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Principal Investigator: Prasant Mohapatra
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2022
Award: $297,763
Funding agency: NIH Office of the Director
Summary
The COVID-19 pandemic constitutes a significant challenge to health care systems in the United States and
abroad. A systemic compromise of the organism following SARS-CoV-2 infection has emerged as an important
factor associated with COVID-19 severity, disproportionally affecting older patients with comorbidities such as
hypertension, diabetes, and dementia. In addition to respiratory symptoms, COVID-19 patients can present
neurological symptoms, ranging from the frequent loss of smell to rare but severe neurovascular and
neuroinflammatory events. These neurological symptoms disproportionally affect patients with Alzheimer’s
disease (AD) and can potentially lead to clinical scenarios previously associated with faster neurodegenerative
progression and worse behavioral outcomes. The involvement of the brain during COVID-19 and the
mechanisms of interaction between SARS-CoV-2 and AD pathological routes, however, remain poorly
understood. Our long-term goal in this project is to further our knowledge on how neuropathology may contribute
to the complex clinical presentation of COVID-19 and how SARS-CoV-2 infection and AD can negatively
synergize in vulnerable patients. The objective of this grant is to characterize the short-term effects of SARS-
CoV-2 in the brain during the acute stage of the infection in both young and aged diabetic animals, and a possible
protective effect of immunotherapeutic prophylaxis. The central hypothesis is that SARS-CoV-2 is both
neuroinvasive and neurotropic, accessing the brain and infecting neurons and potentially other cells within the
CNS, leading to neurodegeneration, inflammation, and a brain environment conducive to dementia. The rationale
is that other human coronaviruses are neuroinvasive and neurotropic, including the closely related SARS-CoV-
1, causing direct damage to neurons and myelin and triggering neuroinflammatory processes. Furthermore, the
SARS-CoV-2 entry receptor ACE2 has been previously implicated in AD, and other coronavirus infections have
been reported to trigger adaptive intracellular cascades linked to neurodegeneration. Our specific aims will test
the following hypotheses: (Aim 1) SARS-CoV-2 is neuroinvasive, neurotropic, and its infection of brain cells
causes neuronal and myelinic damage; (Aim 2) SARS-CoV-2 infection triggers neuroinflammation and cytokine
release, and prophylactic treatment with immunotherapeutic agents, such as convalescent plasma and
monoclonal antibodies, can affect the brain response; (Aim 3) COVID-19 and AD neuropathological routes
interact directly at the molecular level through the regulation of ACE2 and stress response pathways. This
contribution is significant as it will considerably advance our knowledge of COVID-19 pathology, opening new
avenues of treatment and care for a major public health concern, while also providing the necessary framework
to understand the long-term consequences of COVID-19 and its impact on AD pathology. The proposed research
is innovative in its use of a highly translational non-human primate model to reveal the neurobiological aspects
of viral infections.
Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><ACE2><AD dementia><AD pathology><Acute><Address><Adult-Onset Diabetes Mellitus><Affect><Age><Alzheimer><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's brain><Alzheimer's disease brain><Alzheimer's disease dementia><Alzheimer's disease pathology><Alzheimer's disease patient><Alzheimer's pathology><Alzheimer's patient><Alzheimers Dementia><Alzheimers disease><Amentia><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Protein A4><Amyloid beta-Protein><Amyloid β><Amyloid β-Peptide><Amyloid β-Protein><Angiotensin Receptor><Animal Model><Animal Models and Related Studies><Animals><Anosmia><Area><Astrocytes><Astrocytus><Astroglia><Aβ><BBB disruption><Blood Plasma><Brain><Brain Inflammation><Brain Nervous System><Brain region><COVID crisis><COVID disease severity><COVID epidemic><COVID infected patient><COVID pandemic><COVID patient><COVID positive patient><COVID severity><COVID-19><COVID-19 crisis><COVID-19 disease severity><COVID-19 epidemic><COVID-19 exposure><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 infected patient><COVID-19 infection><COVID-19 pandemic><COVID-19 patient><COVID-19 positive patient><COVID-19 public health crisis><COVID-19 severity><COVID-19 therapy><COVID-19 treatment><COVID-19 virus><COVID19><COVID19 crisis><COVID19 disease severity><COVID19 epidemic><COVID19 global health crisis><COVID19 global pandemic><COVID19 health crisis><COVID19 infection><COVID19 pandemic><COVID19 patient><COVID19 positive patient><COVID19 public health crisis><COVID19 severity><COVID19 therapy><COVID19 treatment><COVID19 virus><CV-19><CV19><California><Caring><Causality><Cell Body><Cells><Chronic><Clinical><Clinical Treatment