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Using a novel mTBI model to investigate phosphorylation dependent common mechanisms in tauopathies

Award Number: R01AG075809
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2022
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Using a novel mTBI model to investigate phosphorylation dependent common mechanisms in tauopathies - Alzheimer’s disease (AD) and many related dementias (ADRDs) are tauopathies, characterized by somatodendritic accumulation of tau and intraneuronal inclusion bodies composed of tau species that have undergone extensive post translational modification. Although some disease-specific Tau modifications have been identified, many are conserved across the full range of tauopathies. We do not yet have a deep understanding of the molecular processes that generate these tau protein modifications, or of their functional consequences in promoting pathogenic cascades. This knowledge gap is a major contributor to our current inability to generate effective therapeutic interventions for AD and other tauopathies. The central hypothesis we are testing here is that a range of pathogenic events induce phosphorylation of tau at specific residues, resulting in mislocalization of tau within the cell and subsequent synaptic dysfunctions, and that inhibition of these early tau phosphorylation events will in turn inhibit tau pathologies and associated signaling deficits. This hypothesis is based on our published work, primarily utilizing cultured cell experimental systems. The direct relevance of this mechanism to human disease is further supported by the recent finding that phosphorylation of tau at these same specific residues is an early event preceding tau fibril formation in AD disease progression. Our overall objective here is to test and further refine this hypothesis in a novel mouse model we have developed (MAPT- GR) that expresses all isoforms of human tau at physiologic levels and ratios. We have found that mild traumatic brain injury (mTBI) induces a rapid phosphorylation and somatodendritic mislocalization of the human tau in these mice. Importantly, we can prevent this tau mislocalization by inhibiting phosphorylation. The specific aims are to: 1. Determine the dynamic changes in the subcellular distribution of phosphorylated tau. We will utilize our novel tauopathy model to test the working hypothesis that phosphorylation of tau at specific residues leads to somatodendritic accumulation of tau, tau mislocalization to dendritic spines, and alters micro- components of dendritic spines. 2. Determine the synaptic and circuit dysfunctions associated with the phosphorylation of tau. We will test the working hypothesis that mislocalization of phosphorylated tau to somatodendritic domains and dendritic spines results in synaptic and circuit dysfunction in our model. 3. Identify the impact of inhibiting these early phosphorylation events on tau mislocalization and associated signaling deficits. We will test our working hypothesis that mTBI activates GSK3β and CDK5, which phosphorylate the B and C domain of the tau protein. Expected Outcomes: We expect to identify the early-stage pathologies and dysfunctions caused by phosphorylation of tau and provide proof-of-concept demonstrations of the extent to which these dysfunctions can be prevented by blocking tau phosphorylation at specific residues. Of equal importance, we expect to have optimized a model and experimental platform in which potential therapeutic compounds that target this common disease mechanism can be tested and optimized.


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 = $767,250 )
2026	2026	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Aging Research	000	5	3/3/2026	NON-COMPETING CONTINUATION	$767,250
														Subtotal = $767,250

Issue Date FY: 2025 ( Subtotal = $751,906 )
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	2221 UNIVERSITY AVE SE STE 100	MINNEAPOLIS	MN	55414	HENNEPIN	USA	Aging Research	001	4	7/15/2025	NON-COMPETING CONTINUATION	$61,380
2025	2025	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Aging Research	000	4	2/14/2025	NON-COMPETING CONTINUATION	$690,526
														Subtotal = $751,906

Issue Date FY: 2024 ( Subtotal = $767,250 )
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Aging Research	000	3	2/13/2024	NON-COMPETING CONTINUATION	$690,526
2024	2024	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Aging Research	001	3	6/28/2024	NON-COMPETING CONTINUATION	$76,724
														Subtotal = $767,250

Issue Date FY: 2023 ( Subtotal = $767,250 )
2023	2023	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Aging Research	000	2	2/15/2023	NON-COMPETING CONTINUATION	$767,250
														Subtotal = $767,250

Issue Date FY: 2022 ( Subtotal = $767,250 )
2022	2022	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Aging Research	000	1	5/23/2022	NEW	$767,250
														Subtotal = $767,250

Grand Total All Awards = $3,820,906

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Using a novel mTBI model to investigate phosphorylation dependent common mechanisms in tauopathies

Award Number: R01AG075809

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2022

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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