Wednesday, August 20, 2025 8/20/2025

The Role of Pericytes in Brain Hypoperfusion in Alzheimer's Disease Development

Award Number: R01AG081807
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/15/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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The Role of Pericytes in Brain Hypoperfusion in Alzheimer's Disease Development - PROJECT SUMMARY/ABSTRACT Vascular dysfunction, such as decreases in cerebral blood flow (CBF) and disruption of the blood brain barrier (BBB) are early symptoms of Alzheimer’s disease (AD) and could contribute to AD onset and progression. In the brain, specialized cells called pericytes are integral to proper vascular function, as they play a major role in regulating CBF and maintaining BBB integrity. However, the processes that govern pericyte dysfunction and the role of pericytes in decreases of CBF in AD development have not been fully elucidated. Our previous studies have demonstrated that increases in the transcription factor Fli-1 are associated with pericyte dysfunction and viability via up-regulation of caspase-1 expression. Our preliminary data demonstrated that Fli-1 levels were higher in the hippocampus and superior temporal gyrus regions of brain tissue from AD patients compared to controls. Pericytes undergo apoptosis in the hippocampus of AD patients, and pericyte Fli-1 levels were increased in AD patients. In addition, TNF and aggregated amyloid- induced Fli-1 expression in cultured human brain pericytes. Furthermore, amyloid- induced pericyte apoptosis, as evidenced by decreased pericyte viability, increased TUNEL positive cells, and increased expression of apoptosis marker caspase-3. Knockdown of Fli-1 with antisense oligonucleotide Gapmers suppressed amyloid--induced pericyte death, apoptosis, and caspase-3 levels. Thus, increased Fli-1 levels in AD patients may lead to pericyte loss. To determine the cause- effect relationship between increased Fli-1 and AD development, we conducted studies in the 5xFAD mouse model. Fli-1 levels were higher in the hippocampus in 5xFAD mice and corresponded with spatial learning and memory impairment in Novel Object Recognition and Morris Water Maze tests. Injection of Fli-1 Gapmer into the hippocampus significantly decreased Fli-1 and inflammatory mediator levels, mitigated pericye loss and vascular leakage, suppressed adhesion molecule levels, reduced A deposition, and ameliorated spatial learning and memory impairment. These data provide the first evidence that increased Fli-1 levels contribute to AD development. We hypothesize that the transcription factor Fli-1 elevation in Alzheimer's disease leads to pericyte dysfunction and brain hypoperfusion. Three specific aims are proposed to address this hypothesis: Aim 1: Determine how Fli-1 regulates pericyte and neurovascular cell dysfunction in a mouse AD model. Aim 2: Elucidate the mechanisms by which pericyte dysfunction results in brain hypoperfusion and cognitive impairment in a mouse AD model. Aim 3: Test the therapeutic potential of intrathecal administration of Fli-1 Gapmers in mouse AD models. The successful completion of the proposed studies will result in a better understanding of the role of Fli-1 in regulating pericyte dysfunction in AD and the development of a novel treatment strategy for 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: 2025 ( Subtotal = $608,287 )
2025	2025	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Aging Research	001	3	8/11/2025	NON-COMPETING CONTINUATION	$49,656
2025	2025	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Aging Research	000	3	2/14/2025	NON-COMPETING CONTINUATION	$558,631
														Subtotal = $608,287

Issue Date FY: 2024 ( Subtotal = $620,701 )
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Aging Research	000	2	1/23/2024	NON-COMPETING CONTINUATION	$558,631
2024	2024	THE MEDICAL UNIVERSITY OF SOUTH CAROLINA	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Aging Research	001	2	6/28/2024	NON-COMPETING CONTINUATION	$62,070
														Subtotal = $620,701

Issue Date FY: 2023 ( Subtotal = $620,701 )
2023	2023	MEDICAL UNIVERSITY OF SOUTH CAROLINA THE	179 ASHLEY AVE	CHARLESTON	SC	29425	CHARLESTON	USA	Aging Research	000	1	4/11/2023	NEW	$620,701
														Subtotal = $620,701

Grand Total All Awards = $1,849,689

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The Role of Pericytes in Brain Hypoperfusion in Alzheimer's Disease Development

Award Number: R01AG081807

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/15/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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