key: cord-0772160-gme1zk3n
authors: Reiken, Steve; Sittenfeld, Leah; Dridi, Haikel; Liu, Yang; Liu, Xiaoping; Marks, Andrew R.
title: Alzheimer's‐like signaling in brains of COVID‐19 patients
date: 2022-02-03
journal: Alzheimers Dement
DOI: 10.1002/alz.12558
sha: cb277af56329d72b0ff9fcf9b44b99e8459b676e
doc_id: 772160
cord_uid: gme1zk3n

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.

>80% of COVID-19 patient brains, processes which could contribute to the observed neurological symptoms. 11 Furthermore, another pair of frequent symptoms of infection by SARS-CoV-2 are hyposmia and hypogeusia, the loss of the ability to smell and taste, respectively. 3 Interestingly, hyposmia has been reported in early-stage Alzheimer's disease (AD), 3 and AD type II astrocytosis has been observed in neuropathology studies of COVID-19 patients. 10 Systemic failure in COVID-19 patients is likely due to SARS-CoV-2 invasion via the ACE2 receptor, 9 which is highly expressed in pericytes of human heart 8 and epithelial cells of the respiratory tract, 12 kidney, intestine, and blood vessels. ACE2 is also expressed in the brain, especially in the respiratory center and hypothalamus in the brain stem, the thermal center, and cortex, 13 which renders these tissues more vulnerable to viral invasion, although it remains uncertain whether SARS-CoV-2 virus directly infects neurons in the brain. 14 The primary consequences of SARS-CoV-2 infection are inflammatory responses and oxidative stress in multiple organs and tissues. [15] [16] [17] Recently it has been shown that the high neutrophil-to-lymphocyte ratio observed in critically ill patients with COVID-19 is associated with excessive levels of reactive oxygen species (ROS) and ROS-induced tissue damage, contributing to COVID-19 disease severity. 15 Recent studies have reported an inverse relationship between ACE2 and transforming growth factor-β (TGF-β). In cancer models, decreased levels of ACE2 correlated with increased levels of TGF-β. 18 In the context of SARS-CoV-2 infection, downregulation of ACE2 has been observed, leading to increased fibrosis formation, as well as upregulation of TGF-β and other inflammatory pathways. 19 Moreover, patients with severe COVID-19 symptoms had higher blood serum TGF-β concentrations than those with mild symptoms, 20 thus further implicating the role of TGF-β and warranting further investigation.

Interestingly, reduced angiotensin/ACE2 activity has been associated with tau hyperphosphorylation and increased amyloid beta (Aβ) pathology in animal models of AD. 21, 22 The link between reduced ACE2 activity and increased TGF-β and tau signaling in the context of SARS-CoV-2 infection needs further exploration.

Our laboratory has shown that stress-induced ryanodine receptor (RyR)/intracellular calcium release channel post-translational modifications, including oxidation and protein kinase A (PKA) hyperphosphorylation related to activation of the sympathetic nervous system and the resulting hyper-adrenergic state, deplete the channel stabilizing protein (calstabin) from the channel complex, destabilizing the closed state of the channel and causing RyR channels to leak Ca 2+ out of the endoplasmic/sarcoplasmic reticulum (ER/SR) in multiple diseases. [23] [24] [25] [26] [27] [28] [29] Increased TGF-β activity can lead to RyR modification and leaky channels, 30 and SR Ca 2+ leak can cause mitochondrial Ca 2+ overload and dysfunction. 29 Increased TGF-β activity 31 and mitochondrial dysfunction 32 are also associated with SARS-CoV-2 infection.

Here we show that SARS-CoV-2 infection is associated with adrenergic and oxidative stress and activation of the TGF-β signaling pathway in the brains of patients who have succumbed to COVID-19. One consequence of this hyper-adrenergic and oxidative state is the development of tau pathology normally associated with AD. In this article, we investigate potential biochemical pathways linked to tau hyperphosphorylation. Based on recent evidence that has linked tau pathol- ogy to Ca 2+ dysregulation associated with leaky RyR channels in the brain, 3,33 we investigated RyR2 biochemistry and function in COVID-19 patient brains.

