The viral hypothesis in Alzheimer's disease: SARS-CoV-2 on the cusp

Abstract

Increasing evidence highlights that infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has long-term effects on cognitive function, which may cause neurodegenerative diseases like Alzheimer's disease (AD) in the future. We performed an analysis of a possible link between SARS-CoV-2 infection and AD risk and proposed several hypotheses for its possible mechanism, including systemic inflammation, neuroinflammation, vascular endothelial injury, direct viral infection, and abnormal amyloid precursor protein metabolism. The purpose of this review is to highlight the impact of infection with SASR-CoV-2 on the future risk of AD, to provide recommendations on medical strategies during the pandemic, and to propose strategies to address the risk of AD induced by SASR-CoV-2. We call for the establishment of a follow-up system for survivors to help researchers better understand the occurrence, natural history, and optimal management of SARS-CoV-2-related AD and prepare for the future.

Keywords: Alzheimer’s disease; COVID-19; SARS-CoV-2; neuroinflammation; viral hypothesis.

Figure 1

Several viruses associated with Alzheimer’s disease.

Figure 2

How severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might cause Alzheimer’s disease (AD). Some database-based studies have revealed that SARS-CoV-2 and AD may share common genetic genes. Additionally, SARS-CoV-2-induced inflammatory storms lead to systemic inflammation. Entry of pro-inflammatory factors into the central nervous system through a dysfunctional blood–brain barrier induces neuroinflammation. Excessive viral replication may also penetrate the blood–brain barrier and interfere with hippocampal function leading to neurological damage and neurodegeneration. Furthermore, SARS-CoV-2 may affect amyloid precursor protein processing and phosphorylated tau leading to abnormal amyloid beta metabolism and neurofibrillary tangles.

Figure 3

(A) Systemic inflammation induced by SARS-CoV-2 infection. Early unresolved viral replication may be responsible for the infiltration of infected alveolar epithelial cells, macrophages, and leukocytes into the lung tissue for overproduction of cytokines and chemokines. Therefore, we hypothesized that the neurological complications of COVID-19 may result from systemic cytokine storm and subsequent endothelial and blood–brain barrier dysfunction. (B) Neuroinflammation triggered by SARS-CoV-2 infection. On the one hand, peripheral pro-inflammatory factors enter the central nervous system through the damaged blood–brain barrier, prompting the hyperactivation of microglia. On the other hand, SARS-CoV-2 enters the central nervous system and binds to ACE2 receptors on the surface of glial cells to activate microglia, followed by the release of IL-1α, TNF, and the complement component C1q. Furthermore, exposure to the virus or its components promotes the expression and activation of Toll-like receptors in glial cells. This signal promotes the production and release of pro-inflammatory mediators and induces an inflammatory response in the CNS. Astrocytes can also be infected by SARS-CoV-2. The spike protein on SARS-CoV-2 virus has different receptors for astrocytes and lung cells, which enables them to bind to astrocytes. Because the infected astrocytes could not provide food for neurons, eventually leading to neuron death.

Figure 4

SARS-CoV-2 can enter the central nervous system through the damaged blood–brain barrier and bind to ACE2 receptors on the surface of microglia to activate the immune function. The large-scale replication of the virus over-activates microglia or induces chronic stimulation by long-term latency, which eventually leads to neuronal incapacitation and damage.