various neurological adverse outcomes, SARS-CoV and SARS-CoV-2 can cause encephalitis (Moriguchi T et al. 2020; Efe et al. 2020; Najjar et al. 2020; Wu and Tang 2020; Bohmwald K, et al. 2020; Tsai LK et al. 2005; Xiang P. et al., 2020; Pilotto A et al. 2019; Ye M., et al. 2020; Das G, et al. 2020). Indeed, meningitis/meningoencephalitis has been observed in COVID19 patients (Iaconetta G et al. 2020). For instance, Moriguchi et al. have described SARS-CoV-2 encephalitis in a 24-year old man, 10 days after developing COVID19 symptoms, characterized by headache, fatigue, fever, and consciousness disturbance, and with MRI showing hyperintense signal changes in the hippocampus with slight hippocampal atrophy (Moriguchi T et al. 2020). Early diagnosis of viral encephalitis is critical. In the ongoing pneumonia epidemic, the treatment team of Beijing Ditan Hospital confirmed the presence of SARS-CoV-2 in the cerebrospinal (CSF) fluid of patients with COVID-19 by genome sequencing, thereby clinically verifying viral encephalitis (Xiang et al., 2020). This provided a solid basis for CoV causing encephalitis. CSF of COVID19 patients with encephalitis/meningoencephalitis often shows pleocytosis and elevated total protein and NfL levels (Espíndola et al. 2020) (Koralnik et al. 2020). In SARS-CoV-2 infected patients with neurological manifestations, CSF pleocytosis is associated with para- or post-infectious encephalitis and polyradiculitis. Anti-GD1b and anti-Caspr2 autoantibodies can be identified in certain cases, raising the question of SARS-CoV-2-induced secondary autoimmunity (Guilmot et al., 2020). Intracranial inoculation of murine coronavirus (mouse hepatic virus, MHV), induces optic neuritis and focal encephalitis leading to chronic demyelination in mice (Shindler KS, et al. 2008). SARS-CoV responsible for the 2002–2004 outbreak was reported to induce encephalitis, along with polyneuropathy and ischemic stroke (Tsai et al. 2005). Autopsy results of patients with SARS showed ischemic neuronal damage and demyelination. Viral RNA was detected in brain tissue, particularly accumulating in and around the hippocampus (Gu J, et al. 2005).

Encephalitis may be detected through the following diagnostic tests (<a href="https://www.columbianeurology.org/neurology/staywell/encephalitis" style="color:blue; text-decoration:underline">https://www.columbianeurology.org/neurology/staywell/encephalitis</a>): <ul> <li>Magnetic resonance imaging (MRI)</li> <li>Computed tomography scan (CT or CAT scan)</li> <li>Blood tests</li> <li>Urine and stool tests </li> <li>Electroencephalogram (EEG)</li> <li>Spinal tap (lumbar puncture)</li> <li>Brain biopsy</li> <li>Intracranial pressure monitoring (ICP), measuring the pressure inside the skull. If there is a severe brain injury, head surgery, brain infection, or other problems, the brain may swell.</li> </ul>

UBERON:0000955

UBERON brain

High Mixed

High

Adults

High Bohmwald K, et al. Neurologic Alterations Due to Respiratory Virus Infections. Front Cell Neurosci. 2018 Oct 26;12:386. Das G, et al. Neurological Insights of COVID-19 Pandemic. ACS Chem Neurosci. 2020 May 6; 11(9):1206-1209. Efe et al. COVID-19-Associated Encephalitis Mimicking Glial Tumor. World Neurosurg. 2020 Aug; 140: 46–48. Ellul M., Solomon T. Acute encephalitis - diagnosis and management. Clin. Med. (Lond) 2018;18(2):155–159. Encephalitis, available at: <a href="https://www.columbianeurology.org/neurology/staywell/encephalitis" style="color:blue; text-decoration:underline">https://www.columbianeurology.org/neurology/staywell/encephalitis</a> Espíndola OM et al. Patients with COVID-19 and neurological manifestations show undetectable SARS-CoV-2 RNA levels in the cerebrospinal fluid. Int J Infect Dis. 2020 Jul;96:567-569. Gu J, et al. Multiple organ infection and the pathogenesis of SARS. J Exp Med. 2005;202:415–424. Guilmot A, et al. Immune-mediated neurological syndromes in SARS-CoV-2-infected patients. J Neurol. 2020 Jul 30;1-7. Iaconetta G et al. Meningoencephalitis Associated with SARS-Coronavirus-2. Transl Med UniSa. 2020 Dec 31;23:42-47. Johnson S. What is encephalitis? Healthline, 2018 available at <a href="https://www.healthline.com/health/encephalitis" style="color:blue; text-decoration:underline">https://www.healthline.com/health/encephalitis</a> Koralnik et al. COVID-19: A Global Threat to the Nervous System. Ann Neurol. 2020 Jul;88(1):1-11. Mayo Clinic, Encephalitis. 2021, available at <a href="https://www.mayoclinic.org/diseases-conditions/encephalitis/symptoms-causes/syc-20356136" style="color:blue; text-decoration:underline">https://www.mayoclinic.org/diseases-conditions/encephalitis/symptoms-causes/syc-20356136</a> Moriguchi T et al. A first case of meningitis/encephalitis associated with SARS-Coronavirus-2. Int J Infect Dis. 2020;94:55–58. Najjar et al. Central nervous system complications associated with SARS-CoV-2 infection: integrative concepts of pathophysiology and case reports. J Neuroinflammation. 2020 Aug 6;17(1):231. Pilotto A et al. Steroid-Responsive Encephalitis in Coronavirus Disease 2019. Ann Neurol. 2020 Aug;88(2):423-427. Shindler KS, et al. Experimental optic neuritis induced by a demyelinating strain of mouse hepatitis virus. J Virol. 2008 Sep; 82(17):8882-6. Tsai L.-K., et al. Neurological manifestations in severe acute respiratory syndrome. Acta Neurol Taiwanica. 2005;14:113–119 Wu J. and Tang Y. Revisiting the Immune Balance Theory: A Neurological Insight Into the Epidemic of COVID-19 and Its Alike. Front Neurol. 2020 Oct 15;11:566680. Xiang P., et al. First case of 2019 novel coronavirus disease with Encephalitis. ChinaXiv. 2020;T202003:00015. Ye M., et al. Encephalitis as a clinical manifestation of COVID-19. Brain, Behavior, and Immunity. 2020 S0889159120304657. AOPWiki 2021-02-23T05:18:12

