SARS-CoV-2-Induced Amyloidgenesis: Not One, but Three Hypotheses for Cerebral COVID-19 Outcomes

Abstract

The main neuropathological feature of Alzheimer's disease (AD) is extracellular amyloid deposition in senile plaques, resulting from an imbalance between the production and clearance of amyloid beta peptides. Amyloid deposition is also found around cerebral blood vessels, termed cerebral amyloid angiopathy (CAA), in 90% of AD cases. Although the relationship between these two amyloid disorders is obvious, this does not make CAA a characteristic of AD, as 40% of the non-demented population presents this derangement. AD is predominantly sporadic; therefore, many factors contribute to its genesis. Herein, the starting point for discussion is the COVID-19 pandemic that we are experiencing and how SARS-CoV-2 may be able to, both directly and indirectly, contribute to CAA, with consequences for the outcome and extent of the disease. We highlight the role of astrocytes and endothelial cells in the process of amyloidgenesis, as well as the role of other amyloidgenic proteins, such as fibrinogen and serum amyloid A protein, in addition to the neuronal amyloid precursor protein. We discuss three independent hypotheses that complement each other to explain the cerebrovascular amyloidgenesis that may underlie long-term COVID-19 and new cases of dementia.

Keywords: Aβ; COVID-19; SARS-CoV-2; amyloid; astrocyte; fibrin; serum amyloid A.

Figure 1

Vascular amyloid deposition induced by SARS-CoV-2. The intimate relationship between the endothelial cell (pink) and astrocyte feet (blue) that envelop the endothelial surface is indicated in the 3 panels. The stains (in red) next to the vessel, in all panels, represent microbleeds and emphasize that, in addition to the ischemic event caused by the amyloid deposit, a hemorrhagic event is associated with vascular fragility. In panel (A), a neuron is represented (yellow) with a membrane amyloid precursor protein (APP) and its amyloid peptide fragments (Aβ). The production of astrocyte-derived lipoprotein (ADL), containing ApoE, which is involved in cholesterol (Cho) transport and Aβ clearance, is shown, as well as the membrane transporter for Aβ (LRP1) in the astrocyte and endothelium. With virus-induced dysfunction, there is an accumulation of amyloid (a) between the astrocyte and the endothelium. In panel (B), the amyloid microclots of fibrin and the fibrinoid deposition (f) on the vascular surface are represented. In (C), the non-Aβ amyloid deposit of SAA (s) is represented, where SAA comes from the periphery and from the astrocyte (via ADL), which initially undergoes fibrillogenesis in macrophages (microglia in the CNS are in green). SV-2 = SARS-CoV-2.

Figure 2

An integrative view of amyloid vascular deposition. SARS-CoV-2 (SV-2) triggers a peripheral hypercytokinemia led by IL-6, which, in the liver, leads to exacerbated production of APR proteins, including C-reactive protein, SAA, and fibrinogen. In the CNS, the virus directly affects endothelial cells and astrocytes compromising the BBB by inducing and facilitating vascular fibrinoid deposition. The astroglial response to SARS-CoV-2 and/or hypercytokinemia may be accompanied by increases in serum GFAP and S100B. The virus (via NLRP3) also increases APP metabolism, generating more Aβ. With astroglial dysfunction (also involving NLRP3), there is a reduction in Aβ clearance, leading to perivascular amyloid deposition. Note that IL-6, centrally, leads to an increase in astroglial SAA, which, in turn, could amplify APP neuronal processing through the activation of the TLR/NF-KB/NLRP3 pathway. Dashed ellipses emphasize the production of SAA by IL-6 in the hepatocytes (not shown) and astrocytes. Elevated peripheral production of SAA can accentuate fibrinoid deposition, while astroglial production can lead to non-AB amyloid deposition, which, in the CNS, involves the microglial scavenger receptor B1 (SR-B1).