Our results indicate that SARS-CoV-2 infection activates inflammatory signaling and oxidative stress pathways resulting in hyperphosphory- TGF-β belongs to a family of cytokines involved in the formation of cellular fibrosis by promoting epithelial-to-mesenchymal transition, fibroblast proliferation, and differentiation. 35 TGF-β activation has been shown to induce fibrosis in the lungs and other organs by activation of the SMAD-dependent pathway. We have previously reported that TGF-β/SMAD3 activation leads to NOX2/4 translocation to the cytosol and its association with RyR channels, promoting oxidization of the channels and depletion of the stabilizing subunit calstabin in skeletal muscle and in heart. 28 in cortical pyramidal cells of aged individuals with tau pathology. 33, 40 In contrast to the findings in the brains of COVID-19 patients in the present study, calbindin was not reduced in the cerebellum of AD patients, possibly protecting these cells from AD pathology. 39, 41 Leaky RyR channels, leading to increased mitochondrial Ca 2+ overload and ROS production and oxidative stress, have been shown to contribute to the development of tau pathology associated with AD. 3, [23] [24] [25] [26] [27] [28] [29] 33 Recent studies of the effects of COVID-19 on the central nervous system have found memory deficits and biological markers similar to those seen in AD patients. 42, 43 Our data demonstrate increased activity of enzymes responsible for phosphorylating tau (pAMPK, pGSK3β), as well as increased phosphorylation at multiple sites on tau in COVID-19 patient brains. The tau phosphorylation observed in these samples exhibited some differences from what is typically observed in AD, occurring in younger patients and in areas of the brain, specifically the cerebellum, that usually do not demonstrate tau pathology in AD patients. Taken together, these data suggest a potential contributing mechanism to the development of tau pathology in COVID-19 patients involving oxidative overload-driven RyR2 channel dysfunction. Furthermore, we propose that these pathological changes could be a significant contributing factor to the neurological manifestations of COVID-19 and in particular the "brain fog" associated with long COVID, and represent a potential therapeutic target for ameliorating these symptoms. For example, tau pathology in the cerebellum could explain the recent finding that 74% of hospitalized COVID-19 patients experienced coordination deficits. 44 The data presented also raise the possibility that prior COVID-19 infection could be a potential risk factor for developing AD in the future.

The present study was limited to the use of existing autopsy brain tissues at the Columbia University Biobank from SARS-CoV-2- 

There were increased markers of oxidative stress (glutathione disulfide [GSSG]/ glutathione [GSH]) in the cortex (mesial temporal lobe) and cerebellum (cerebellar cortex, lateral hemisphere) of COVID-19 tissue. Kynurenic acid, a marker of inflammation, was increased in COVID-19 cortex and cerebellum brain lysates compared to controls, is in accordance with recent studies showing a positive correlation between kynurenic acid and cytokines and chemokine levels in COVID-19 patients. [48] [49] [50] To determine whether SARS-CoV-2 infection also increases tissue TGF-β activity, we measured SMAD3 phosphorylation, a downstream signal of TGF-β, in control and COVID-19 tissue lysates. Phosphorylated SMAD3 (pSMAD3) levels were increased in COVID-19 cortex and cerebellum brain lysates compared to controls, indicating that SARS-CoV-2 infection increased TGF-β signaling in these tissues. Interestingly, brain tissues from COVID-19 patients exhibited activation of the TGF-β pathway, despite the absence of the detectable (by immunohistochemistry and polymerase chain reaction, data not shown) virus in these tissues. These results suggest that the TGF-β pathway is activated systemically by SARS-CoV-2, resulting in its upregulation in the brain, as well as other organs. In addition to oxidative stress, COVID-19 brain tissues also demonstrated increased PKA and calmodulindependent protein kinase II association domain (CaMKII) activity, most likely associated with increased adrenergic stimulation. Both PKA and CaMKII phosphorylation of tau have been reported in tauopathies. 51, 52 The hallmarks of AD brain neuropathology are the formation of Aβ plaques from abnormal APP processing by BACE1, as well as tau ''tangles'' caused by tau hyperphosphorylation. 53 Brain lysates from COVID-19 patients' autopsies demonstrated normal BACE1 and APP levels compared to controls. The patients analyzed in the present study were grouped by age (young ≤ 58 years old, old ≥ 66 years old) to account for normal, age-dependent changes in APP and tau pathology. Abnormal APP processing was only observed in brain lysates from patients diagnosed with AD. However, AMPK and GSK3β phosphorylation were increased in both the cortex and cerebellum in COVID-19 brains. Activation of these kinases in SARS-CoV-2-infected brains leads to a hyperphosphorylation of tau consistent with AD tau pathology in the cortex. COVID-19 brain lysates from older patients showed increased tau phosphorylation at S199, S202, S214, S262, and S356.