2021-02-23T05:22:21

<upstream-id>2ba43802-f9d3-46e8-81db-de5d765402a4</upstream-id> <downstream-id>6ca5e573-3dd3-4749-b4bc-accbc6f6e2ef</downstream-id> Some cytokines released in the blood circulation can cross the BBB and activate the resident brain immune cells like microglia and astrocytes to produce neural cytokines, further worsening the condition (Tjalkens et al. 2017). Astrocytes regulate a wide variety of functions, which may aggravate neuroinflammation. Activated microglia may engulf the neighboring neurons on activation (Mariani  et al. 2009; Mahmoud et al. 2019). Furthermore, microglia are the primary source of pro-inflammatory cytokines, nitric oxide, prostaglandin E2, and reactive oxygen and nitrogen species (Mariani  et al. 2009). Microglia express ACE-2, along with ACE and AT1 (Cui et al. 2019). These receptors play a significant role in microglia activation and balance the pro-inflammatory or anti-inflammatory effects (Jackson L, et al. 2018) (Murta et al., 2020). More specifically, SARS-CoV-2 infection can hamper the ACE-2-mediated signaling, creating a glitch in the AT1 receptor-mediated path, thereby inducing a pro-inflammatory response (Jackson L, et al. 2018). In vivo studies suggest induction of pro-inflammatory cytokines in microglia and the mouse brain and spinal cord (Li et al. 2004). The situation becomes dreadful when the pro-inflammatory substances produced by astrocytes and microglia fenestrate the BBB (Mariani et al. 2009; Mahmoud et al. 2019). It was found that the level of neurovirulence of the virus correlates with its differential ability to induce proinflammatory cytokines (interleukin 12 [IL-12] p40, tumor necrosis factor alpha, IL-6, IL-15, and IL-1beta) in astrocytes and microglia and in mouse brains and spinal cords. These findings suggest that coronavirus neurovirulence may depend on a novel discriminatory ability of astrocytes and microglia to induce a proinflammatory response in the CNS (Li et al. 2004).

High Mixed

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Adults

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Cui C, et al. Vitamin D receptor activation regulates microglia polarization and oxidative stress in spontaneously hypertensive rats and angiotensin II-exposed microglial cells: role of renin-angiotensin system. Redox Biol. 2019;26:101295. Jackson L, et al. Within the brain: the renin angiotensin system. Int J Mol Sci. 2018;19. Li Y, et al. E. Coronavirus neurovirulence correlates with the ability of the virus to induce proinflammatory cytokine signals from astrocytes and microglia. J Virol. 2004;78:3398–3406. Mahmoud S, et al. Astrocytes maintain glutamate homeostasis in the CNS by controlling the balance between glutamate uptake and release. Cells. 2019 Feb 20;8(2):184. Mariani MM, Kielian T. Microglia in infectious diseases of the central nervous system. J Neuroimmune Pharmacol. 2009;4:448– 61. Murta et al. Severe Acute Respiratory Syndrome Coronavirus 2 Impact on the Central Nervous System: Are Astrocytes and Microglia Main Players or Merely Bystanders? ASN Neuro. 2020. PMID: 32878468 Tjalkens RB, et al. Inflammatory activation of microglia and astrocytes in manganese neurotoxicity. Adv Neurobiol. 2017;18:159–81. AOPWiki 2021-02-23T05:29:54

