Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Mechanistic Investigation of Chronic Neuropathologic Interaction Between Viral Infection and Progression of Lewy Pathology and Dementia

Award Number: R01NS148641
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/13/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

Group Awards By:

View Award Description

Mechanistic Investigation of Chronic Neuropathologic Interaction Between Viral Infection and Progression of Lewy Pathology and Dementia - Project Summary/Abstract Neuropathological interactions between COVID-19 and ADRD suggest shared molecular and cellular mechanisms. A recent case series study revealed striking cutaneous Lewy pathology (phosphorylated α- synuclein) in Long-COVID Postural orthostatic tachycardia syndrome (POTS) patients. Animal studies consistently show that viral infection can trigger α-synucleinopathies in hamster and macaque SARS-CoV-2 infection models. SARS-CoV-2 N-and Spike protein can bind to α-Synuclein to induce Lewy pathology in vitro. Recent human single-neuron sequencing findings of accumulation of non-germline inherited somatic mutations associated with neurodegenerative disorders support the pathogenic role of genotoxic stress in age-dependent long-lasting neurologic deficits and cognitive decline. These observations support the role of infection in the pathogenesis of synucleinopathy, a pathological intracellular proteinaceous α-Synuclein (α-Syn) inclusions that are characteristic of neurological disorders, including dementia with Lewy body (DLB), with DLB being the second most common type of dementia after AD. Ours and other studies have begun to reveal the role of genotoxic stress interplaying with autophagy-lysosome function in synucleinopathy. To study the impact of virus infection on synucleinopathy in vivo, we generated a human ACE2 transgenic mouse model with full-length human ACE2 regulatory regions that faithfully recapitulated the structure, tissue distribution, and gene regulation of the human gene. SARS-CoV-2 infection in ABSL-3 facility established the feasibility of our model to study post-acute sequelae of COVID-19 (PASC) and age-dependent progression of neuropathology without viral neuroinvasion and lethal encephalitis, providing distinct advantages over the existing animal models. Compelling vivo data indicates that inhibiting genotoxic stress can effectively lessen inflammation, cell senescence, accumulation of α-Synuclein, autophagy deficits, neuroinflammation, and cognitive and anosmia symptoms in an immunopathology model without viral neural invasion. ATM inhibition only in genotoxic stressed cells via a novel genetic strategy also rescued α-Synuclein aggregates spreading and cognitive deficits, suggesting a causal pathogenic role of genotoxic stress in synucleinopathy and long COVID symptoms. We hypothesize viral infection-driven brain genotoxic stress mediates the pathologic interaction between COVID-19 and DLB via perpetuating DDR/cell senescence, autophagy/lysosome acidification dysfunction, and neuroinflammation that sustains chronic cognitive and neurological deficits. To test the hypothesis, Aims 1 and 2 will determine how viral infection as an etiologic factor can drive chronic olfactory and cognitive deficits, as well as Lewy pathology, with genotoxic stress as a prominent feature and key initiating factor. Aim 3 will establish the causal role of brain genotoxic stress and pathogenic mechanisms in PASCs, Lewy pathology, and dementia. The findings will transform the current paradigm of the viral origin of neurodegeneration and advance the therapeutic targeting of genotoxic stress for PASCs, Lewy pathology, and dementia.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $582,172 )
2026	2026	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	5/14/2026	NEW	$582,172
														Subtotal = $582,172

Grand Total All Awards = $582,172

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mechanistic Investigation of Chronic Neuropathologic Interaction Between Viral Infection and Progression of Lewy Pathology and Dementia

Award Number: R01NS148641

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 05/13/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer