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The role of SARS-CoV-2-induced senescence in the development of Alzheimer's Disease

Award Number: R01NS138600
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: 06/09/2025
PERIOD OF PERFORMANCE END DATE: 03/31/2030

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The role of SARS-CoV-2-induced senescence in the development of Alzheimer's Disease - Project Summary/Abstract SARS-CoV-2 has been associated with neurological symptoms, although there is no strong evidence of a direct viral infection in the brain. Recent reports indicate that SARS-CoV-2-induced systemic inflammation and the cleaved S1 subunit of the S protein remain detectable in patients with COVID-19 for months after diagnosis and may cause neurological manifestations. Also, COVID-19 tends to be more severe in older people, and although various biological responses change with aging, the induction of cellular senescence (SC) is predominant. New findings indicate that SARS-CoV-2 induces senescence in the lung epithelium with an exacerbated senescence- associated secretory phenotype (SASP) in response to the S1 subunit of the SARS-CoV-2 spike protein. Here, we will investigate how SARS-CoV-2 promotes CS in the brain and the role of SASP components in conveying senescence and promoting AD pathogenesis. Our preliminary data show that the S1 protein enters the systemic circulation and accumulates in the choroid plexus (CP) epithelium that expresses the ACE2 receptor. When S1 is combined with systemic inflammation, it induces a senescence-like phenotype in the brain of aged mice, initially restricted to epithelial cells in the CP, but it spreads to other brain regions, including the cortex and hippocampus, within a month. Transcriptome analysis in the brains of aged S1-challenged mice with systemic inflammation 30 days post S1 administration identified the metabolic pathways, pathways in neurodegeneration, and Alzheimer's disease among the top 10 enriched pathways. We also investigated how the S1 cleaved subunit induces cellular senescence (CS) in the choroid plexus epithelial cells when combined with systemic inflammation, and our results indicate that S1 induces dysfunction of the Nrf2-antioxidant response, which leads to accelerated CS when it is accompanied by LPS-induced ROS production. Most importantly, SASP analysis revealed the role of soluble factors SASP and EV-miRNA SASP components in conveying CS of neurons and regulating CS and AD pathways, respectively. Therefore, our goal is to explore whether miRNA replacement therapy can abrogate secondary SASP-induced senescence and AD pathogenesis and progression. Furthermore, analysis of postmortem brain sections and CSF from AD patients revealed the presence of CS markers in the CP long before the robust accumulation of β-amyloid and tau tangles in HPC, suggesting that CS may play an important role in Alzheimer's pathogenesis. Analysis of CSF from the early stages of AD also showed high levels of soluble SASP factors, which correlates well with the cellular senescent burden in the CP that produces the CSF. These findings prompted us to examine the relationship between CS and SARS-CoV-2 infection further and how it may increase the risk for AD. Our hypothesis is that SARS-CoV- 2-induced SASP in the CSF induces neuronal senescence and increases AD risk. Patients with severe COVID- 19 may be predisposed to develop AD later in life. These studies will allow us to identify better diagnostic markers and therapeutic targets and enable early intervention to prevent the development and progression of AD.


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 = $369,823 )
2026	2026	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/23/2026	NON-COMPETING CONTINUATION	$369,823
														Subtotal = $369,823

Issue Date FY: 2025 ( Subtotal = $369,823 )
2025	2025	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	6/6/2025	NEW	$369,823
														Subtotal = $369,823

Grand Total All Awards = $739,646

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The role of SARS-CoV-2-induced senescence in the development of Alzheimer's Disease

Award Number: R01NS138600

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: 06/09/2025

PERIOD OF PERFORMANCE END DATE: 03/31/2030

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