2021-02-23T05:33:52

<upstream-id>6ca5e573-3dd3-4749-b4bc-accbc6f6e2ef</upstream-id> <downstream-id>258ba338-f623-41b2-b9e3-4c5e3a7c36e7</downstream-id> It is well accepted that chronic neuroinflammation is involved in the pathogenesis of neurodegenerative diseases (McNaull et al., 2010; Tansey and Goldberg, 2009; Thundyil and Lim, 2015 ). Chronic neuroinflammation can cause secondary damage (Kraft and Harry, 2011). The mechanisms by which neuroinflammation (i.e. activated microglia and astrocytes) can kill neurons and induce/exacerbate the neurodegenerative process has been suggested to include the release of nitric oxide that causes inhibition of neuronal respiration, ROS and RNS production, and rapid glutamate release resulting in excitotoxic death of neurons (Brown & Bal-Price, 2003; Kraft & Harry, 2011; Taetzsch & Block, 2013). Glial reactivity is also associated with excessive production and release of pro-inflammatory cytokines that not only affect neurons, but also have detrimental feedback effects on microglia (Heneka et al., 2014). For example, sustained exposure to bacterial lipopolysaccharide (LPS) or to other pro-inflammatory mediators was shown to restrict microglial phagocytosis of misfiled and aggregated proteins (Sheng et al., 2003). Systemic immune challenge during pregnancy leading to microglial activation caused increased deposition of amyloid plaques and tau hyperphosphorylation in aged mice (Krstic et al., 2012, 2013), suggesting that neuroinflammation is involved in the amyloid plaques and neurofibrillary tangles formation. There is further evidence that the formation of neurofibrillary tangles is caused by microglial cell-driven neuroinflammation, since LPS-induced systemic inflammation increased tau pathology (Kitazawa et al., 2005). Sars-CoV-2 specific evidence: Studies on post-mortem cases indicate that lymphocytes and monocytes infiltrate in brain vessel walls, exacerbating the neuronal degeneration and demyelination process (Wu et al., 2020) The aberrant immune response characterized by a surge in cytokine levels (e.g., IL-6) derived by SARS-CoV-2 accelerates the process of neurodegeneration that may contribute to the development of neurodegenerative diseases (Debnath et al. 2020). SARS-CoV-2 can infect human brain organoids resulting in unique metabolic changes and the death of infected and neighbouring neurons. This phenotype is accompanied by impaired synaptogenesis (Song et al., 2020) (Mesci et al, 2020). Moreover, it is hypothesized that an autoimmune reaction mediated by the cross-reaction between viral particles and myelin basic protein may provide the driving force for neural demyelination, as part of the neurodegenerative process. This hypothesis is supported by the fact that the genome of other coronaviruses like CoV-OC43 and CoV-229E, as well as their antibodies, has been isolated from the CNS of Multiple Sclerosis (MS) patients, and coronavirus-like particles have been found in perivascular cuffs of human MS brain (Montalvan et al. 2020). In fact, the virus might lie dormant in astrocytes and oligodendrocytes and trigger the autoimmunity mediated by molecular mimicry (Mohammadi et al., 2020). Neurons are the target cells undergoing degeneration during infection, in part due to apoptosis (de Assis et al. 2020). Intracerebral inoculation with CoV-OC43 in susceptible mice led to an acute encephalitis, with neuronal cell death by necrosis and apoptosis (Jacomy H, et al. 2006). SARS-CoV infection causes neuronal death (even in the absence of encephalitis) in mice transgenic for human ACE2. Death of the animal likely results from dysfunction and/or death of infected neurons, especially those located in cardiorespiratory centres in the medulla. The absence of the host cell receptor prevents severe murine brain disease (Netland J, et al. 2008).

Neuroinflammation is a component of neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease (Neumann, 2001) which may play a secondary or an active primary role in the disease process (Hirsch and Hunot, 2009). McNaull and coworkers (McNaull et al., 2010) suggested that early developmental onset of brain inflammation could be linked with late onset of Alzheimer’s disease. A recent paper by Krstic and coworkers (2012) showed that a systemic immune challenge during late gestation predispose mice to develop Alzheimer’s like pathology when aging, suggesting a causal link between systemic inflammation, neuroinflammation, and the onset of Alzheimer’s disease. Regarding toxicant-induced neuroinflammation, microglial/astrocyte activation and chronic neuron damage may continue for years after initial exposure (Taetsch and Block, 2013), suggesting that chronical neuroinflammation and neurodegeneration have a slow long-term temporal evolution. Ongoing neuroinflammation can be visualized in patients using the positron emission tomography (PET) ligand [11C] (R)-PK11195 (Cagnin et al., 2001). Recent genome-wide association study (GWAS) analyses of sporadic Alzheimer's disease revealed a set of genes that point to a pathogenic role of neuroinflammation in Alzheimer's disease (for review, see Heneka et al., 2014). High levels of pro-inflammatory cytokines produced by activated microglia and astrocytes are detected in the brain of Alzheimer's subjects and animal models (McGeer and McGeer, 1998; Janelsins et al., 2005).

