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Cell Type-Specific Proteins that Promote Resilience to Cognitive Aging and Alzheimer's Disease

Award Number: R01AG075818
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/30/2021
PERIOD OF PERFORMANCE END DATE: 04/18/2025

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Cell Type-Specific Proteins that Promote Resilience to Cognitive Aging and Alzheimer's Disease - Resilience to brain aging and Alzheimer’s disease (AD) is a phenomenon whereby cognitive functioning is better than predicted based on chronological age, genetic risk and/or advanced neuropathology, likely because of the presence of as yet unidentified protective factors. These factors, once identified, are expected to provide key targets for treatment and prevention of AD. However, significant barriers limit discovery of the genetic mechanisms of resilience using human genetic methods alone, including: difficulties in identifying large numbers of individuals with asymptomatic AD, extracting age and interacting genetic effects from complex human genomes, controlling environmental factors, and obtaining brain tissue from asymptomatic AD cases. Moreover, it is well known that transcript abundance is not sufficient to infer protein abundance, as they differ spatially, temporally, and in response to learning tasks. Yet, our ability to discern how proteomes change across aging and AD progression is limited by the impossibility of longitudinal molecular analyses on human brain tissues, as well as the technology needed to profile cell type-specific proteomes associated with susceptibility versus resilience to AD. To fill these significant technological and knowledge gaps, here we will develop a robust pipeline using the most translationally relevant mouse models of human brain aging and AD (i.e., the AD-BXDs and their non-transgenic Ntg-BXDs controls) to obtain a longitudinal knowledge base of proteomes in specific cell types that we have found to exhibit robust changes in gene expression associated with highly susceptible and highly resilient phenotypes. We will focus on the hippocampus as it is required for spatial memory formation and recall in mice and humans, and hippocampus-dependent memory deficits are common in AD. Indeed, our work and preliminary data suggest that mouse strain differences in the age at onset and progression of cognitive deficits in the AD-BXDs (from extremely susceptible to resilient) result from cell type-specific differences in gene expression in the hippocampus. We will integrate these mouse data with clinical and omics data from NIA-sponsored AMP-AD and Resilience-AD Consortia to identify molecular drivers of cognitive resilience. In Aim 1, we will identify cell type-specific changes in neuron and microglia protein expression associated with resilience to AD using bioorthogonal non-canonical amino acid tagging (BONCAT) in AD-BXDs. In Aim 2, we will translate drivers and molecular networks underlying cognitive resilience to human AD cohorts. In Aim 3, we will leverage the unmatched genetic engineering resources at The Jackson Laboratory to functionally validate ‘in-hand’ resilience candidates by determining their effects on memory, hippocampal neuronal excitability, and synaptic plasticity in CRISPRed AD-BXDs. Using this pipeline, we will thereby discover novel and translationally relevant proteins and complexes for consideration under AMP-AD/TREAT-AD drug discovery pipelines to delay or prevent cognitive symptoms in susceptible AD mice, and ultimately AD 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: 2025 ( Subtotal = $0 )
2025	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE STE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	000	4	4/29/2025	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $1,739,209 )
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	005	4	7/8/2024	SUPPLEMENT FOR EXPANSION	$138,313
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	003	3	1/9/2024	SUPPLEMENT FOR EXPANSION	$56,123
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	006	4	8/30/2024	NON-COMPETING CONTINUATION	-$138,313
2024	2024	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	004	4	5/31/2024	NON-COMPETING CONTINUATION	$1,683,086
2024	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	002	3	11/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,934,622
2024	2022	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Aging Research	001	2	11/15/2023	NON-COMPETING CONTINUATION	-$1,197,499
2024	2021	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Aging Research	000	1	11/15/2023	NEW	-$737,123
														Subtotal = $1,739,209

Issue Date FY: 2023 ( Subtotal = $1,558,434 )
2023	2023	REGENTS OF THE UNIVERSITY OF MICHIGAN	1109 GEDDES AVE, SUITE 3300	ANN ARBOR	MI	48109	WASHTENAW	USA	Aging Research	001	3	7/20/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1,558,434
2023	2022	JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Aging Research	000	2	7/17/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,558,434

Issue Date FY: 2022 ( Subtotal = $1,197,499 )
2022	2022	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Aging Research	000	2	5/27/2022	NON-COMPETING CONTINUATION	$1,197,499
														Subtotal = $1,197,499

Issue Date FY: 2021 ( Subtotal = $1,281,085 )
2021	2021	THE JACKSON LABORATORY	600 MAIN ST	BAR HARBOR	ME	04609	HANCOCK	USA	Aging Research	000	1	9/21/2021	NEW	$1,281,085
														Subtotal = $1,281,085

Grand Total All Awards = $5,776,227

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Cell Type-Specific Proteins that Promote Resilience to Cognitive Aging and Alzheimer's Disease

Award Number: R01AG075818

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/30/2021

PERIOD OF PERFORMANCE END DATE: 04/18/2025

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