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Deciphering tau phosphorylation and Abeta/tau strain interactions in Alzheimer’s pathogenesis

Award Number: R01AG078734
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2027

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Deciphering tau phosphorylation and Abeta/tau strain interactions in Alzheimer’s pathogenesis - Abstract The clinical symptoms of Alzheimer disease (AD) dementia occur downstream of pathological deposition of Aβ peptides in extracellular cored-neuritic plaques and aggregated tau protein in intracellular neurofibrillary tangles (NFT) in the brain. Since deposition of Aβ precedes tauopathy in early-onset familial AD (fAD), it is accepted that Aβ can trigger tau misfolding into NFT, initiating a cascade of cumulative pathology that progressively leads to dementia. In sporadic AD, the coincident deposition of Aβ appears to correlate with tau misfolding and the severity of NFT pathology. Collectively, these findings suggest that Aβ deposition can exacerbate tau misfolding and NFT formation leading to cognitive deficits and dementia. However, the underlying mechanisms and characteristics of Aβ and tau that synergize resulting in NFT pathology and pathological sequelae is still unclear. Our proposal is designed to provide experimental insights into the individual contribution of tau (Aim 1) and Aβ (Aim 2) in driving Aβ-tau synergy in mouse models of AD. Evidence suggests that a major mechanism by which Aβ synergizes with tau misfolding involves the hyper-phosphorylation of tau. A recent study of AD patients that quantitatively mapped the progressive emergence of phosphorylated epitopes in tau identified 19 Ser/Thr residues that are most frequently phosphorylated in individuals that exhibit concurrent Aβ pathology. The main objective in Aim 1 is to dissect the contribution of these phosphorylation events in the misfolding and aggregation of tau that occurs in the presence of concurrent Aβ pathology. Using AAV technology, we have the capability to generate and express a large number of tau phospho-mimetic variants in APP TgCRND8 mice. Using this mouse model, in Aim 1 we propose a broad study to systematically dissect the phosphorylation events that drive tau misfolding and NFT formation in the presence of Aβ. Over many years of research, our laboratories have created mouse models that exhibit a spectrum of Aβ pathologies, including mice that develop primarily diffuse Aβ pathology and mice that primarily develop cored- neuritic pathology. Given that there are questions regarding the type of Aβ pathology that underlie Aβ-tau synergy, in Aim 2, we propose to use our AAV approach to examine Aβ-tau interactions in this diverse collection of APP transgenic models that exhibit different types of Aβ pathology. Additionally, in Aim 2, we will use pharmacologics and inducible APP models to examine the role of newly-made soluble Aβ vs long-lived insoluble Aβ in tau phosphorylation/aggregation process. Phospho-proteomic analysis will help us determine the relationship of different types of Aβ to the resulting tau phosphorylation profile. Collectively, this work will improve our understanding of the Aβ-driven phosphorylation cascade that appears to promote tau misfolding and aggregation into NFT.


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 = $481,006 )
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	001	4	6/30/2025	NON-COMPETING CONTINUATION	$39,267
2025	2025	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	000	4	5/8/2025	NON-COMPETING CONTINUATION	$441,739
														Subtotal = $481,006

Issue Date FY: 2024 ( Subtotal = $497,937 )
2024	2024	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	000	3	5/31/2024	NON-COMPETING CONTINUATION	$497,937
														Subtotal = $497,937

Issue Date FY: 2023 ( Subtotal = $490,314 )
2023	2023	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	000	2	6/13/2023	NON-COMPETING CONTINUATION	$490,314
														Subtotal = $490,314

Issue Date FY: 2022 ( Subtotal = $455,239 )
2022	2022	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Aging Research	000	1	9/23/2022	NEW	$455,239
														Subtotal = $455,239

Grand Total All Awards = $1,924,496

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Deciphering tau phosphorylation and Abeta/tau strain interactions in Alzheimer’s pathogenesis

Award Number: R01AG078734

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2027

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