Include consideration of temporal concordance here Pb Rats treated from gestation day 5 till postnatal day 180 with a mixture of Pb/Cd/As showed in early adulthood increased levels of IL-1b, IL-6 and TNF-a in hippocampus and frontal cortex associated with increased Ab levels, where Pb applied alone triggered maximal Ab induction (Ashok et al., 2015). Similarly, monkeys exposed during infancy to Pb (from birth to 400 days to 1 mg Pb /kg/day) showed in aging (23 y old) an overexpression of APP and Abeta (Bihaqi et al., 2011), and of Tau mRNA and protein (Bihaqi and Zawa, 2013). Similar observations were made in old rats (18-20 months) when exposed to Pb (0.2% in drinking water) from postnatal day 1 to 20 (Basha et al., 2005; Zawia and Basha, 2005; Bihaqi et al., 2014). This was associated with cognitive impairment, observed only if animals were exposed when young (Bihaqi et al., 2014). Perinatal exposure to Pb leading to a blood concentration of 10 mg/dl (a concentration considered as safe for human) promotes Tau phosphorylation in forebrain, cerebellum and hippocampus (Gassowska et al., 2016). However, adult exposure may also increase the risk of neurodegeneration, as suggested by the two following studies: - human Tg-SwD1 APP transgenic mice treated with Pb (27 mg/kg/day by gavage) for 6 weeks beginning at 8 weeks of age showed increased accumulation of Abeta and amyloid plaques (Gu et al., 2012). - former organolead workers had increased tibia Pb level associated with peristent brain damage measured by MRI (Stewart et al., 2006). Some in vitro and in vivo experiments show also that neuroinflammation can lead to degeneration: - the conditioned medium of Pb-treated microglial cells (10 microM for 12h) caused the death of neuroblastoma cells (Kumawak et al., 2014). - immature 3D cultures treated with Pb for 10 days exhibited neuroinflammation and neuronal death was exacerbated 10 days after the end of treatment, supporting the fact that neuroinflammation leads to neurodegeneration  (Zurich et al., 2002). - In vivo and in vitro experiments showed that Pb cause microglial activation, which upregulate the levels of pro-inflammatory cytokines (IL-1b, TNF-a) and of iNOS and cause neuronal injury and neuronal death in hippocampus. These effects are significantly reversed by minocycline, an antibiotic blocking microglial reactivity, showing the essential role of neuroinflammation in hippocampal neurodegeneration (Liu et al., 2012) - gestational exposure of mouse to Pb (0.1 mM in drinking water) led at PND 21 to increased brain mRNA expression of IL-6 and glial finbrillary acidic protein (GFAP) as marker of astrogliosis, as well as of caspase 1 and NOS 2, suggesting  a link between Pb-induced neuroinflammation and deletrious effects on neurons (Kasten-Jolly et al., 2011, 2012)   Domoic acid DomA promotes the expression of inflammatory genes in the brain, such as cyclooxygenase 2 (COX2) and the development of neurodegeneration (Ryan et al., 2005). By using COX2 inhibitors that causes decrease the appearance of DomA-induced neurodegeneration, they have concluded that neuroinflammation contributes towards the development of neurodegeneration (Ryan et al., 2011).

Long-term treatments with NSAIDs (non-steroidal anti-inflammatory drugs) have a preventive effect on Alzheimer's disease development (Piertrzick and Behl, 2005; Wang et al., 2015), but such treatment has no effect or is even detrimental if administered once the disease is at an advanced stage (Lichtenstein et al., 2010), This may be due to the dual protective/destructive effects of neuroinflammation and to its complexity. Serum Pb level negatively correlates with verbal memory score, but not with abnormal cognition in Alzheimer's disease (Park et al., 2014). Epidemiologic studies are not well-suited to accomodate the long latency period between exposures during early life and late onset of Alzheimer's disease, even if bone Pb content is an accurate measurement of historical Pb exposure in adult (Bakulski et al., 2012). Besides neuroinflammation or effects associated with neuroinflammation, other mechanisms may be involved in neurodegeneration with Abeta and tau accumulation: Pb-induced epigenetic modifications of genes involved in the amyloid cascade or tau expression may contribute to the accumulation of Abeta and tau accumulation following developmental exposure to Pb (Zawia and Basha, 2005; Basha and Reddy, 2010). Also oxidative damage to DNA was shown to be involved in delayed effects observed in old rats (PD 600), if exposed early postanatally (PD 1 to 20) (Bolin et al., 2006) Gap of knowledge: there are no studies showing that glufosinate-induced neuroinflammation leads to neurodegeneration.

Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships? There are few studies where markers of neuroinflammation are measured simultaneously with markers of cell death and neurodegeneration. In addition, neuroinflammation is a complex KE, since the neurodegenerative consequences depend on the microglial phenotype, which has been measured only in very recent studies. An attempt to link KEup to KEdown quantitatively is provided below.   <div> <div> <table border="1" cellpadding="0" cellspacing="0" class="MsoTableGrid" style="border-collapse:collapse; border:none"> <tbody> <tr> <td style="width:140.2pt"> Endpoints relevant for KEup Neuroinflammation </td> <td style="width:140.2pt"> Endpoints relevant for KEdown Neurodegeneration </td> <td style="width:140.2pt"> Model and treatments </td> <td style="width:140.25pt"> Reference </td> </tr> <tr> <td style="width:140.2pt">   </td> <td style="width:140.2pt">   </td> <td style="width:140.2pt">   </td> <td style="width:140.25pt">   </td> </tr> <tr> <td style="width:140.2pt"> IL-6, IL-1b, TNF-a increased about 2x in hippocampus and frontal cortex </td> <td style="width:140.2pt"> Abeta 1-42 and Abeta 1-40 increased of 50% in frontal cortex and hippocampus Among individual metals, Pb triggered the maxiumum induction </td> <td style="width:140.2pt"> Exposure to a mixture of arsenic (0.38 ppm), cadmium (0.098 ppm) and Pb (0.22 ppm) or Pb alone (2.2 ppm) Rat: from gestational day 05 to postnatal day 180. Observation in early adulthood </td> <td style="width:140.25pt">   Ashok et al., 2015 </td> </tr> <tr> <td style="width:140.2pt"> Modulation of IL-6, TGF-b1 and IL-1beta Upregulation of GFAP (astrocyte reactivity) </td> <td style="width:140.2pt">   Caspase 1 and NOS2 gene expression increased </td> <td style="width:140.2pt"> Mouse treated with Pb (0.1mM) in drinking water from gestation-day 8 to PND21 </td> <td style="width:140.25pt">   Kasten-Jolly et al., 2011, 2012 </td> </tr> <tr> <td style="width:140.2pt"> Microglial reactivity about 3x, about 4X increase of IL-1 beta, TNF-alpha, iNOS   Blockade by minocycline (in vivo and in vitro) </td> <td style="width:140.2pt"> About 5x increase of neuronal death in hippocampus     back to control levels in vivo and in vitro   </td> <td style="width:140.2pt"> Rat exposed to Pb (100ppm) from 24 to 80 days of age   hippocampal neurons+ microglia co-cultures (50 mmol /L Pb for 48 h) </td> <td style="width:140.25pt">   Liu et al., 2012 </td> </tr> <tr> <td style="width:140.2pt"> Microglial and astrocyte reactivities observed at the end of the 10-day treatment </td> <td style="width:140.2pt"> Decrease in markers of cholinergic and GABAergic neurons that was exacerbated (30-60% increased) if harvest was performed not immediately after the 10-day treatment but after another 10-day period devoid of treatment </td> <td style="width:140.2pt"> Immature 3D cultures of fetal rat brain cells Pb (10-6 -10-4 M) applied for 10 days followed by another period of 10 days without treatment </td> <td style="width:140.25pt">   Zurich et al., 2002 </td> </tr> </tbody> </table>   </div> </div>

