COVID-19 amplifies damage to the central nervous system in Alzheimer's disease

By Pooja Toshniwal PahariaReviewed by Aimee MolineuxNov 7 2022

In a recent study published in the journal Annals of Diagnostic Pathology, researchers in the United States evaluated the impact of coronavirus disease 2019 (COVID-19) on central nervous system (CNS) damage in Alzheimer's disease (AD).

Studies have reported that the human brain is highly susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-associated pathological changes. In addition, pre-existing AD has been established to increase the risk of fatal COVID-19, and conversely, COVID-19 has been linked to enhanced unmasked AD incidence rates. However, the molecular mechanisms of AD amplification by SARS-CoV-2 have not been understood completely.

Study: The amplification of CNS damage in Alzheimer's disease due to SARS-CoV2 infection. Image Credit: jm13129 / Shutterstock

About the study

In the present study, researchers analyzed molecular alterations in samples of autopsied cranial tissues of five individuals with dementia history and SARS-CoV-2 infection-associated deaths, in comparison to those of eight individuals with COVID-19-associated deaths lacking dementia history, ten individuals diagnosed with AD in the pre-pandemic period between 2015 and 2018 and ten aged-matched control individuals (death before 2016 and no dementia history).

The study participants were aged between 50 years and 92 years, and most of them (n=7) were men. Samples were obtained from the frontal cortex, hippocampus, or brainstem/midbrain regions of the brain and subjected to immunohistochemistry (IHC) analysis to determine titers of antibodies (Abs) against the SARS-CoV-2 spike (S) protein subunits 1 (S1) and 2 (S2), nucleocapsid (N) protein, furin, angiotensin-converting enzyme (ACE2) and hyperphosphorylated tau (T) protein.

In addition, Abs against β-amyloid 42, α-synuclein, caspase-3, interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), basic leucine zipper transcription factor 1 (BACH-1), SH2-containing inositol phosphatase 1 (SHIP-1), major facilitator superfamily domain-containing protein 2 (MFSD2A), NMDA receptor 2 (NMDAR2), cluster of differentiation (CD)-3, 11b, 20, 31, 41, 163, and 206, transmembrane protein 119 (TMEM-119) and monocyte chemoattractant protein-1 (MCP-1) were used.

In situ hybridization was performed for SARS-CoV-2 ribonucleic acid (RNA) detection. HBEC (human cerebral microvascular endothelial cell line) and THP-1 (human monocytic cell line) cells were used for the in vitro cell culture experiments, and protein co-expression analyses were performed. Out of the five SARS-CoV-2-positive individuals with dementia, one and four were diagnosed with LBD (Lewy body dementia) and AD, respectively, and only the LBD patient was obese. There were eight severe COVID-19 cases without dementia history, seven of whom were obese, and six of them had diabetes type 2 (T2D).

Results

IHC analyses for β-amyloid-42, T protein, and α-synuclein confirmed AD and LBD diagnoses among SARS-CoV-2-positive individuals. In addition, brain samples of individuals with COVID-19-associated deaths without dementia history exhibited diffuse microangiopathy (MAP) and S1 protein and S2 protein endocytosis by CD31+ endothelial cells with strong caspase-3, ACE2, IL-6, complement component 6 and TNF-α co-localization unrelated to SARS-CoV2 RNA levels.

Out of 13 COVID-19 samples, SARS-CoV-2 RNA was detected in only two samples. Activation of microglia indicated by elevated MCP-1 and TMEM-119 expression in alignment with the endocytosed SARS-CoV-2 S. SARS-CoV-2-infected tissues of individuals without dementia displayed five-fold to 10-fold greater neuronal NMDAR2 and nitric oxide synthase (NOS) expression and remarkably lower (greater than 50%) expression of MFSD2a, SHIP-1, B-cell lymphoma (BCL)-6, -10, and BACH-1 proteins, the loss of which has been linked to AD worsening.

In SARS-CoV-2-infected tissues of demented individuals, widespread microencephalitis induced by the S protein with simultaneous activation of microglial cells coexisted in regions where the neuronal cells had hyperphosphorylated T protein. The findings indicated that neurons with pre-existing dysfunction were stressed additionally due to MAP induced by SARS-CoV-2. Treating ACE2-expressing endothelial brain cells with S1 in high doses (not equivalent to vaccines) showed similar molecular alterations observed among SARS-CoV-2-infected tissues and SARS-CoV-2-infected and AD brain tissues in vivo.

Microencephalitis in SARS-CoV-2-infected tissues was MAP-based and marked by degeneration of endothelial cells, microthrombi, and perivascular edema with immunological responses seated primarily in the reactive endogenous microglia. Microthrombi were observed in the SARS-CoV-2-infected tissues only, with density equivalent for SARS-CoV-2-positive non-dementia cases and COVID-19/AD individuals of 5.3+ microvessels (MV) per cm² [standard electron microscopy (SEM) 1.5].

The microthrombi were CD41-positive indicative of platelet aggregation. The LBD/COVID-19 displayed 4.9+ MV per cm² at SEM 0.8 with microthrombi. Among SARS-CoV-2 infection non-dementia cases and AD/SARS-CoV-2 infection cases, microvascular damage was observed in 13 MV per cm² at SEM 2.0 and 14 MV per cm² at SEM 1.8, respectively. The LBD case displayed 11 MV per cm² at SEM 1.4 with microvascular injury.

The density of TMEM119+ processes increased by four to six-fold, in relation to controls, in the SARS-CoV-2-infected brain tissues with equivalent results for the COVID-19/AD tissues. Among COVID-19 non-dementia cases with a history of T2D and obesity, the ACE2 expression was significantly greater (76%) compared to non-obese COVID-19/AD cases (23%). The average proportions of MV with ≥1 cell with positive Caspase-3, IL-6, TNF-α, or complement component 6 staining were 22 in the SARS-CoV-2 infection and non-dementia cases and 24 in the SARS-CoV-2 infection and AD cases.

The study findings showed that severe SARS-CoV-2 infections induce widespread microencephalitis with microglial cell activation in human cranial tissues through SARS-CoV-2 S protein endocytosis that leads to dementia amplification by modulating AD-worsening protein expression and elevating the stress on dysfunctional neuronal cells. In addition, SARS-CoV-2 creates an acute hypercoagulable/hypoxic/proinflammatory microenvironment at sites with an abundance of βA-42 and hyperphosphorylated T protein.