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p66Shc in Cerebrovascular Impairment in Alzheimer’s Disease

Award Number: R21AG094068
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2026
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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p66Shc in Cerebrovascular Impairment in Alzheimer’s Disease - Age-related cognitive impairment is often associated with vascular changes which accompany or precede progression of Alzheimer's disease (AD) and related dementias. Molecular mechanisms of vascular dysfunction, causing cognitive deficiency, remain to be defined. We will test the hypothesis that adaptor protein p66Shc signaling contributes to cognitive deficiencies and loss of cerebral vascular reactivity associated with AD. Our preliminary data in support of our hypothesis include: 1) Demonstration of the critical role of p66Shc in cerebral vascular function and proof that p66Shc plays a critical role in the maintenance of vascular tone and autoregulation of cerebral arteries; 2) Establishing the AD rat model TgF344-AD and measurements of brain hypoperfusion in our labs. The TgF344-AD rat is an AD model that exhibits age-dependent increases in Aβ42 by overexpressing mutated APP and PS1; 3) Expression of p66Shc is increased in AD brain tissues; 4) SHetA2 (modulator of p66Shc signaling) restores renal microvascular reactivity in rat models of renal pathologies. 5) SHetA2 restores the myogenic response of the MCA in AD rats but not in WT control rats. We have generated a panel of unique genetically modified rats with targeted editing of Shc1 gene, which enables us to evaluate the role p66Shc in AD. Specific Aim 1 will test the hypothesis that progression of AD, accompanied by loss of cerebral vascular reactivity and progression of cognitive dysfunction, is mitigated in genetically modified rats with targeted mutations for Shc1 gene. We will carry out crossbreeding of TgF344-AD rats with either p66Shc-KO rats or rats expressing constitutively active p66Shc mutant to generate p66Shc knockouts and p66Shc constitutively active mutants on the genetic background of TgF344-AD rat. We will compare cerebral vascular reactivity of TgF344- AD rats which differ in p66Shc expression and/or signaling and establish whether loss of p66Shc expression would be accompanied by mitigation of cognitive deficiencies associated with progression of AD. Pressure myography will be used to detect the myogenic response of cerebral arteries and precapillary arterioles, as well as functional hyperemia in newly generated p66Shc knockout rats and rats with constitutively signaling p66Shc on the TgF344-AD genetic background. Laser Doppler flowmetry and Laser Speckle Imaging will be used to detect cerebral blood flow autoregulation, functional hyperemia, and brain perfusion. To evaluate cognitive dysfunction, we will employ behavior tests (Morris Water Maze, Novel Object Recognition Test and Fear Conditioning Test) using wild type and genetically modified rats. Specific Aim 2 will test the hypothesis that SHetA2 restores cerebral vascular reactivity and mitigates the progression of cognitive dysfunction associated with AD in rats. We will administer SHetA2 to TgF344-AD rats and test whether modulation of p66Shc signaling will affect brain hypoperfusion and cognitive deficits. We will establish the role of p66Shc in the control of cerebral vascular reactivity and progression of cognitive deficiencies and will set the base for development of novel therapy 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: 2026 ( Subtotal = $441,460 )
2026	2026	THE MEDICAL COLLEGE OF WISCONSIN, INC.	8701 WATERTOWN PLANK RD	MILWAUKEE	WI	53226	MILWAUKEE	USA	Aging Research	000	1	1/22/2026	NEW	$441,460
														Subtotal = $441,460

Grand Total All Awards = $441,460

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p66Shc in Cerebrovascular Impairment in Alzheimer’s Disease

Award Number: R21AG094068

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2026

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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