Mechanisms of Alzheimers disease pathogenesis in SARS CoV2 infection

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Principal Investigator: L Lee HAMM
Organization: TULANE UNIVERSITY OF LOUISIANA
Fiscal Year: 2023
Award: $311,220
Funding agency: NIH Office of the Director

PROJECT SUMMARY
This application is a supplement request to our P51 base grant to Tulane National Primate Research Center
(TNPRC) to further the investigation of the Post-Acute Sequelae of SARS-CoV-2 infection (PASC). This
application investigates the overarching hypothesis that SARS-CoV-2-induced dysregulation of metabolic
pathways involved in tryptophan metabolism and upregulation of DNER, a potential marker of ongoing
neurodegeneration, contributes to Alzheimer’s disease (AD) progression. We hypothesize that these alterations
contribute to major pathogenic features of CoVID-19 infection and PASC, particularly neurocognitive
disturbances, which have increased prevalence in persons previously infected with SARS-CoV-2. Alterations in
the Kyn/Tryp levels are known to accelerate AD. Our published studies have shown that systemic Kyn/Typ levels
correlate with the severity of lung pathology in the NHP model of SARS-CoV-2 infection. Our in-vitro studies
demonstrate that spike enhances amyloid beta aggregation and neurotoxicity in hippocampal neurons. The
studies proposed in Aim 1 will utilize samples from ongoing studies on PASC in African Green monkeys (AGMs).
Aim 2 studies will be performed in 5XFAD mice, a well-established AD model, to assess the impact of SARS-
CoV-2 Spike subunit S1 to recapitulate in vitro studies that Spike enhances the acceleration of amyloid beta
aggregation and plaque formation leading to cognitive impairment. This application leverages our ongoing PASC
studies in the African green monkey providing all the necessary samples for this investigation. This application
also takes advantage of the CoVID-19 NHP Coordinating Center at TNPRC, where three other Centers and we
are engaged in Long-CoVID studies and will deposit our data for further analysis. This application represents a
novel inquiry into an exciting hypothesis that may provide new insights into novel and effective therapeutic
strategies for SARS-CoV-2 infection and PASC.

Terms: <2019 novel corona virus><2019 novel coronavirus><2019-nCoV><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><5-HT><5-Hydroxytryptamine><5HT><AD dementia><AD model><AD pathology><APP processing><Acceleration><Acute><African Green Monkey><Age><Alzheimer Type Dementia><Alzheimer beta-Protein><Alzheimer disease dementia><Alzheimer sclerosis><Alzheimer syndrome><Alzheimer's><Alzheimer's Amyloid beta-Protein><Alzheimer's Disease><Alzheimer's amyloid><Alzheimer's disease model><Alzheimer's disease pathology><Alzheimer's pathology><Alzheimers Dementia><Ammon Horn><Amyloid (Aβ) plaques><Amyloid A4 Protein Precursor><Amyloid Alzheimer's Dementia Amyloid Protein><Amyloid Beta-Peptide><Amyloid Plaques><Amyloid Protein A4><Amyloid Protein Precursor><Amyloid beta-Protein><Amyloid beta-Protein Precursor><Amyloid β><Amyloid β oligomer><Amyloid β-Peptide><Amyloid β-Protein><Amyloid β-Protein Precursor><Anthelone U><Assay><Astrocytes><Astrocytus><Astroglia><Astroprotein><Autopsy><Autoregulation><Aβ><AβO><BBB penetration><Bioassay><Biologic Assays><Biological><Biological Assay><Biological Markers><Blood Plasma><Blood Serum><Brain><Brain Nervous System><CNS Injury><COVID infected patient><COVID patient><COVID positive patient><COVID survivors><COVID-19><COVID-19 S protein><COVID-19 affected><COVID-19 consequence><COVID-19 effect><COVID-19 impact><COVID-19 impacted><COVID-19 infected patient><COVID-19 infection><COVID-19 infection survivors><COVID-19 patient><COVID-19 positive patient><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID-19 survivors><COVID-19 virus><COVID-19 virus infection><COVID19><COVID19 S protein><COVID19 infection><COVID19 patient><COVID19 positive patient><COVID19 spike glycoprotein><COVID19 spike protein><COVID19 virus><CV-19><CV19><Catabolism><Cell Communication and Signaling><Cell Signaling><Chlorocebus aethiops><Chlorocebus sabaeus><Chronic><Circulation><CoV-2><CoV2><Cognitive Disturbance><Cognitive Impairment><Cognitive