Moab><CoV-2><CoV2><Cognition><Cognitive deficits><Complex><Confocal Microscopy><Coronaviridae Infections><Coronavirus Infections><Delirium><Dementia><Demyelinations><Development><Diabetes Mellitus><Disease><Disease Progression><Disorder><ER stress><Economics><Elements><Encephalitis><Encephalon><Entorhinal Area><Environment><Etiology><Event><Future><Glia><Glial Cells><Goals><Grant><HCoV><Health Care Systems><Healthcare Systems><Hortega cell><Human><Hypertension><Immune><Immune response><Immunes><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunological response><Immunotherapeutic agent><In Situ Hybridization><Incidence><Individual><Infection><Inflammation><Inflammatory Myelopathy><Ketosis-Resistant Diabetes Mellitus><Knowledge><Kolliker's reticulum><Lead><Life><Link><M mulatta><M. mulatta><MT-bound tau><Macaca><Macaca mulatta><Macaque><Maturity-Onset Diabetes Mellitus><Memory><Microglia><Microscopy><Modeling><Modern Man><Molecular><Monkeys><Monoclonal Antibodies><Monoclonal Antibody Therapy><Morphology><Myelin><Myelitis><NIDDM><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neurobiology><Neurocyte><Neuroglia><Neuroglial Cells><Neuroimmune><Neurologic><Neurologic Manifestations><Neurologic Signs and Symptoms><Neurologic Symptoms><Neurological><Neurological Manifestations><Neurological Signs and Symptoms><Neuron Degeneration><Neurons><Non-Insulin Dependent Diabetes><Non-Insulin-Dependent Diabetes Mellitus><Non-neuronal cell><Noninsulin Dependent Diabetes><Noninsulin Dependent Diabetes Mellitus><Nonneuronal cell><Organism><Pathologic><Pathology><Pathway interactions><Patients><Pb element><Peripheral><Phase><Plasma><Plasma Serum><Primary Senile Degenerative Dementia><Primates><Primates Mammals><Process><Prophylactic treatment><Prophylaxis><Proteins><Public Health><Receptor Protein><Regulation><Reporting><Research><Resolution><Respiratory Signs and Symptoms><Reticuloendothelial System, Serum, Plasma><Rhesus Macaque><Rhesus Monkey><Route><SARS Virus><SARS corona virus><SARS corona virus 2><SARS coronavirus><SARS-Associated Coronavirus><SARS-CO-V2><SARS-COVID-2><SARS-CoV><SARS-CoV-1><SARS-CoV-2><SARS-CoV-2 disease severity><SARS-CoV-2 epidemic><SARS-CoV-2 exposure><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 pandemic><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 severity><SARS-CoV-2 therapy><SARS-CoV-2 treatment><SARS-CoV2><SARS-CoV2 epidemic><SARS-CoV2 exposure><SARS-CoV2 infection><SARS-CoV2 pandemic><SARS-Related Coronavirus><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Severe Acute Respiratory Coronavirus><Severe Acute Respiratory Coronavirus 2><Severe Acute Respiratory Distress Syndrome CoV 2><Severe Acute Respiratory Distress Syndrome Corona Virus 2><Severe Acute Respiratory Distress Syndrome Coronavirus 2><Severe Acute Respiratory Syndrome CoV 2><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome Virus><Severe Acute Respiratory Syndrome corona virus><Severe Acute Respiratory Syndrome coronavirus><Severe Acute Respiratory Syndrome-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 exposure><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome related corona virus 2><Severity of illness><Slow-Onset Diabetes Mellitus><Social isolation><Spinal Cord Inflammation><Stable Diabetes Mellitus><Symptoms><T2 DM><T2D><T2DM><Testing><Therapeutic><Therapeutic Effect><Therapeutic Intervention><Tropism><Type 2 Diabetes Mellitus><Type 2 diabetes><Type II Diabetes Mellitus><Type II diabetes><United States><Vascular Hypertensive Disease><Vascular Hypertensive Disorder><Viral><Viral Diseases><Viral Gene Products><Viral Gene Proteins><Viral Proteins><Virus><Virus Diseases><Wuhan coronavirus><a beta peptide><aberrant folded protein><aberrant folded proteins><abeta><abeta accumulation><abeta aggregation><abnormal folded protein><abnormal folded proteins><adult onset diabetes><after COVID-19 infection><after SARS-CoV-2 infection><after SARS-CoV2 infection><after severe acute respiratory distress syndrome CoV-2 infection><age dependent><age related><aged><ages><airway symptom><amyloid beta><amyloid beta accumulation><amyloid beta aggregation><amyloid β accumulation><amyloid β aggregation><amyloid-b protein><angiotensin converting enzyme 2><angiotensin converting enzyme II><anosphrasia><astrocytic glia><aβ accumulation><aβ aggregation><behavior outcome><behavioral outcome><beta amyloid fibril><biological adaptation to stress><blood-brain barrier disruption><bloodbrain barrier disruption><brain cell><causation><cell type><chronic effect of COVID-19><co-morbid><co-morbidity><cognitive defects><cohort><comorbidity><convalescent plasma><corona virus disease 2019><corona virus disease 2019 epidemic><corona virus disease 2019 pandemic><coronavirus disease 2019><coronavirus disease 2019 crisis><coronavirus disease 2019 disease severity><coronavirus disease 2019 epidemic><coronavirus disease 2019 exposure><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 pandemic><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 public health crisis><coronavirus disease 2019 severity><coronavirus disease 