The amplification of CNS damage in Alzheimer's disease due to SARS-CoV2 infection

• Published in: Annals of diagnostic pathology Vol. 61; p. 152057
• Main Authors: Nuovo, Gerard J., Suster, David, Sawant, Dwitiya, Mishra, Aditi, Michaille, Jean-Jacques, Tili, Esmerina
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.12.2022
• Subjects: Aged; Alzheimer Disease - complications; Alzheimer Disease - genetics; Angiotensin-Converting Enzyme 2; Central Nervous System; COVID-19; COVID-19 - complications; Encephalitis; Endothelial Cells - metabolism; Endothelialitis; Humans; Microvasculature; RNA, Viral; SARS-CoV-2; Spike Glycoprotein, Coronavirus; Spike Protein; tau Proteins - metabolism; COVID-19; Endothelialitis; Encephalitis; Microvasculature; Spike Protein
• ISSN: 1092-9134; 1532-8198
• DOI: 10.1016/j.anndiagpath.2022.152057

Pre-existing Alzheimer's disease is a risk factor for severe/fatal COVID-19 and infection by SARS-CoV2 virus has been associated with an increased incidence of un-masked Alzheimer's disease. The molecular basis whereby SARS-CoV2 may amplify Alzheimer's disease is not well understood. This study analyzed the molecular changes in autopsy brain tissues from people with pre-existing dementia who died of COVID-19 (n = 5) which was compared to equivalent tissues of people who died of COVID-19 with no history of dementia (n = 8), Alzheimer's disease pre-COVID-19 (n = 10) and aged matched controls (n = 10) in a blinded fashion. Immunohistochemistry analyses for hyperphosphorylated tau protein, α-synuclein, and β-amyloid-42 confirmed the diagnoses of Alzheimer's disease (n = 4), and Lewy body dementia (n = 1) in the COVID-19 group. The brain tissues from patients who died of COVID-19 with no history of dementia showed a diffuse microangiopathy marked by endocytosis of spike subunit S1 and S2 in primarily CD31+ endothelia with strong co-localization with ACE2, Caspase-3, IL6, TNFα, and Complement component 6 that was not associated with SARS-CoV2 RNA. Microglial activation marked by increased TMEM119 and MCP1 protein expression closely paralleled the endocytosed spike protein. The COVID-19 tissues from people with no pre-existing dementia showed, compared to controls, 5-10× fold increases in expression of neuronal NOS and NMDAR2 as well as a marked decrease in the expression of proteins whose loss is associated with worsening Alzheimer's disease: MFSD2a, SHIP1, BCL6, BCL10, and BACH1. In COVID-19 tissues from people with dementia the widespread spike-induced microencephalitis with the concomitant microglial activation co-existed in the same areas where neurons had hyperphosphorylated tau protein suggesting that the already dysfunctional neurons were additionally stressed by the SARS-CoV2 induced microangiopathy. ACE2+ human brain endothelial cells treated with high dose (but not vaccine equivalent low dose) spike S1 protein demonstrated each of the molecular changes noted in the in vivo COVID-19 and COVID-19/Alzheimer's disease brain tissues. It is concluded that fatal COVID-19 induces a diffuse microencephalitis and microglial activation in the brain due to endocytosis of circulating viral spike protein that amplifies pre-existing dementia in at least two ways: 1) modulates the expression of proteins that may worsen Alzheimer's disease and 2) stresses the already dysfunctional neurons by causing an acute proinflammatory/hypercoagulable/hypoxic microenvironment in areas with abundant hyperphosphorylated tau protein and/or βA-42. •Microvascular damage is a central part of CNS COVID-19.•Endocytosis of the viral spike protein is highly correlated with this damage.•The microvascular damage is superimposed on the plaques and tangles of Alzheimer's disease.