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Advanced glycation endproducts (AGEs) as metabolic by-products that mediate neurodegeneration.

Award Number: R01AG061165
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/15/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Advanced glycation endproducts (AGEs) as metabolic by-products that mediate neurodegeneration. - PROJECT SUMMARY/ ABSTRACT Aging and chronic hyperglycemia results in several metabolic and biochemical perturbations including elevation of a series of highly reactive α-dicarbonyl compounds (α-DCs, e.g., Methylglyoxal(MGO). α-DCs are unavoidable byproducts largely of anaerobic glycolysis which react indiscriminately with proteins, lipids, and DNA to yield a heterogeneous group of molecules called advanced glycation end products (AGEs). A large body of evidence has linked accelerated glucose metabolism and diabetes to neurodegenerative diseases like Alzheimer's disease (AD). We hypothesize that toxic byproducts of glucose metabolism that result in the formation of AGEs explain the enhanced risk of AD due to hyperglycemia and diabetes. In support of this AGEs in serum and AGE crosslinking in protein aggregates have been associated with enhanced neurodegeneration in AD. However, AGEs are hard to model as they take years to accumulate in humans and the mechanism by which they cause cellular damage remains to be elucidated. To overcome this gap, we have established C. elegans (worm) models that significantly accumulate α-DCs and AGEs, exhibiting several age- related pathologies, such as hypersensitivity to touch, neuronal damage, paralysis, and early mortality, all within three weeks of adulthood. In addition, we have observed that direct administration of synthetic methylglyoxal derived AGEs can directly cause neurotoxicity. Furthermore, we have observed that a C. elegans model overexpressing the pro-aggregating form of tau, that has been implicated in Alzheimer's disease, is sensitive to feeding either glucose or AGEs in the diet. In this proposal, we will test the hypothesis that changes in glucose and lipid metabolism pathways, especially with age, influence MGO and associated AGEs thereby causing neurodegeneration associated with AD. We will also determine the mechanisms by which AGEs influence metabolic dysfunction and contribute to neurodegeneration in AD. In Aim 1 we will explore a causal role for the effects of AGEs on neurodegeneration in normal aging and in Alzheimer's disease models using synthetically derived AGEs. We will also examine the role of age-associated changes in glucose metabolism in influencing the levels of MGO and AGEs and enhancing neurodegeneration in models of AD. In Aim 2 we will determine the relationship between lipid metabolism and production of AGEs. We will genetically and pharmacologically manipulate fatty acid oxidation pathways to examine their influence on modulating neurodegeneration in normal aging and AD models through modulation of AGEs. In Aim 3 we propose to identify the mechanisms by which AGEs mediate their toxicity leading to inhibition of fatty acid oxidation and neurodegeneration. We will identify AGE-binding proteins and therapeutic targets to modulate AGE-related neurodegeneration. These studies will identify several genetic and pharmacological targets to ameliorate AGEs and slow down the progression of neurodegeneration in AD.


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	2023	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	5	12/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $646,911 )
2023	2023	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	5	5/10/2023	NON-COMPETING CONTINUATION	$646,911
														Subtotal = $646,911

Issue Date FY: 2022 ( Subtotal = $646,911 )
2022	2022	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	4	5/19/2022	NON-COMPETING CONTINUATION	$646,911
														Subtotal = $646,911

Issue Date FY: 2021 ( Subtotal = $646,911 )
2021	2021	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	3	6/3/2021	NON-COMPETING CONTINUATION	$646,911
														Subtotal = $646,911

Issue Date FY: 2020 ( Subtotal = $646,911 )
2020	2020	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	2	7/9/2020	NON-COMPETING CONTINUATION	$646,911
														Subtotal = $646,911

Issue Date FY: 2019 ( Subtotal = $670,411 )
2019	2019	BUCK INSTITUTE FOR RESEARCH ON AGING	8001 REDWOOD BLVD	NOVATO	CA	94945	MARIN	USA	Aging Research	000	1	9/12/2019	NEW	$670,411
														Subtotal = $670,411

Grand Total All Awards = $3,258,055

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Advanced glycation endproducts (AGEs) as metabolic by-products that mediate neurodegeneration.

Award Number: R01AG061165

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/15/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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