High Mixed

High

During brain development, adulthood and aging

High High High

The hypotheisis of developmental origin of Pb-induced neurodegeneration was tested and observed in Zebra fish by Lee and Freeman (2014).

Ashok A, Rai NK, Tripathi S, Bandyopadhyay S., Exposure to As-, Cd-, and Pb-mixture induces Abeta, amyloidogenic APP processing and cognitive impairments via oxidative stress-dependent neuroinflammation in young rats. Toxicol Sci., 2015, 143(1): 64-80. Bakulski KM, Park SK, Weisskopf MG, Tucker KL, Sparrow D, Spiro A, 3rd, et al. 2014. Lead exposure, B vitamins, and plasma homocysteine in men 55 years of age and older: the VA normative aging study. Environ Health Perspect 122(10): 1066-1074. Basha MR, Murali M, Siddiqi HK, Ghosal K, Siddiqi OK, Lashuel HA, et al. 2005. Lead (Pb) exposure and its effect on APP proteolysis and Abeta aggregation. FASEB J 19(14): 2083-2084. Basha R, Reddy GR. 2010. Developmental exposure to lead and late life abnormalities of nervous system. Indian journal of experimental biology 48(7): 636-641. Bihaqi SW, Huang H, Wu J, Zawia NH. 2011. 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Behl., Concepts for the treatment of Alzheimer's disease: molecular mechanisms and clinical application. Int J Exp Pathol., 2005, 86(3): 173-185. Ryan JC, Morey JS, Ramsdell JS, Van Dolah FM. Acute phase gene expression in mice exposed to the marine neurotoxin domoic acid. Neuroscience 2005. 136: 1121-1132. Ryan JC, Cross CA, Van Dolah FM. Effects of COX inhibitors on neurodegeneration and survival in mice exposed to the marine neurotoxin domoic acid. Neurosci Lett. 2011. 487: 83-87. Sheng JG, Bora SH, Xu G, Borchelt DR, Price DL, Koliatsos VE., Lipopolysaccharide-induced-neuroinflammation increases intracellular accumulation of amyloid precursor protein and amyloid beta peptide in APPswe transgenic mice. Neurobiol Dis., 2003, 14(1): 133-145. Stewart WF, Schwartz BS, Davatzikos C, Shen D, Liu D, Wu X, et al. 2006. Past adult lead exposure is linked to neurodegeneration measured by brain MRI. Neurology 66(10): 1476-1484. Taetzsch T, Block ML., Pesticides, microglial NOX2, and Parkinson's disease. J Biochem Mol Toxicol., 2013, 27(2): 137-149. Tansey MG, Goldberg MS., Neuroinflammation in Parkinson's disease: Its role in neuronal death and implications for therapeutic intervention. Neurobiol Dis., 2010, 37(3):510-8. Thundyil J, Lim KL. 2015. DAMPs and neurodegeneration. Ageing research reviews 24(Pt A): 17-28. Wang J, Tan L, Wang HF, Tan CC, Meng XF, Wang C, Tang SW, Yu JT (2015) Anti-inflammatory drugs and risk of Alzheimer's disease: an updated systematic review and meta-analysis. J Alzheimers Dis 44: 385-96 Zawia NH, Basha MR. 2005. Environmental risk factors and the developmental basis for Alzheimer's disease. Rev Neurosci 16(4): 325-337. Zurich M-G, Eskes C, Honegger P, Bérode M, Monnet-Tschudi F. 2002. Maturation-dependent neurotoxicity of lead aceate in vitro: Implication of glial reactions. J Neurosc Res 70: 108-116. Sars-CoV-2-related references: Debnath M et al. Changing dynamics of psychoneuroimmunology during COVID-19 pandemic. Brain Behav Immun Health. 2020 May;5:100096. Jacomy H, et al. Human coronavirus OC43 infection induces chronic encephalitis leading to disabilities in BALB/C mice. Virology. (2006) 349:335–46 Mesci P et al. Sofosbuvir protects human brain organoids against SARS-CoV-2. bioRxiv. 2020. Available at: doi: <a href="https://doi.org/10.1101/2020.05.30.125856" style="color:blue; text-decoration:underline">https://doi.org/10.1101/2020.05.30.125856</a> Mohammadi S. et al. Understanding the Immunologic Characteristics of Neurologic Manifestations of SARS-CoV-2 and Potential Immunological Mechanisms. Mol Neurobiol. 2020 Dec;57(12):5263-5275. Montalvan V, Lee J, Bueso T, De Toledo J, Rivas K (2020) Neurological manifestations of COVID-19 and other coronavirus infections: a systematic review. Clin Neurol Neurosurg. 2020 Jul;194:105921. Netland J, et al. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2. J Virol. 2008;82:7264–7275. Song et al. Neuroinvasive potential of SARS-CoV-2 revealed in a human brain organoid model. bioRxiv. 2020. Available at: <a href="https://www.biorxiv.org/content/10.1101/2020.06.25.169946v1" style="color:blue; text-decoration:underline">https://www.biorxiv.org/content/10.1101/2020.06.25.169946v1</a> Wu Y, et al. Nervous system involvement after infection with COVID19 and other coronaviruses. Brain Behav Immun. 2020 Jul;87:18-22. Zanin L, et al. SARS-CoV-2 can induce brain and spine demyelinating lesions. Acta Neurochir (Wien). 2020 Jul;162(7):1491-1494. AOPWiki 2016-11-29T18:41:33

