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. 2022 Dec:61:152057.
doi: 10.1016/j.anndiagpath.2022.152057. Epub 2022 Oct 28.

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

Gerard J Nuovo  1 , David Suster  2 , Dwitiya Sawant  3 , Aditi Mishra  3 , Jean-Jacques Michaille  4 , Esmerina Tili  5
Affiliations

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

Gerard J Nuovo et al. Ann Diagn Pathol. 2022 Dec.

Abstract

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.

Keywords: COVID-19; Encephalitis; Endothelialitis; Microvasculature; Spike Protein.

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Conflict of interest statement

Declaration of competing interest The authors have no conflicts of interest to disclose.

Figures

Fig. 1
Fig. 1
Basic pathologic changes in the brain in people with pre-existing Alzheimer's disease who died of COVID-19. The normal brain shows an inconspicuous microvasculature in the brain parenchyma (panel A). The microvasculature is likewise inconspicuous in Alzheimer's disease where retraction artifact around the small vessels can be seen at high magnification (panel B, oval). Note the microvascular changes in the brain in fatal COVID-19, seen as marked perivascular edema and endothelial cell degeneration (swelling or pyknosis) (panel C, COVID-19). Also note the close proximity of the microvasculature changes to neurons (panel D, ovals, COVID-19/Alzheimer's disease). Microthrombi are highlighted with the CD41 immunohistochemistry (signal red, oval). COVID-19 in pre-existing Alzheimer's disease shows the marked heterogeneity of hyperphosphorylated tau protein distribution with sections only 0.5 cm away showing either an intense signal (panel F) or no signal (panel G, signal brown). Panels H-J show the marked increased in microglial TMEM119 signal in COVID-19 (panel I) and COVID-19/Alzheimer's disease (panel J) relative to the control brains (panel H, signal brown). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 2
Fig. 2
Detection of SARS-CoV2 RNA and proteins in the brain in people with pre-existing Alzheimer's disease who died of COVID-19. Although lung sections commonly showed intense signal for SARS-CoV2 RNA (panel A) and nucleocapsid protein (panel C), these signals were usually absent in the corresponding brain tissues (panels B and D; each signal brown). Panel E shows the close proximity of the endocytosed spike protein (circles, fluorescent red) in a microvessel to the MCP1 protein being expressed in microglia and neurons (fluorescent green); panel J shows the lack of a signal for spike and rare MCP1 expression in the normal brain control. Panels F and G are serial sections from the brain of a person with pre-existing Alzheimer's disease who died of COVID-19. Note the localization of the spike S1 signal to the microvasculature (fluorescent red) and its close proximity to neurofibrillary tangles (fluorescent green) after co-expression (panel F). Panel G shows the S2 spike signal has the same distribution (signal red, circles); note the perivascular edema and endothelial cell swelling. Panels H and I show the absence of any signal for spike S1 or S2, respectively, in the normal control brains or Alzheimer's disease brains (not shown). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 3
Fig. 3
Documentation of the host response to the endocytosed spike protein in the brain in people with pre-existing Alzheimer's disease who died of COVID-19. Panels A-C show the co-expression of ACE2 (panel A), spike S1 (panel B) and the merged image in panel C; note the strong co-localization of the two proteins (fluorescent yellow). Panel D shows the strong signal for complement component 6 in a microvessel with marked microangiopathy (oval, signal red); panel E shows the lack of any signal in the control brains. Panel F demonstrates that complement component 6 (fluorescent green) strongly co-localizes with the endocytosed spike protein (fluorescent red merged image shows co-localization as fluorescent yellow). Panel G shows the damaged microvessel after testing for TNFα and spike S1 where panel H shows the fluorescent derived image documenting strong co-localization as fluorescent yellow. Panels I and J show that IL6 likewise co-localizes with spike S1 (panel I) and ACE2 (panel J) in the brains of people with pre-existing Alzheimer's disease who died of COVID-19. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 4
Fig. 4
Dysregulation of key Alzheimer's disease-related proteins in the brain in people with pre-existing Alzheimer's disease who died of COVID-19. Panel A shows the lack of signal in the control brain for NMDAR2 and the intense signal in the brain of people who died of COVID-19; note the endothelial (oval) and neuron-based signal (brown). Panel C shows the strong co-localization of NMDAR2 (fluorescent green) and the spike (fluorescent red) proteins (fluorescent yellow) in the brain of a case of COVID-19 with pre-existing Alzheimer's disease. Panel E shows the strong microvasculature-based signal for BCL10 (signal is brown) and the loss of the signal in the brains of people who died of COVID-19 with no pre-existing dementia. Panels G-I show the rare expression of Furin in the control brains (panel G) and the marked expression, mostly endothelial cell-based, in the brains from people who died of COVID-19 (panel H) including those with pre-existing Alzheimer's disease (panel I). Panel J shows that the increased nNOS signal (fluorescent green) in the fatal COVID-19 brain strongly co-localizes with spike S1 (fluorescent red). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig. 5
Fig. 5
The molecular changes in human brain endothelial cells (HBEC) closely mirror those in the brain in people who died of COVID-19. Panel A shows the strong expression of ACE-2 in the human brain endothelial cells at baseline. Note the strong reduction of the signal induced by high dose spike S1 (panel B, signal is red). Panels C-E show the lack of signal in the brain endothelial cells for spike S1 in the controls (panel C), the weak signal for S1 after incubation with the low dose of S1 (panel D) and the strong signal after incubation with high dose S1 (panel E, signal is red). MFSD2A is highly expressed in the endothelial cells at baseline (panel F) and the protein is nearly lost after 2 days incubation with high dose spike S1 (panel G, signal is brown). NMDAR2 was not expressed by the endothelial cells at baseline (not shown). Panels H-J show the increased expression of NMDAR2 in the cultured brain endothelial cells after high dose S1; note that the NMDAR2 (fluorescent green) co-localizes with the spike protein (fluorescent red). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
Fig 6
Fig 6
Schematic of theory.
See this image and copyright information in PMC

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