Lysates from younger COVID-19 patients showed increased tau phosphorylation at S214, S262, and S356, but not at S199 and S202, demonstrating increased tau phosphorylation in both young and old individuals and suggesting a tau pathology similar to AD in COVID-19-affected patients. Interestingly, both young and old patient brains demonstrated increased tau phosphorylation in the cerebellum, which is not typical of AD.

RyR channels may be oxidized due to the activation of the TGF-β signaling pathway. 30 NOX2 binding to RyR2 causes oxidation of the channel, which activates the channel, manifested as an increased open probability that can be assayed using 3 [H]ryanodine binding. 54 When the oxidization of the channel is at pathological levels, there is destabilization of the closed state of the channel, resulting in spontaneous Ca 2+ release or leak. 27, 30 To determine the effect of the increased TGF-β signaling associated with SARS-CoV-2 infection on NOX2/RyR2 interaction, RyR2 and NOX2 were co-immunoprecipitated from brain lysates of COVID-19 patients and controls. NOX2 associated with RyR2 in brain tissues from SARS-CoV-2-infected individuals were increased compared to controls.

Given the increased oxidative stress and increased NOX2 binding to RyR2 seen in COVID-19 brains, RyR2 post-translational modifications were investigated. Immunoprecipitated RyR2 from brain lysates demonstrated increased oxidation, PKA phosphorylation on serine 2808, and depletion of the stabilizing protein subunit calstabin2 in SARS-CoV-2-infected tissues compared to controls. This biochemical remodeling of the channel is known as the ''biochemical signature'' of leaky RyR2 23,55,56 that is associated with destabilization of the closed state of the channel. This leads to SR/ER Ca 2+ leak, which contributes to the pathophysiology of a number of diseases including AD. 23, 24, 26, 30, [55] [56] [57] RyR channel activity was determined by binding of 3 

De-identified human heart, lung, and brain tissue were obtained from the COVID BioBank at Columbia University. The cortex samples were from the mesial temporal lobe and the cerebellum samples were from the cerebellar cortex, lateral hemisphere. The Columbia University

BioBank functions under standard operating procedures, quality assurance, and quality control for sample collection and maintenance. Ageand sex-matched controls exhibited absence of neurological disorders and cardiovascular or pulmonary diseases. Sex, age, and pathology of patients are listed in Table 1 .

Tissues (50 mg 

Tissue lysates (0.1 mg) were treated with buffer or 10 μM Rycal (ARM210) at 4 • C. RyR2 was immunoprecipitated from 0.1 mg lung, heart, and brain using an anti-RyR2 specific antibody (2 μg 

Kynurenic acid (KYNA) concentration in brain lysates was determined using an enzyme-linked immunosorbent assay (ELISA) kit for KYNA (ImmuSmol). Briefly, samples (50 μl) were added to a microtiter plate designed to extract the KCNA from the samples. An acylation reagent was added for 90 minutes at 37 • C to derivatize the samples. After derivatization, 50 μl of the prepared standards and 100 μl samples were pipetted into the appropriate wells of the KYNA microtiter plate.

