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TDP-43 in Alzheimer's disease

Award Number: R01AG066729
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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TDP-43 in Alzheimer's disease - Alzheimer’s disease, a severe progressive neurodegenerative disease of aging and the most common form of dementia, affects an estimated 30 million people worldwide. Pathologically, Alzheimer’s disease is defined by the presence of both amyloid plaques comprised of the protein amyloid-β (Aβ) and neurofibrillary tangles containing the protein tau in disease affected brain regions. However, 30-57% of Alzheimer’s disease patients also exhibit TDP-43 aggregates as an additional co-pathology. The presence of TDP-43 pathology in Alzheimer’s disease correlates with hippocampal sclerosis, worse brain atrophy, more severe cognitive impairment, and more rapid cognitive decline. Given the recent recognition of TDP-43 as a frequent co- pathology in Alzheimer’s disease, understanding its contribution to neurodegenerative disease processes and potential synergies with other pathological disease-promoting proteins is a critical need in the field. Recent work using C. elegans found that co-expressed tau and TDP-43 leads to increased neurotoxicity and pathological protein accumulation. Building on this foundation, the proposed Aims will develop and utilize new tractable models of co-expressed tau and TDP-43 in order to understand the biology underlying their toxicity. Aim 1 will define consequences of low or regulatable levels of co-expressed tau and TDP-43 using behavioral and neuroimaging assays, and test relationships between tau and TDP-43. Aims 2 and 3 will employ RNA sequencing to reveal gene expression underlying comorbid tau and TDP-43 through aging in simple models, and in human post-mortem brain tissue from patients with Alzheimer’s disease with TDP-43 pathology. Candidates nominated from transcriptomic approaches will be tested for functional roles in tau and TDP-43 synergistic proteinopathy using genetic and transgenic approaches. This work will characterize mechanisms underlying tau and TDP-43 neurotoxicity in Alzheimer’s disease and identify new therapeutic targets and strategies. Completion of this project will significantly advance understanding Alzheimer’s disease with comorbid TDP-43, and provide the groundwork for future therapeutic development targeting TDP-43 in Alzheimer’s disease.


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 = $0 )
2026	2025	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	000	5	4/15/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $501,206 )
2025	2025	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	001	5	6/13/2025	NON-COMPETING CONTINUATION	$40,915
2025	2025	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	000	5	4/28/2025	NON-COMPETING CONTINUATION	$460,291
														Subtotal = $501,206

Issue Date FY: 2024 ( Subtotal = $530,161 )
2024	2024	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY	SEATTLE	WA	98108	KING	USA	Aging Research	000	4	5/17/2024	NON-COMPETING CONTINUATION	$530,161
														Subtotal = $530,161

Issue Date FY: 2023 ( Subtotal = $530,161 )
2023	2023	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Aging Research	000	3	5/22/2023	NON-COMPETING CONTINUATION	$530,161
														Subtotal = $530,161

Issue Date FY: 2022 ( Subtotal = $531,273 )
2022	2022	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Aging Research	000	2	5/23/2022	NON-COMPETING CONTINUATION	$531,273
														Subtotal = $531,273

Issue Date FY: 2021 ( Subtotal = $520,153 )
2021	2021	SEATTLE INSTITUTE FOR BIOMEDICAL AND CLINICAL RESEARCH	1660 S COLUMBIAN WAY # 151F	SEATTLE	WA	98108	KING	USA	Aging Research	000	1	8/25/2021	NEW	$520,153
														Subtotal = $520,153

Grand Total All Awards = $2,612,954

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TDP-43 in Alzheimer's disease

Award Number: R01AG066729

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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