decline><Cognitive deficits><Cognitive function abnormal><Complex><Contracting Opportunities><Contracts><Cornu Ammonis><Data><Deposit><Deposition><Disease><Disease Progression><Disorder><Disturbance in cognition><Elderly><Encephalon><Enteramine><Epidermal Growth Factor><Epidermal Growth Factor-Urogastrone><Evaluation><Exhibits><Fatigue><Female><GFA-Protein><GFAP><Glial Fibrillary Acid Protein><Glial Fibrillary Acidic Protein><Glial Intermediate Filament Protein><Grant><Green Monkey><Hippocampus><Hippophaine><Homeostasis><Human><Immunochemical Immunologic><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Immunologic><Immunological><Immunologically><Immunologics><Impaired cognition><In Vitro><Incidence><Individual><Indolylethylamines><Infection><Inflammation><Injury><Intracellular Communication and Signaling><Investigation><Kynurenine><L-Tryptophan><Lack of Energy><Learning><Levotryptophan><Light><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><MT-bound tau><Mediating><Memory Deficit><Memory impairment><Metabolic Pathway><Mice><Mice Mammals><Modeling><Modern Man><Murine><Mus><Nerve Cells><Nerve Degeneration><Nerve Unit><Neural Cell><Neuritic Plaques><Neurocognitive><Neurocyte><Neurofibrillary Tangles><Neurologic><Neurologic Effect><Neurological><Neurology><Neuron Degeneration><Neurons><Non-Polyadenylated RNA><PASC><Pathogenesis><Pathogenicity><Pathologic><Pathology><Patients><Persons><Photoradiation><Physiological Homeostasis><Plasma><Plasma Serum><Post Acute Sequelae of COVID19><Post Acute Sequelae of SARS-CoV-2><Post Acute Sequelae of SARS-CoV2><Post Acute Sequelae of severe acute respiratory syndrome coronavirus 2><Post-Acute Sequelae of SARS-CoV-2 Infection><Prevalence><Primary Senile Degenerative Dementia><Primates><Primates Mammals><Proteins><Proteomics><Public Health><Publishing><Pulmonary Pathology><RNA><RNA Gene Products><Receptor Protein><Research><Reticuloendothelial System, Serum, Plasma><Ribonucleic Acid><SARS corona virus 2><SARS-CO-V2><SARS-COVID-2><SARS-CoV-2><SARS-CoV-2 S protein><SARS-CoV-2 infected patient><SARS-CoV-2 infection><SARS-CoV-2 patient><SARS-CoV-2 positive patient><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV-2 survivors><SARS-CoV2><SARS-CoV2 S protein><SARS-CoV2 infection><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><SARS-associated corona virus 2><SARS-associated coronavirus 2><SARS-coronavirus-2><SARS-related corona virus 2><SARS-related coronavirus 2><SARSCoV2><Sampling><Senile Plaques><Serotonin><Serum><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-associated coronavirus 2><Severe Acute Respiratory Syndrome-related coronavirus 2><Severe acute respiratory syndrome associated corona virus 2><Severe acute respiratory syndrome coronavirus 2><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 infection><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Severe acute respiratory syndrome related corona virus 2><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Symptoms><Synapses><Synaptic><Testing><Time><Tissue Harvesting><Tryptamines><Tryptophan><Tryptophan Metabolism><Tryptophan Metabolism Pathway><Up-Regulation><Upregulation><Urogastrone><Vaccines><Viral><Wuhan coronavirus><a beta peptide><abeta><abeta accumulation><abeta aggregation><abeta oligomer><advanced age><adverse sequelae of COVID><adverse sequelae of COVID-19><adverse sequelae of coronavirus disease><adverse sequelae of coronavirus disease 2019><ages><alzheimer model><amyloid beta><amyloid beta accumulation><amyloid beta aggregation><amyloid beta oligomer><amyloid beta plaque><amyloid precursor protein><amyloid precursor protein processing><amyloid β accumulation><amyloid β aggregation><amyloid-b plaque><amyloid-b protein><anthranilate><astrocytic glia><aβ accumulation><aβ aggregation><aβ oligomer><aβ plaques><base><bases><beta amyloid fibril><beta-Urogastrone><bio-markers><biologic><biologic marker><biological signal transduction><biomarker><blood-brain barrier penetration><bloodbrain barrier penetration><brain fog><brain tissue><cell type><central nervous system injury><chronic COVID><chronic COVID-19><chronic COVID-19 sequelae><chronic novel coronavirus disease 2019><cognitive defects><cognitive dysfunction><cognitive