Alzheimer's‐like signaling in brains of COVID‐19 patients

INTRODUCTION: The mechanisms that lead to cognitive impairment associated with COVID‐19 are not well understood. METHODS: Brain lysates from control and COVID‐19 patients were analyzed for oxidative stress and inflammatory signaling pathway markers, and measurements of Alzheimer’s disease (AD)‐linked signaling biochemistry. Post‐translational modifications of the ryanodine receptor/calcium (Ca2(+)) release channels (RyR) on the endoplasmic reticuli (ER), known to be linked to AD, were also measured by co‐immunoprecipitation/immunoblotting of the brain lysates. RESULTS: We provide evidence linking SARS‐CoV‐2 infection to activation of TGF‐β signaling and oxidative overload. The neuropathological pathways causing tau hyperphosphorylation typically associated with AD were also shown to be activated in COVID‐19 patients. RyR2 in COVID‐19 brains demonstrated a “leaky” phenotype, which can promote cognitive and behavioral defects. DISCUSSION: COVID‐19 neuropathology includes AD‐like features and leaky RyR2 channels could be a therapeutic target for amelioration of some cognitive defects associated with SARS‐CoV‐2 infection and long COVID.