Shared Mechanisms of Blood-Brain Barrier Dysfunction and Neuroinflammation in Coronavirus Disease 2019 and Alzheimer Disease
Meredith G. Mayer, Tracy Fischer
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), highlighted the virus's impact on the central nervous system and its potential to exacerbate neurodegenerative diseases, similar to that in Alzheimer disease (AD). Emerging evidence suggests that SARS-CoV-2 infection contributes to chronic neuroinflammation, a key driver in the etiopathogenesis of AD. Shared mechanisms, including blood-brain barrier (BBB) dysfunction, systemic inflammation, and activation of immune pathways, may link SARS-CoV-2 infection to AD onset and/or progression, particularly among vulnerable individuals, such as those of advanced age. This review explores convergent pathways involving the renin-angiotensin-aldosterone system, Wnt/β-catenin signaling, NF-κB activation, and interferon signaling, focusing on their roles in BBB integrity and neuroinflammation. SARS-CoV-2-mediated angiotensin-converting enzyme 2 depletion disrupts renin-angiotensin-aldosterone system homeostasis, favoring proinflammatory signaling that parallels vascular dysfunction in AD. Dysregulation of Wnt/β-catenin signaling exacerbates BBB permeability, whereas NF-κB and interferon pathways contribute to BBB breakdown and propagate central nervous system inflammation via endothelial and immune cell activation. These interactions may amplify prodromal AD pathology and/or initiate AD pathogenesis. By identifying mechanistic overlaps between COVID-19 and AD, this review underlines the need for therapeutic strategies targeting shared pathways of inflammation and BBB dysfunction. Understanding these connections is critical for mitigating the long-term neurologic sequelae of COVID-19 and reducing the burden of AD.