loss><cored plaque><corona virus disease 2019><coronavirus disease 2019><coronavirus disease 2019 S protein><coronavirus disease 2019 consequence><coronavirus disease 2019 effect><coronavirus disease 2019 impact><coronavirus disease 2019 infected patient><coronavirus disease 2019 infection><coronavirus disease 2019 patient><coronavirus disease 2019 positive patient><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><coronavirus disease 2019 virus><coronavirus disease infected patient><coronavirus disease patient><coronavirus disease positive patient><coronavirus disease-19><coronavirus disease-19 impact><coronavirus disease-19 patient><coronavirus disease-19 virus><coronavirus infectious disease-19><coronavirus patient><diffuse plaque><elders><extracellular><geriatric><glial activation><glial cell activation><hCoV19><hippocampal><hyper-phosphorylated tau><hyperphosphorylated tau><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><injured CNS><injuries><insight><late life><later life><life-threatening COVID><life-threatening COVID-19><life-threatening SARS-CoV-2><life-threatening coronavirus disease><life-threatening coronavirus disease 2019><life-threatening severe acute respiratory syndrome coronavirus 2><long haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long haul sequelae of COVID-19><long haul sequelae of coronavirus disease 2019><long-hauler COVID><long-hauler COVID-19><long-hauler coronavirus disease 2019><long-hauler syndrome><long-term COVID><long-term COVID-19><long-term coronavirus disease><long-term coronavirus disease 2019><long-term sequelae of COVID-19><long-term sequelae of SARS-CoV-2><long-term sequelae of coronavirus disease 2019><long-term sequelae of severe acute respiratory syndrome coronavirus 2><longterm COVID><longterm COVID-19><longterm coronavirus disease><longterm coronavirus disease 2019><lung pathology><male><memory dysfunction><metabolism measurement><metabolomics><metabonomics><microtubule bound tau><microtubule-bound tau><mouse model><murine model><nCoV2><necropsy><nerve cell death><nerve cell loss><neural degeneration><neurodegeneration><neurodegenerative><neurofibrillary degeneration><neurofibrillary lesion><neurofibrillary pathology><neurofilament><neurological degeneration><neuron cell death><neuron cell loss><neuron death><neuron loss><neuron toxicity><neuronal><neuronal cell death><neuronal cell loss><neuronal death><neuronal degeneration><neuronal loss><neuronal toxicity><neuroprotection><neuroprotective><neurotoxicity><notch><notch protein><notch receptors><novel><oAβ><older adult><older person><oligomeric amyloid beta><oligomeric amyloid-β><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><post COVID syndrome><post COVID-19 syndrome><post acute COVID syndrome><post acute COVID-19><post acute COVID-19 syndrome><post acute SARS-CoV-2><post acute coronavirus disease 2019><post acute coronavirus disease 2019 syndrome><post acute coronavirus disease syndrome><post acute severe acute respiratory syndrome coronavirus 2><post coronavirus disease 2019 syndrome><post coronavirus disease syndrome><post-acute phases of COVID-19><post-acute sequelae following SARS-CoV-2 infection><post-acute sequelae of COVID-19><post-acute sequelae of acute COVID infection><post-acute sequelae of coronavirus disease 2019><postmortem><primary degenerative dementia><receptor><senile dementia of the Alzheimer type><senior citizen><serious COVID><serious COVID-19><serious SARS-CoV-2><serious coronavirus disease><serious coronavirus disease 2019><serious severe acute respiratory syndrome coronavirus 2><severe COVID><severe COVID-19><severe COVID19><severe SARS-CoV-2><severe acute respiratory syndrome coronavirus 2 infected patient><severe acute respiratory syndrome coronavirus 2 patient><severe acute respiratory syndrome coronavirus 2 positive patient><severe coronavirus disease><severe coronavirus disease 19><severe coronavirus disease 2019><severe severe acute respiratory syndrome coronavirus 2><soluble amyloid precursor protein><survive COVID-19><survive SARS-CoV-2><synapse><tangle><tau><tau Proteins><tau factor><therapeutic agent development><therapeutic development><therapeutically effective><time interval><τ Proteins>