2021-02-23T05:47:35

<upstream-id>258ba338-f623-41b2-b9e3-4c5e3a7c36e7</upstream-id> <downstream-id>4c1fbde6-b34a-4723-afbd-806c40e4a2f4</downstream-id> Intracerebral inoculation with CoV-OC43 in susceptible mice was found to cause acute encephalitis, with neuronal cell death by necrosis and apoptosis (de Assis et al. 2020; Jacomy H, et al. 2006).

Moderate Mixed

Moderate

Adults

High

de Assis et al. Respiratory Syndrome Coronavirus Infections: Possible Mechanisms of Neurological Implications-A Systematic Review. Front Neurol. 2020 Aug 21;11:864. Jacomy H, et al. Human coronavirus OC43 infection induces chronic encephalitis leading to disabilities in BALB/C mice. Virology. (2006) 349:335–46. AOPWiki 2021-02-23T06:02:41

2021-02-23T06:04:56

<upstream-id>6ca5e573-3dd3-4749-b4bc-accbc6f6e2ef</upstream-id> <downstream-id>4c1fbde6-b34a-4723-afbd-806c40e4a2f4</downstream-id> Coronavirus infection can infect macrophages, microglia, and astrocytes in the CNS leading to encephalitis (Wu et al. 2020; Wu and Tang. 2020) (Koralnik et al. 2020). Patients with PCR-confirmed SARS-CoV-2 infection and encephalitis (COV-Enc), encephalitis without SARS-CoV-2 infection (ENC) and healthy controls (HC) underwent an extended panel of CSF neuronal (NfL, T-tau), glial (GFAP, TREM2, YKL-40) and inflammatory biomarkers (IL-1β, IL-6, Il-8, TNF- α, CXCL-13 and β2-microglobulin). In COV-Enc cases, CSF was negative for SARS-CoV-2 real-time PCR but exhibited increased IL-8 levels independently from presence of pleocytosis/hyperproteinorracchia. COV-Enc patients showed increased IL-6, TNF- α, and β2-microglobulin and glial markers (GFAP, sTREM-2, YKL-40) levels similar to ENC but normal CXCL13 levels. Neuronal markers NfL and T-Tau were abnormal only in severe cases. The pattern of CSF alterations suggested a cytokine-release syndrome as the main inflammatory mechanism of SARS-CoV-2 related encephalitis (Pilotto A et al. 2021).

Koralnik et al. COVID-19: A Global Threat to the Nervous System. Ann Neurol. 2020 Jul;88(1):1-11. Pilotto A et al. SARS-CoV-2 encephalitis is a cytokine release syndrome: evidences from cerebrospinal fluid analyses. Clin Infect Dis. 2021 Jan 4;ciaa1933. Wu J. and Tang Y. Revisiting the Immune Balance Theory: A Neurological Insight Into the Epidemic of COVID-19 and Its Alike. Front Neurol. 2020 Oct 15;11:566680. Wu Y, et al. Nervous system involvement after infection with Covid-19 and other coronaviruses. Brain Behav Immun. 2020;87:18–22. AOPWiki 2021-02-23T06:13:36

2021-02-23T06:17:18

Binding of Sars-CoV-2 spike protein to ACE 2 receptors expressed on brain cells (neuronal and non-neuronal) leads to neuroinflammation resulting in encephalitis