2019 therapy><coronavirus disease 2019 treatment><coronavirus disease 2019 virus><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease infected patient><coronavirus disease pandemic><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease severity><coronavirus disease-19><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><cytokine><delirious><dementia of the Alzheimer type><demyelinate><developmental><diabetes><diabetic><disease causation><disease severity><elderly patient><endoplasmic reticulum stress><entorhinal cortex><experience><exposure to COVID-19><exposure to SARS-CoV-2><exposure to SARS-CoV2><exposure to Severe acute respiratory syndrome coronavirus 2><exposure to coronavirus disease 2019><following COVID-19 infection><following SARS-CoV-2 infection><following SARS-CoV2 infection><following severe acute respiratory distress syndrome CoV-2 infection><gitter cell><global health><hCoV19><heavy metal Pb><heavy metal lead><high blood pressure><host response><human CoV><human corona virus><human coronavirus><hyperpiesia><hyperpiesis><hypertensive disease><hypertensive disorder><immune drugs><immune system response><immune-based therapeutics><immunologic preparation><immunologic therapeutics><immunoresponse><immunotherapeutics><immunotherapy agent><in situ Hybridization Genetics><in situ Hybridization Staining Method><infected with COVID-19><infected with COVID19><infected with SARS-CoV-2><infected with SARS-CoV2><infected with coronavirus disease 2019><infected with severe acute respiratory syndrome coronavirus 2><innovate><innovation><innovative><intervention therapy><ketosis resistant diabetes><living system><long term consequences of COVID-19><long term consequences of SARS-CoV-2 infection><long term consequences of coronavirus disease-19><long term effects of COVID-19><long term health consequences of COVID-19><long term health consequences of SARS-CoV2 infection><long term impact of COVID-19><long term impact of SARS-CoV-2 infection><long-term consequence of severe acute respiratory distress syndrome-cov-2 infection><long-term effects of coronavirus disease-19><longterm consequences of COVID-19><longterm consequences of SARS-CoV-2 infection><longterm effects of COVID-19><longterm health consequences of COVID-19><longterm health consequences of SARS-CoV2 infection><longterm impact of COVID-19><longterm impact of SARS-CoV-2 infection><loss of smell><mAb therapy><mAbs><maturity onset diabetes><mesoglia><microglial cell><microgliocyte><microtubule bound tau><microtubule-bound tau><misfolded protein><misfolded proteins><model of animal><model organism><mortality><mouse model><murine model><nCoV2><nerve cell death><nerve cell loss><nerve cement><neural degeneration><neural manifestation><neuro-vascular><neurobiological><neurobiological mechanism><neurochemical><neurochemistry><neurodegeneration><neurodegenerative><neuroinflammation><neuroinflammatory><neurological degeneration><neuron cell death><neuron cell loss><neuron death><neuron loss><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal degeneration><neuronal loss><neuropathology><neurotropic><neurovascular><non-human primate><nonhuman primate><novel><older patient><olfactory loss><over-treatment><overtreatment><pathway><patient infected with COVID><patient infected with COVID-19><patient infected with SARS-CoV-2><patient infected with coronavirus disease><patient infected with coronavirus disease 2019><patient infected with severe acute respiratory syndrome coronavirus 2><patient with COVID><patient with COVID-19><patient with COVID19><patient with SARS-CoV-2><patient with coronavirus disease><patient with coronavirus disease 2019><patient with severe acute respiratory distress syndrome coronavirus 2><perivascular glial cell><piriform cortex><post SARS-CoV-2 infection><previous COVID-19 infection><previous SARS-CoV-2 infection><previous SARS-CoV2 infection><previous severe acute respiratory distress syndrome CoV-2 infection><primary degenerative dementia><prior COVID-19 infection><prior SARS-CoV-2 infection><prior SARS-CoV2 infection><prior severe acute respiratory distress syndrome CoV-2 infection><protective effect><proteotoxic protein><proteotoxin><reaction; crisis><receptor><recruit><respiratory><respiratory symptom><respiratory virus><response><senile dementia of the Alzheimer type><severe acute respiratory syndrome coronavirus 2 disease severity><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe acute respiratory syndrome coronavirus 2 severity><severe acute respiratory syndrome coronavirus 2 therapy><severe acute respiratory syndrome coronavirus 2 treatment><severe acute respiratory syndrome-CoV><social><soluble amyloid precursor protein><spatial relationship><stress response><stress; reaction><tau><tau Proteins><tau factor><treat COVID-19><treat COVID19><treat SARS-CoV-2><treat coronavirus disease 2019><treat severe acute respiratory syndrome coronavirus 2><type 2 DM><type II DM><type two diabetes><viral RNA><viral infection><virus RNA><virus infection><virus protein><virus-induced disease><τ Proteins>