Alzheimer’s-like remodeling of neuronal ryanodine receptor in COVID-19

COVID-19, caused by SARS-CoV-2 involves multiple organs including cardiovascular, pulmonary and central nervous system. Understanding how SARS-CoV-2 infection afflicts diverse organ systems remains challenging^1,2. Particularly vexing has been the problem posed by persistent organ dysfunction known as “long COVID,” which includes cognitive impairment³. Here we provide evidence linking SARS-CoV-2 infection to activation of TGF-ß signaling and oxidative overload. One consequence is oxidation of the ryanodine receptor/calcium (Ca²⁺) release channels (RyR) on the endo/sarcoplasmic (ER/SR) reticuli in heart, lung and brains of patients who succumbed to COVID-19. This depletes the channels of the stabilizing subunit calstabin2 causing them to leak Ca²⁺which can promote heart failure^4,5, pulmonary insufficiency⁶and cognitive and behavioral defects^7–9.Ex-vivotreatment of heart, lung, and brain tissues from COVID-19 patients using a Rycal drug (ARM210)¹⁰prevented calstabin2 loss and fixed the channel leak. Of particular interest is that neuropathological pathways activated downstream of leaky RyR2 channels in Alzheimer’s Disease (AD) patients were activated in COVID-19 patients. Thus, leaky RyR2 Ca²⁺channels may play a role in COVID-19 pathophysiology and could be a therapeutic target for amelioration of some comorbidities associated with SARS-CoV-2 infection.