KYNA Antiserum was added to all wells and the plate was incubated overnight at 4 • C. After washing the plate four times, the enzyme conjugate was added to each well. The plate was incubated for 30 minutes at RT on a shaker at 500 rpm. The enzyme substrate was added to all wells and the plate was incubated for 20 minutes at RT. Stop solution was added to each well. A plate reader was used to determine the absorbance at 450 nm. The sample signals were compared to a standard curve.

PKA activity in brain lysates was determined using a PKA activity kit (Thermo Fisher, EIAPKA). Briefly, samples were added to a microtiter plate containing an immobilized PKA substrate that is phosphorylated by PKA in the presence of ATP. After incubating the samples with ATP at RT for 2 hours, the plate was incubated with the phospho-PKA substrate antibody for 60 minutes. After washing the plate with wash buffer, goat anti-rabbit IgG horseradish peroxidase (HRP) conjugate was added to each well. The plate was aspirated, washed, and TMB substrate was added to each well, which was then incubated for 30 minutes F I G U R E 2 Hyperphosphorylation of tau but normal amyloid precursor protein (APP) processing in COVID-19 brains. A, Brain (CB, cerebellum; Ctx, cortex) lysates were separated by 4% to 20% polyacrylamide gel electrophoresis. Immunoblots were developed for pAMPK, AMPK, GSK3β, pGSK3β (T216), APP, BACE1, and GAPDH loading control. The numbers (1-10) above immunoblots refer to patient numbers listed in Table 1 . B, Bar graphs showing quantification of pAMPK, pGSK3β, APP/GAPDH, and BACE1/GAPDH from Western blots in (A). Data are mean ± standard deviation (SD). *P < .05 control versus COVID-19; **P < .05 CB versus Ctx; #P < .05 COVID (Young) versus COVID (Old). C, Immunoblots of brain lysates showing total tau and tau phosphorylation on residues S199, S202/T205, S214, S262, and S356. D, Bar graphs showing quantification phosphorylated tau at the residues shown on Western blots in (C). Data are mean ± SD. *P < .05 control versus COVID-19; **P < .05 CB versus Ctx; #P < .05 COVID (Young) versus COVID (Old) at RT. A plate reader was used to determine the absorbance at 450 nm.

The sample signals were compared to a standard curve.

CaMKII activity in brain lysates was determined using the CycLex CaM 

Group data are presented as mean ± standard deviation. Statistical comparisons between the two groups were determined using an unpaired t-test. Values of P < .05 were considered statistically significant. All statistical analyses were performed with GraphPad Prism 8.0.

