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Amyloid-β Disruption of Pericyte Control of Capillary Hemodynamics

Award Number: R01AG081935
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Amyloid-β Disruption of Pericyte Control of Capillary Hemodynamics - PROJECT SUMMARY Alzheimer's Diseases—the most common cause of dementia in aging adults—is a slow, but progressive, deterioration of the brain that leads to neurodegeneration and cognitive impairment. The classic neuropathological sign of the disease is the accumulation of amyloid-β (Aβ)-containing plaques, which can lead to neuronal damage when free Aβ oligomers form Ca2+-permeable pores, causing membrane permeabilization and neuronal cell death. More recently, cardiovascular pathologies have been implicated in the progression of Alzheimer's Disease and other forms of dementia. However, how these pathologies contribute to the pathogenesis of Alzheimer's Disease is poorly understood; how vascular dysfunction potentiates the failure to clear toxic Aβ from ageing brains. Our recent work provides evidence that capillaries—the smallest vascular conduits and the point of nutrient delivery and waste removal blood and surrounding neurons—act as a sensory network that detects and responds to neural activity by promoting an increase in local blood flow. In addition, we observe that contractile ensheathing pericytes maintain the efficiency of network perfusion by controlling blood flow at capillary junctions. In Preliminary Results, we provide new evidence that Aβ peptide for Ca2+ permeable pores, leading to the increases of Ca2+ events in contractile pericytes, but not in nearby vascular smooth muscle cells. In addition, we show that Aβ peptide- mediated increases in the frequency of Ca2+ events lead to Ca2+ store depletion and inhibition of the voltage- gated Ca2+ channels. We propose to test our overarching hypothesis that Aβ leads to the progressive loss of pericyte function at capillary junctions leading to a reduction in capillary network perfusion efficiency, ultimately affecting the health and function of surrounding neurons. The aims of the current study are 1) To test the hypothesis that differences in membrane lipid environments enable free Aβ oligomers to form Ca2+-permeable pores in capillary pericytes; 2) To test the hypothesis that free Aβ oligomers deplete internal Ca2+ stores, leading to STIM1-mediated inhibition of voltage-gated Ca2+ channels; and 3) To elucidate the effects of Aβ oligomers on local and regional blood flow. Successful completion of these studies is expected to provide insights into how amyloid-β peptide accumulation disrupts blood flow within the microenvironment to negatively impact neuronal vitality and provide therapeutic targets for the prevention of the neurodegeneration that leads to cognitive impairment 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: 2025 ( Subtotal = $499,103 )
2025	2025	BOARD OF REGENTS OF THE NEVADA SYSTEM OF HIGHER ED	1664 N VIRGINIA ST # 285	RENO	NV	89557	WASHOE	USA	Aging Research	001	3	6/13/2025	NON-COMPETING CONTINUATION	$40,742
2025	2025	BOARD OF REGENTS OF THE NEVADA SYSTEM OF HIGHER ED	1664 N VIRGINIA ST # 285	RENO	NV	89557	WASHOE	USA	Aging Research	000	3	4/8/2025	NON-COMPETING CONTINUATION	$458,361
														Subtotal = $499,103

Issue Date FY: 2024 ( Subtotal = $509,289 )
2024	2024	BOARD OF REGENTS OF THE NEVADA SYSTEM OF HIGHER ED	1664 N VIRGINIA ST # 285	RENO	NV	89557	WASHOE	USA	Aging Research	000	2	4/18/2024	NON-COMPETING CONTINUATION	$509,289
														Subtotal = $509,289

Issue Date FY: 2023 ( Subtotal = $511,420 )
2023	2023	NEVADA SYSTEM OF HIGHER EDUCATION	1664 N VIRGINIA ST	RENO	NV	89557	WASHOE	USA	Aging Research	000	1	3/30/2023	NEW	$511,420
														Subtotal = $511,420

Grand Total All Awards = $1,519,812

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Amyloid-β Disruption of Pericyte Control of Capillary Hemodynamics

Award Number: R01AG081935

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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