Thursday, November 20, 2025 11/20/2025

Treating neurotoxicity and cognitive deficits due to hyperphosphorylated tau.

Award Number: R01NS135693
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: 09/22/2023
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Treating neurotoxicity and cognitive deficits due to hyperphosphorylated tau. - PROJECT SUMMARY (Description) Hyperphosphorylated tau is the major component of neurofibrillary tangles existing in the brains of Alzheimer’s Disease patients, but whether soluble hyperphosphorylated tau oligomers are already toxic to neurons, and if so, through what mechanisms, have remained unclear. This is largely due to the lack of experimental system to tackle these questions directly. This project will test the hypothesis that hyperphosphorylated tau oligomers promote neurotoxicity before the formation of insoluble tau fibrils, which is amplified by Ab peptides and/or the ApoE4 allele, but either apomorphine and raloxifene treatment mitigates these deleterious effects. This project has three specific aims. Aim 1 will compare the effects of intrahippocampal injection of tau and hyperphosphorylated tau (hyper-ptau) in wildtype and AD-mutant mice (J20 and ApoE KI). We will also compare the onset of behavioral/histological deficit and insoluble tau fibrils in these mice after intrahippocampal injection. Aim 2 will test the effects of hyper-ptau on the viability, mitochondrial functions, and axonal trasnport of cultured neurons. We will also confirm mitochondrial dysfunctions after brain injection of hyper-ptau in vivo. Aim 3 will test the protective effects of apomorphine and raloxifene in preventing hyper-ptau-induced toxicity and cognitive deficits in mice. Both compounds attenuates ptau aggregation in vitro and have a high potential to be repurposed for clinical treatment 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: 2025 ( Subtotal = $603,078 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	8/7/2025	NON-COMPETING CONTINUATION	$603,078
														Subtotal = $603,078

Issue Date FY: 2024 ( Subtotal = $608,361 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	7/29/2024	NON-COMPETING CONTINUATION	$608,361
														Subtotal = $608,361

Issue Date FY: 2023 ( Subtotal = $628,844 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/22/2023	NEW	$628,844
														Subtotal = $628,844

Grand Total All Awards = $1,840,283

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Treating neurotoxicity and cognitive deficits due to hyperphosphorylated tau.

Award Number: R01NS135693

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: 09/22/2023

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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