Oxidative stress and TGF-β, PKA, and CaMKII activation Oxidative stress levels were determined in brain tissues (cortex, cerebellum) from COVID-19 patient autopsy tissues and controls by measuring the ratio of GSSG to GSH by an ELISA kit. COVID-19 patients F I G U R E 3 Dysregulation of calcium-handling proteins in COVID-19 brains. A, Western blots depicting ryanodine receptor 2 (RyR2) oxidation, protein kinase A (PKA) phosphorylation, and calstabin2 or NADPH oxidase 2 (NOX2) bound to the channel from brain (CB, cerebellum; Ctx, cortex) lysates. B, Bar graphs quantifying DNP/RyR2, pS2808/RyR2, and calstabin2 and NOX2 bound to the channel from the Western blots. Data are mean ± standard deviation (SD). *P < .05 control versus COVID-19; # P < .05 COVID-19 versus COVID-19+ARM210. C, 3 [H]ryanodine binding from immunoprecipitated RyR2. Bar graphs show ryanodine binding at 150 nM Ca 2+ as a percent of maximum binding (Ca2+ = 20 μM). Data are mean ± SD. *P < .05 control versus COVID-19; #P < .05 COVID-19 versus COVID-19+ARM210. D, Western blots showing the levels of glutamate carboxypeptidase 2 (GCPII), calbindin, and GAPDH loading control in brain (Ctx, CB). E, Bar graphs quantifying GCPII/GAPDH and calbindin/GAPDH from the western blots. Data are mean ± SD. *P < .05 control versus COVID-19 exhibited significant oxidative stress with a 3.8-and 3.2-fold increase in GSSG/GSH ratios in cortex (Ctx) and cerebellum (CB) compared to controls, respectively ( Figure 1A ). High circulating levels of kynurenine have been reported in COVID-19. [48] [49] [50] However, the expression of KYNA in COVID-19 brain tissue has not been examined. Levels in the Ctx and CB were measured using an ELISA kit. COVID-19 brains had a significant increase in the Ctx and CB compared to controls ( Figure 1A ). An additional marker of tissue inflammation is increased cytokine expression. SMAD3 phosphorylation, a downstream signal of TGF-β, was increased in COVID-19 Ctx and CB tissue lysates compared to controls ( Figure 1B and 1C) . Increased adrenergic activation in the brain of patients infected with SARS-CoV-2 was also demonstrated by measuring PKA activity in the Ctx and CB and CaMKII activity was increased as well ( Figure 1D ).

Both PKA and CaMKII have been directly implicated in the increased phosphorylation of tau associated with AD. 51, 52 Because COVID-19 brain lysates had increased PKA and CaMKII activity, AD-linked biochemistry was evaluated in the COVID-19 brain lysates. Normal APP processing was observed in COVID-19 brain lysates as demonstrated by normal BACE1 and APP levels compared to controls (Figure 2A and B). Abnormal APP processing was only observed in brain lysates from patients diagnosed with AD (see Table 1 for patient details). How-ever, phosphorylation/activation of AMPK and GSK3β was observed in SARS-CoV-2-infected patient brain lysates. Activation of these kinases along with the activation of PKA and CaMKII (Figure 1 ) leads to a hyperphosphorylation of tau at multiple residues ( Figure 2C and D).

Tau hyperphosphorylation in the cerebellum is not typical of AD pathology. The CB tau pathology demonstrated in COVID-19 warrants further investigation.

RyR2 biochemistry was investigated to determine whether RyR2 in COVID-19 brain tissues demonstrated a "leaky" phenotype.

Increased NOX2/RyR2 binding was shown in Ctx and CB lysates from SARS-CoV-2-infected individuals compared to controls using co-immunoprecipitation ( Figure 3A and B ). In addition, RyR2 from SARS-CoV-2-infected brains had increased oxidation, increased serine 2808 PKA phosphorylation, and depletion of the stabilizing protein subunit calstabin2 compared to controls ( Figure 3A and B) . RyR channels exhibiting these characteristics can be inappropriately activated at low cytosolic Ca 2+ concentrations resulting in a pathological ER/SR Ca 2+ leak. 3 [H]Ryanodine binding to immunoprecipitated RyR2 was measured at both 150 nM and 20 μM free Ca 2+ . Because ryanodine binds only to the open state of the channel under these conditions, 3 [H]Ryanodine binding may be used as a surrogate measure of channel open probability. The total amount of RyR immunoprecipitated was the F I G U R E 4 SARS-CoV-2 infection results in leaky ryanodine receptor 2 (RyR2) that may contribute to cardiac, pulmonary, and cognitive dysfunction. SARS-CoV-2 infection targets cells via the angiotensin-converting enzyme 2 (ACE2) receptor, inducing inflammasome stress response/activation of stress signaling pathways. This results in increased transforming growth factor-β (TGF-β) signaling, which activates SMAD3 (pSMAD) and increases NADPH oxidase 2 (NOX2) expression and the amount of NOX2 associated with RyR2. Increased NOX2 activity at RyR2 oxidizes the channel, causing calstabin2 depletion from the channel macromolecular complex, destabilization of the closed state, and ER/SR calcium leak that is known to contribute to cardiac dysfunction, 55 arrhythmias, 61 pulmonary insufficiency, 23, 25 and cognitive and behavioral abnormalities associated with neurodegenreation. 24, 26 Decreased calbindin in COVID-19 may render brain more susceptible to tau pathology. Rycal drugs fix the RyR2 channel leak by restoring calstabin2 binding and stabilizing the channel closed state. Fixing leaky RyR2 may improve cardiac, pulmonary, and cognitive function in COVID-19.

