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Preventing Tau uptake by novel inhibitors of tau binding to LRP1

Award Number: R01AG075084
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Preventing Tau uptake by novel inhibitors of tau binding to LRP1 - PROJECT SUMMARY Several neurodegenerative diseases, such as Alzheimer's disease (AD), are characterized by the spread and aggregation of the protein tau. Tau aggregates or neurofibrillary tangles (NFTs) accumulate throughout the brain of patients and lead to dementia. No effective treatments currently exist for tauopathies. Those approaches that have been considered, such as tau antibodies and antisense oligonucleotides, directly target tau. The complexity of tau cell biology, however, makes this approach challenging. A completely novel approach is to take advantage of the tau spreading pathway. The spread of NFTs correlate with disease progression and is a likely mediator for the observed neurotoxicity. 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. Therefore, the main objective of this project is to identify small-molecule chemical probes that prevent the binding of tau to LRP1, with the hypothesis that these molecules would serve as key starting points for novel therapeutics. In preliminary work, we have identified the primary interaction surface for tau on LRP1 and have developed a TR-FRET high-throughput screening (HTS) assay to identify compounds that can disrupt this interaction. We have optimized the assay to 1536-well format and conducted a pilot screen of 5,000 compounds with excellent performance, Z'~0.7 and a hit rate of ~0.4%. Analysis of the 20 hits from this screen in primary, artifact, and orthogonal assays identified several compounds with modest potency in dose response. To fully develop this work, we propose three aims. In Aim 1, we will use the TR-FRET assay to screen a 420,000 chemical library and, in parallel, conduct an affinity screen of a 4.4-billion- member DNA encoded library leveraging the DELopen platform (WuXi AppTec). In Aim 2, we will narrow our hit selection using orthogonal and novel biochemical profiling assays to determine mechanism of action. Finally, in Aim 3 we will validate hits with advanced biophysical and cell-based assays. We expect our multi-pronged approach will identify multiple chemical series with different mechanisms of action. Subsequent hit expansion efforts will produce chemical probes with properties suitable to test our hypothesis that small molecule LRP1-tau inhibitors can prevent tau uptake and spread. In future studies we intend to develop these probes into drugs that prevent tau spreading in tauopathies such as AD. As the critical path testing funnel is in place, we anticipate we can rapidly obtain and evaluate selective in vitro hits, explore their activity, and ultimately their suitability as starting points for hit-to-lead studies and for future in vivo evaluation in animal models and eventually patients.


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	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Aging Research	000	4	4/15/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $786,735 )
2025	2025	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Aging Research	000	4	11/15/2024	NON-COMPETING CONTINUATION	$722,511
2025	2025	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Aging Research	001	4	7/16/2025	NON-COMPETING CONTINUATION	$64,224
														Subtotal = $786,735

Issue Date FY: 2024 ( Subtotal = $809,235 )
2024	2024	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Aging Research	001	3	5/2/2024	NON-COMPETING CONTINUATION	$80,923
2024	2024	"UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Aging Research	000	3	11/9/2023	NON-COMPETING CONTINUATION	$728,312
														Subtotal = $809,235

Issue Date FY: 2023 ( Subtotal = $853,145 )
2023	2023	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Aging Research	000	2	1/6/2023	NON-COMPETING CONTINUATION	$853,145
														Subtotal = $853,145

Issue Date FY: 2022 ( Subtotal = $885,722 )
2022	2022	UNIVERSITY OF CALIFORNIA, SANTA BARBARA	3227 CHEADLE HALL	SANTA BARBARA	CA	93106	SANTA BARBARA	USA	Aging Research	000	1	3/1/2022	NEW	$885,722
														Subtotal = $885,722

Grand Total All Awards = $3,334,837

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Preventing Tau uptake by novel inhibitors of tau binding to LRP1

Award Number: R01AG075084

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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