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Deciphering the Molecular Features Underlying LRP1-Mediated Tau Spread

Award Number: R01AG077672
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: 03/31/2027

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Deciphering the Molecular Features Underlying LRP1-Mediated Tau Spread - Several neurodegenerative diseases, such as Alzheimer’s disease (AD), are characterized by the spread and aggregation of the protein tau. Recently, we identified a cellular receptor, LRP1 (Low-density lipoprotein Receptor-related Protein 1), that regulates the tau spread pathway. Knockdown of LRP1 prevents tau spread in human iPS neurons and the mouse brain, suggesting that the tau-LRP1 interaction could be an important entry point for disease intervention. Unfortunately, a detailed understanding of the tau-LRP1 molecular complex is still lacking. Therefore, the main objective of this project is to define the tau-LRP1 structural interface and discern how post-translation modifications (PTMs) to tau’s structure influence tau uptake and spread. In preliminary work, we have developed protocols to purify and measure interactions between tau and LRP1. We have established cellular platforms to model tau propagation and have shown that this process can be influenced by tau PTMs. To fully develop this work, we propose three aims. In Aim 1, we will use TR-FRET to establish in vitro affinities between tau and LRP1 and mass spectrometry to map the protein-protein interface. In Aim 2, we will look at how tau phosphorylation can influence the tau-LRP1 complex and what effect this has on tau spread and aggregation. In Aim 3, we will focus on tau PTMs that alter lysine residues. We will assess if ubiquitination or acetylation can impact the tau-LRP1 interaction, if they influence tau aggregation, and if they promote or inhibit tau uptake and seeding in cells. The innovative experimental methods and comprehensive analyses outlined herein will provide important mechanistic insight and develop our understanding of pathogenic tau regulation in AD. This will be an essential first step forward for the development and evaluation of potential AD therapeutics.


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 = $379,711 )
2025	2025	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Aging Research	002	4	6/18/2025	NON-COMPETING CONTINUATION	$30,997
2025	2025	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Aging Research	000	4	3/14/2025	NON-COMPETING CONTINUATION	$387,460
2025	2025	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Aging Research	001	4	4/22/2025	NON-COMPETING CONTINUATION	-$38,746
														Subtotal = $379,711

Issue Date FY: 2024 ( Subtotal = $475,336 )
2024	2024	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Aging Research	002	3	4/24/2024	SUPPLEMENT FOR EXPANSION	$87,281
2024	2024	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Aging Research	000	3	4/18/2024	NON-COMPETING CONTINUATION	$388,055
2024	2023	UNIVERSITY OF MASSACHUSETTS	101 COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Aging Research	001	2	4/19/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $475,336

Issue Date FY: 2023 ( Subtotal = $439,563 )
2023	2023	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Aging Research	001	2	8/4/2023	SUPPLEMENT FOR EXPANSION	$50,913
2023	2023	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Aging Research	000	2	3/16/2023	NON-COMPETING CONTINUATION	$388,650
														Subtotal = $439,563

Issue Date FY: 2022 ( Subtotal = $389,245 )
2022	2022	UNIVERSITY OF MASSACHUSETTS	COMMONWEALTH AVE	AMHERST	MA	01003	HAMPSHIRE	USA	Aging Research	000	1	5/16/2022	NEW	$389,245
														Subtotal = $389,245

Grand Total All Awards = $1,683,855

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Deciphering the Molecular Features Underlying LRP1-Mediated Tau Spread

Award Number: R01AG077672

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: 03/31/2027

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