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Reprogramming myeloid cell metabolism to prevent cognitive aging and Alzheimer's Disease

Award Number: R01AG070839
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Reprogramming myeloid cell metabolism to prevent cognitive aging and Alzheimer's Disease - REPROGRAMMING MYELOID CELL METABOLISM TO PREVENT COGNITIVE AGING AND ALZHEIMER’S DISEASE SUMMARY The brain is highly vulnerable to aging, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer’s disease (AD). Human genome-wide association studies demonstrate a dominant role for dysfunctional myeloid cells, which include brain microglia as well as peripheral monocytes/macrophages (Mo/Mph), in increasing risk of AD. Microglia lose their normal capacities to maintain immune homeostasis within the brain, provide trophic support to neurons, and clear misfolded proteins. Circulating factors in aged plasma influence microglial activation and are linked to age-associated cognitive decline. These observations point to a causal role of brain and/or systemic myeloid dysfunction in development of cognitive decline in aging and AD. In our recent studies, we have identified an important role for cellular bioenergetics in regulating immune responses in aging macrophages and microglia. Maintenance of homeostatic and healthy immune function requires robust glycolytic and mitochondrial metabolism to meet demand for energy and biosynthetic precursors. Indeed, our recent studies demonstrate that glycolysis and mitochondrial respiration are significantly suppressed in aging microglia and Mo/Mph, leading to an energy deficient state that promotes maladaptive pro-inflammatory responses and decreased phagocytic potential. In this proposal we will test whether reprogramming cellular metabolism in aging microglia and/or peripheral Mo/Mph by modulating a major inflammatory pathway, the PGE2 signaling pathway, is disease-modifying in aging and in AD model mice. There is a growing literature on how cellular metabolism regulates immune cell function, particularly in the areas of infection and cancer. This conceptual framework has not yet been applied to aging, nor has it been applied to cognitive aging and age- associated neurodegenerative diseases like AD. Our approach proposed here will answer several fundamental questions including: (1) whether myeloid metabolic deficits drive brain aging, (2) whether peripheral or brain myeloid compartments are critical in this process, and (3) whether targeting myeloid metabolism represents a new therapeutic approach for 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: 2025 ( Subtotal = $602,463 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	000	3	3/7/2025	NON-COMPETING CONTINUATION	$553,282
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	001	3	6/9/2025	NON-COMPETING CONTINUATION	$49,181
														Subtotal = $602,463

Issue Date FY: 2024 ( Subtotal = $614,780 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	000	2	3/6/2024	EXTENSION WITH OR WITHOUT FUNDS	$564,276
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	001	2	8/1/2024	EXTENSION WITH OR WITHOUT FUNDS	$50,482
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Aging Research	002	2	8/12/2024	EXTENSION WITH OR WITHOUT FUNDS	$22
														Subtotal = $614,780

Grand Total All Awards = $1,217,243

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Reprogramming myeloid cell metabolism to prevent cognitive aging and Alzheimer's Disease

Award Number: R01AG070839

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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