Sars-CoV-2 causes encephalitis

Anna Price

European Commission, Join Research Centre (JRC), Ispra, Italy Cinzia La Rocca

BY-SA

Under Development

1.96

2.0

Although the severe acute respiratory syndrome COVID-19 caused by the virus SARS-CoV-2 mainly manifests as an effect of acute respiratory infection (Radnis et al. 2020), recent evidence also suggests that approximately 36% of affected patients exhibit neurological sequelae (Mao et al., 2020). Many studies have shown that SARS-CoV-2 coronavirus is neuroinvasive, neurotropic, and neurovirulent in humans. The presence of SARS-CoV-2 has been identified in the central nervous system (CNS) and cerebrospinal fluid (CSF) of patients with acute neurologic symptoms, including encephalitis (Wu et al., 2020).  Post-mortem examination of SARS-CoV-2-infected patients revealed the presence of SARS-CoV-2 viral particles in endothelial cells and pericytes of brain capillaries and neurons (Paniz-Mondolfi et al., 2020; Nath, 2020; Chigr et al. 2020) as well as in glial cells (microglia and astrocytes) (Vargas et al. 2020; Nakagaki et al., 2005; Lannes et al., 2017). There are several routes of Sars-CoV-2 entry into the CNS. The presence of viral-like particles of SARS-CoV-2 in endothelial cells and pericytes of brain capillaries, as well as astrocytic processes, strongly supports a hematogenous endothelial neuroinvasion-based hypothesis (Paniz-Mondolfi et al., 2020). Indeed, SARS-CoV-2 induced over-activation of systemic immune cells and the release of pro-inflammatory chemokines and cytokines, provokes a cytokine storm possibly leading to the to disruption of the tight junctions and increased permeability of the blood brain barrier (BBB) (Savarin and Bergmann 2018). In parallel, SARS-CoV-2 could also infect the endothelial cells of the blood-cerebrospinal fluid barrier, and then spread into the CNS. Olfactory pathway (through nasal epithelium), vagus and trigeminal nerves, as well as the enteric nervous system are other possible routes of probable Sars-CoV-2 entry into the CNS. Binding of S protein to ACE2 receptors on microglia triggers their activation, which results in the release of proinflamatory cytokines/chemokines, nitric oxide, prostaglandin E2, and reactive oxygen and nitrogen species. As a consequence, activation of astrocytes occurs, which ultimately may lead to neuronal cell death (Ransohoff and Perry, 2009; Chatterjee et al., 2013; Wheeler et al., 2018). This proinflamatory factors can trigger neuronal cell death by well-known mechanisms contributing, together with brain neuroinflammation, to encephalitis. Encephalitis has been documented in clinical observations in COVID-19 patients, characterized by acute onset and common symptoms include headache, fever, vomiting, convulsions, and consciousness disorders (Wu Y et al., 2020).  In the ongoing pneumonia epidemic, the presence of Sars-CoV-2 in the CSF of patients with COVID-19 was confirmed by genome sequencing, thereby clinically verifying viral encephalitis (Xiang et al., 2020), providing a solid basis for Sars-CoV-2 as a cause of this disease. The present AOP describes current mechanistic understanding of causative links between binding of Spike protein to ACE2 receptors on brain cells, which leads to glia activation, neuronal inflammation and cell death, resulting in encephalitis (adverse outcome), which manifests through a variety of symptoms including headache, high fever, vomiting, convulsions, and consciousness disorders, as observed in several clinical studies in COVID-19 patients. Two KEs of this AOP (i.e., neuroinflammation and neurodegeneration) have been described in other AOPs (i.e., neuroinflammation (in AOP 12, AOP 48, AOP 3, and AOP 17); neurodegeneration (in AOP 12, AOP 48, AOP 281); however, quantitative information of KERs is limited or non-existing.

Receptor recognition is an essential determinant of molecular level in this AOP. ACE2 was reported as an entry receptor for SARS-CoV-2. The viral entry process is mediated by the envelope-embedded surface-located spike (S) glycoprotein.  Jun Lan and Walls, A.C et al (Nature 581, 215–220; Cell 180, 281–292) demonstrated a critical initial step of infection at the molecular level from the interaction of ACE2 and S protein. ACE2 has shown that receptor binding affinity to S protein is nM range. To elucidate the interaction between the SARS-CoV-2 RBD and ACE2 at a higher resolution, they also determined the structure of the SARS-CoV-2 RBD–ACE2 complex using X-ray crystallography. The expression and distribution of the ACE2 in human body may indicate the potential infection of SARS-CoV-2. Through the developed single-cell RNA sequencing (scRNA-Seq) technique and single-cell transcriptomes based on the public database, researchers analyzed the ACE2 RNA expression profile at single-cell resolution. High ACE2 expression was identified in type II alveolar cells (Zou, X. et al. Front. Med.2020) SARS-CoV-2 belongs to the Coronaviridae family, which includes evolutionary related enveloped (+) strand RNA viruses of vertebrates, such as seasonal common coronaviruses, SARS-CoV and CoV-NL63, SARS-CoV (Kim Young Jun et al) <table cellspacing="0" class="Table" style="border-collapse:collapse; width:1248px"> <tbody> <tr> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:206px"> Human viruses strains </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:172px"> Genus </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:172px"> Major cell receptor </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:172px"> First report </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:172px"> Animal reservoir </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:204px"> Intermediate host </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:340px"> Pathology </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:252px"> Diagnostic test </td> <td style="background-color:#a5a5a5; border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:1px solid black; height:19px; vertical-align:bottom; width:182px"> Evidence </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:206px"> HCoV-NL63 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> Alphacoronavirus </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> ACE2 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> 2004 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> Bat </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:204px"> Unknown </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:340px"> Mild respiratory tract illness </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:252px"> RT-PCR, IF, ELISA, WB </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:182px"> Strong </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:206px"> SARS-CoV </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> Betacoronavirus </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> ACE2 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> 2003 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> Bat </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:204px"> Pangolin </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:340px"> Severe acute respiratory syndrome </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:252px"> RT-PCR, IF, ELISA, WB </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:182px"> Strong </td> </tr> <tr> <td style="border-bottom:1px solid black; border-left:1px solid black; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:206px"> SARS-CoV-2 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> Betacoronavirus </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> ACE2 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> 2020 </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:172px"> Bat </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:204px"> Pangolin </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:340px"> Severe acute respiratory syndrome </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:252px"> RT-PCR, IF, ELISA, WB </td> <td style="border-bottom:1px solid black; border-left:none; border-right:1px solid black; border-top:none; height:19px; vertical-align:bottom; width:182px"> Strong </td> </tr> </tbody> </table>