same for control and COVID-19 samples (data not shown). Increased RyR2 channel activity at resting conditions (150 nM free Ca 2+ ) was observed in COVID-19 channels compared to controls ( Figure 3C ).

Under these conditions, RyR channels should be closed. Rebinding of calstabin2 to RyR2, using a Rycal, has been shown to reduce SR/ER Ca 2+ leak, despite the persistence of the channel remodeling. Indeed, calstabin2 binding to RyR2 was increased when COVID-19 patient brain tissue lysates were treated ex vivo with the Rycal drug ARM210 ( Figure 3A and B) . Abnormal RyR2 activity observed at resting Ca 2+ concentration was also decreased by Rycal treatment ( Figure 3C ).

An interesting finding concerning the tau phosphorylation in brain lysates from SARS-CoV-2 patients was the increase of phosphorylation at multiple sites in the cerebellum. This is atypical of AD. One potential mechanism to explain this finding is the significantly decreased levels of calbindin expressed in COVID-19 cerebellum ( Figure 3D, 3E) . The decreased cerebellar calbindin levels could make this area of the brain more susceptible to Ca 2+ -induced activation of enzymes upstream of tau phosphorylation. Moreover, increased GCPII expression was observed in COVID-19 cortex and cerebellar lysates ( Figure 3D, 3E) , which would reduce mGluR3 inhibition of PKA signaling and could contribute to the PKA hyperphosphorylation of RyR2.

Model for the role for leaky RyR2 in the pathophysiology of

Our data indicate a role for leaky RyR2 in the pathophysiology of SARS-CoV-2 infection (Figure 4 ). In addition to the brain of COVID-19 patients, we observed increased systemic oxidative stress and activation of the TGF-β signaling pathway in lung, and heart, which correlates with oxidation-driven biochemical remodeling of RyR2 (Figure 3 and S1 in supporting inormation). This RyR2 remodeling results in intracellular Ca 2+ leak, which can play a role in heart failure progression, pulmonary insufficiency, as well as cognitive dysfunction. [23] [24] [25] [26] 28 The alteration of cellular Ca 2+ dynamics has also been implicated in COVID-19 pathology. 58, 59 Taken together, the present data suggest that leaky RyR2 may play a role in the long-term sequelae of COVID-19, including the "brain fog" associated with SARS-CoV-2 infection which could be a forme fruste of AD, 60 and could predispose long COVID patients to developing AD later in life. Leaky RyR2 channels may be a therapeutic target for amelioration of some of the persistent cognitive deficits associated with long COVID.

The Authors would like to acknowledge the COVID BioBank at Columbia University for providing human heart, lung, and brain tissue for this study.

Andrew R. Marks conceived the study; Steve Reiken, Leah Sittenfeld, Haikel Dridi, Yang Liu, Xiaoping Liu, and Andrew R. Marks designed experiments, analyzed data, and edited/wrote the paper.

Columbia University and Andrew Marks own stock in ARMGO Pharma, Inc., a company developing compounds targeting RyR and have patents on Rycals. Steven Reiken has consulted for ARMGO Pharma, Inc. in the last 36 months. All other authors declare no competing interests or conflicts.

Steve Reiken https://orcid.org/0000-0002-5807-3574

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