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Defining roles of genetic and age in extracellular elimination of neurotoxic aggregates

Award Number: R37AG056510
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2017
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Defining roles of genetic and age in extracellular elimination of neurotoxic aggregates - Summary Alzheimer’s disease is ravaging the world’s elderly population and creating a heath and societal burden that appears likely to increase. Basic research can inform on mechanisms relevant to late onset neurodegenerative disease and suggest avenues of treatment. Healthy aging of the brain requires meticulous maintenance of protein synthesis/folding/degradation systems, and this capacity is often disrupted in neurodegenerative disease. Recently it has come to be appreciated that disease neurons can produce toxic products like aggregated proteins that can be taken up by neighboring cells—there is speculation that this mechanism might be involved in disease spread within the brain. How neurons generate and send out large-sized extracellular material in vivo is an open question that must be addressed as we consider therapeutic intervention. We study the aging nervous system in the simple animal model C. elegans, in which individual neurons, as well as labeled aggregates within them, can easily be visualized in the living animal. We have unexpectedly discovered that some C. elegans neurons can exude large packets we call “exophers”. The contents of these dramatically expelled exophers can contain introduced human disease protein aggregates. Multiple approaches to exaggerating protein folding stresses in those neurons, including over-expressing human Alzheimer’s disease associated fragment A 1-42, and genetically or pharmacologically impairing branches of protein homeostasis, increase exopher formation. Aggregated proteins extruded in exophers can be taken up by distant cells. We hypothesize that we have identified a previously unrecognized alternative route for adult neurons to clear protein aggregates. We speculate that this mechanism, and the associated mechanism of release and uptake by surrounding cells, is conserved across species and related to currently unknown mechanisms operating in human brain relevant to neurodegenerative disease. We propose to exploit the considerable advantages of the C. elegans model system (transparent body, easy genetic manipulation, exquisitely defined nervous system, powerful cell biology, short lifespan) to advance understanding of exopher biology. Our goals are to: 1) probe the biology of old age exophers (induction, functionality, and longevity gene interface); 2) screen human neurodegenerative disease-related genes for roles in C. elegans exopher formation; 3) begin to decipher the mechanism whereby AIP-1, needed for exopher production and known to protect against broad proteotoxicity, influences exopher-genesis under proteo-stress. Our work should inform on a novel pathway of cell maintenance relevant to both healthy brain aging and a neurodegenerative disease, defining a new area for study and for development of clinical interventions.


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 = $526,379 )
2025	2025	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	9	4/11/2025	NON-COMPETING CONTINUATION	$483,409
2025	2025	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	001	9	6/18/2025	NON-COMPETING CONTINUATION	$42,970
														Subtotal = $526,379

Issue Date FY: 2024 ( Subtotal = $575,030 )
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	001	8	3/21/2024	SUPPLEMENT FOR EXPANSION	$34,118
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	002	8	7/1/2024	NON-COMPETING CONTINUATION	$53,713
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	8	3/19/2024	NON-COMPETING CONTINUATION	$483,409
2024	2024	RUTGERS, THE STATE UNIVERSITY	3 RUTGERS PLZ	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	003	8	7/2/2024	SUPPLEMENT FOR EXPANSION	$3,790
														Subtotal = $575,030

Issue Date FY: 2023 ( Subtotal = $688,753 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	7	4/5/2023	NON-COMPETING CONTINUATION	$537,122
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	001	7	4/15/2023	SUPPLEMENT FOR EXPANSION	$151,631
														Subtotal = $688,753

Issue Date FY: 2022 ( Subtotal = $650,845 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	6	3/25/2022	EXTENSION WITH OR WITHOUT FUNDS	$537,122
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	001	6	6/24/2022	SUPPLEMENT FOR EXPANSION	$113,723
2022	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	002	5	9/16/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $650,845

Issue Date FY: 2021 ( Subtotal = $461,980 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	5	3/31/2021	NON-COMPETING CONTINUATION	$461,980
														Subtotal = $461,980

Issue Date FY: 2020 ( Subtotal = $461,980 )
2020	2020	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	4	4/2/2020	NON-COMPETING CONTINUATION	$461,980
														Subtotal = $461,980

Issue Date FY: 2019 ( Subtotal = $461,980 )
2019	2019	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	3	4/1/2019	NON-COMPETING CONTINUATION	$461,980
														Subtotal = $461,980

Issue Date FY: 2018 ( Subtotal = $461,980 )
2018	2018	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	2	4/14/2018	NON-COMPETING CONTINUATION	$461,980
														Subtotal = $461,980

Issue Date FY: 2017 ( Subtotal = $458,880 )
2017	2017	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	3 RUTGERS PLZA	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Aging Research	000	1	7/28/2017	NEW	$458,880
														Subtotal = $458,880

Grand Total All Awards = $4,747,807

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Defining roles of genetic and age in extracellular elimination of neurotoxic aggregates

Award Number: R37AG056510

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2017

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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