adjacent

Low

High adjacent

Not Specified

High adjacent

Low

Low adjacent

Low

High

High Mixed

High

Adults

High

Essentiality for MIE: SARS-CoV-2 was able to infect and kill neural cells, including cortical neurons. This phenotype was accompanied by impaired synaptogenesis. Sofosbuvir, an FDA-approved antiviral drug, was able to rescue these alterations (Mesci et al, 2020). It is speculated that the viral mediated production of autoantibodies against glial cells might be responsible for neural injury (Zanin et al., 2020). Neural infection can be prevented by using either anti-ACE2 antibodies or anti-spike antibodies from the cerebrospinal fluid (CSF) of COVID-19 patients (Mesci et al., 2020). Organoids incubated with either anti-ACE2 antibodies or anti-spike antibodies from the CSF of COVID-19 patients saw a significant decrease in SARS-CoV-2 infection. Likewise, transgenic mice overexpressing human ACE2 were used to demonstrate viral replication in the brain and the lethal consequences of SARS-CoV-2 CNS infection. SARS-CoV-2 infected mice overexpressing human ACE2 showed increase viral titers in the brain and death associated to neuroinvasion (Song et al., 2020).

High

Moderate

AOP 12 Chronic binding of antagonist to N-methyl-D-aspartate receptors (NMDARs) during brain development leads to neurodegeneration with impairment in learning and memory in aging. Available at <a href="https://aopwiki.org/aops/12" style="color:#0563c1; text-decoration:underline">https://aopwiki.org/aops/12</a> AOP 17 Binding of electrophilic chemicals to SH(thiol)-group of proteins and /or to seleno-proteins involved in protection against oxidative stress during brain development leads to impairment of learning and memory. Available at <a href="https://aopwiki.org/aops/17" style="color:#0563c1; text-decoration:underline">https://aopwiki.org/aops/17</a> AOP 281 Acetylcholinesterase Inhibition Leading to Neurodegeneration. Available at <a href="https://aopwiki.org/aops/281" style="color:#0563c1; text-decoration:underline">https://aopwiki.org/aops/281</a> AOP 3 Inhibition of the mitochondrial complex I of nigro-striatal neurons leads to parkinsonian motor deficits. Available at <a href="https://aopwiki.org/aops/3" style="color:#0563c1; text-decoration:underline">https://aopwiki.org/aops/3</a> AOP 48 Binding of agonists to ionotropic glutamate receptors in adult brain causes excitotoxicity that mediates neuronal cell death, contributing to learning and memory impairment. Available at <a href="https://aopwiki.org/aops/48" style="color:#0563c1; text-decoration:underline">https://aopwiki.org/aops/48</a> Chatterjee D, et al. Microglia play a major role in direct viral-induced demyelination. Clin Dev Immunol. 2013; 2013():510396. Chigr F., et al. Comment on “The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients”. J Med Virol. 2020 Jul;92(7):703-704. Lannes N., Neuhaus V., Scolari B., Kharoubi-Hess S., Walch M., Summerfield A., Filgueira L. Interactions of human microglia cells with Japanese encephalitis virus. Virol. J. 2017;14(1):8. Mao et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurology (2020) 77(6): 683–690. Mesci P et al. Sofosbuvir protects human brain organoids against SARS-CoV-2. bioRxiv. 2020. Available at: doi: <a href="https://doi.org/10.1101/2020.05.30.125856" style="color:blue; text-decoration:underline">https://doi.org/10.1101/2020.05.30.125856</a> Nakagaki K., Nakagaki K., Taguchi F. Receptor-independent spread of a highly neurotropic murine coronavirus JHMV strain from initially infected microglial cells in mixed neural cultures. J. Virol. 2005;79(10):6102–6110. Nath A, Smith B. Neurological issues during COVID-19: An overview. Neurosci Lett. 2021 Jan 18;742:135533. Paniz-Mondolfi et al. Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Med Virol. 2020 Jul;92(7):699-702. Radnis C, et al. Radiographic and clinical neurologic manifestations of COVID-19 related hypoxemia. J Neurol Sci. 2020 Nov 15;418:117119. Gallagher et al., 2006; Ransohoff RM, Perry VH. Microglial physiology: unique stimuli, specialized responses. Annu Rev Immunol. 2009; 27():119-45. Savarin C, Bergmann CC. Fine Tuning the Cytokine Storm by IFN and IL-10 Following Neurotropic Coronavirus Encephalomyelitis. Front Immunol. 2018 Dec 20;9:3022. Song et al. Neuroinvasive potential of SARS-CoV-2 revealed in a human brain organoid model. bioRxiv. 2020. Available at: <a href="https://www.biorxiv.org/content/10.1101/2020.06.25.169946v1" style="color:blue; text-decoration:underline">https://www.biorxiv.org/content/10.1101/2020.06.25.169946v1</a> Vargas G. et al. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and glial cells: Insights and perspectives. Brain Behav Immun Health. 2020 Aug; 7: 100127. Wheeler DL, et al. Microglia are required for protection against lethal coronavirus encephalitis in mice. J Clin Invest. 2018 Mar 1; 128(3):931-943. Wu Y, et al. Nervous system involvement after infection with COVID-19 and other coronaviruses. Brain Behav Immun. 2020 Jul;87:18-22. Xiang YT, et al. The COVID-19 outbreak and psychiatric hospitals in China: managing challenges through mental health service reform. Int J Biol Sci. 2020 Mar 15;16(10):1741-1744. Zanin L, et al. SARS-CoV-2 can induce brain and spine demyelinating lesions. Acta Neurochir (Wien). 2020 Jul;162(7):1491-1494. AOPWiki 2021-02-23T04:11:26

2023-04-29T16:03:04