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Structure and Function of Gamma-Secretase in Familial Alzheimer's Disease

Award Number: R01AG066986
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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Structure and Function of Gamma-Secretase in Familial Alzheimer's Disease - Familial Alzheimer’s disease (FAD) is caused by dominant mutations in the amyloid-β (Aβ) precursor protein (APP) and presenilin-1 and -2 (PSEN1, PSEN2). APP is cleaved by β-secretase, then within its single transmembrane domain (TMD) by γ-secretase to produce Aβ, which deposits as cerebral plaques. PSEN is the catalytic component of γ-secretase, a membrane-embedded protease complex. Thus, FAD mutations are only in the substrate and protease that produce Aβ; nevertheless, pathogenic mechanisms remain controversial. Most PSEN FAD mutations show reduced proteolysis (loss of function) but also increase proportions of aggregation-prone 42-residue Aβ peptide (Aβ42) (gain of function). However, γ-secretase has multiple proteolytic functions: Initial endoproteolytic (ε) cleavage of APP substrate produces long Aβ that is trimmed via a carboxypeptidase activity, and FAD-mutant γ-secretases are deficient in this trimming function. New understanding of multiple proteolytic functions of γ-secretase along with recent cryo-EM structure elucidation of the protease-substrate complex now make possible a deeper understanding of effects of FAD mutations. The goal here is to combine chemical, structural, and computational biology to elucidate how presenilin FAD mutations alter γ-secretase structure, dynamics, and function. Such understanding should give insight into how this membrane-embedded protease complex recognizes and processively proteolyzes transmembrane substrates, provide critical clues to pathogenic mechanisms of FAD, and suggest new strategies for prevention of FAD. To this end, we propose to: (1) Develop chemical probes to trap γ-secretase in different stages of substrate interaction for structural analysis by cryo-EM. We developed full TMD substrate mimics to trap active enzyme in a conformation poised for intramembrane proteolysis. Designed variations should allow visualization of the transition states for ε proteolysis, carboxypeptidase cleavage, TMD helix unwinding, and lateral gating of substrate. (2) Perform molecular dynamics (MD) simulations of substrate interaction with FAD-mutant γ-secretase. We computationally restored catalytic aspartates, modeled entry of water to the active site, and captured activation of the computationally restored WT enzyme. We will determine effects of FAD PSEN1 mutations on γ-secretase structural dynamics and interaction with APP substrate and TMD mimics. (3) Develop synthetic substrate probes for analysis of proteolytic dysfunction of FAD-mutant γ-secretase. We developed a set of such functional probes of γ-secretase processing of APP TMD, validating them as convenient and appropriate synthetic surrogates for APP substrate. We will employ these and other proposed substrate probes to determine effects of FAD-mutant γ-secretases on ε proteolysis and specific carboxypeptidase trimming steps.


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 = $643,210 )
2026	2026	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	001	6	12/23/2025	COMPETING CONTINUATION	$643,210
2026	2024	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	000	5	12/15/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $643,210

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	000	5	2/3/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $582,098 )
2024	2024	UNIVERSITY OF KANSAS CENTER FOR RESEARCH INC	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	000	5	4/16/2024	NON-COMPETING CONTINUATION	$582,098
														Subtotal = $582,098

Issue Date FY: 2023 ( Subtotal = $582,098 )
2023	2023	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	000	4	4/6/2023	NON-COMPETING CONTINUATION	$582,098
														Subtotal = $582,098

Issue Date FY: 2022 ( Subtotal = $582,098 )
2022	2022	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	000	3	4/7/2022	NON-COMPETING CONTINUATION	$582,098
														Subtotal = $582,098

Issue Date FY: 2021 ( Subtotal = $582,098 )
2021	2021	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	000	2	4/8/2021	NON-COMPETING CONTINUATION	$582,098
														Subtotal = $582,098

Issue Date FY: 2020 ( Subtotal = $582,098 )
2020	2020	UNIVERSITY OF KANSAS CENTER FOR RESEARCH, INC.	2385 IRVING HILL RD	LAWRENCE	KS	66045	DOUGLAS	USA	Aging Research	000	1	4/27/2020	NEW	$582,098
														Subtotal = $582,098

Grand Total All Awards = $3,553,700

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Structure and Function of Gamma-Secretase in Familial Alzheimer's Disease

Award Number: R01AG066986

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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