Wednesday, October 22, 2025 10/22/2025

Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients

Award Number: RF1AG056306
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2017
PERIOD OF PERFORMANCE END DATE: 08/31/2027

Group Awards By:

View Award Description

Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients - SUMMARY Alzheimer’s disease (AD) affects over 50 million people worldwide. The vast majority of patients, AD develops sporadically in the absence of any known etiology other than advanced age. Despite the fact that AD has been studied for over a century, its pathogenesis is still not completely understood, and drugs that could stop or reverse the disease progression are not yet available. Similar to the age-dependent incidence of many cancers, AD onset is believed to be caused by multiple hits of environmental, genomic, and aging-related factors. To better understand the cellular and molecular interactions between human aging and AD pathogenesis, induced neurons (iNs) directly converted from AD patient fibroblasts offer unique possibilities to model and study the disease in a human age-equivalent neuronal model. The teams around Dr. Gage and Dr. Mertens have recently shown that direct conversion of human AD patient-derived fibroblasts into induced neurons (iNs) preserves signatures of cell aging and sporadic AD and allows for the detection of cellular pathologies and disease drivers. Neuronal hypo-maturity represents a fundamental AD-related cellular state in iNs, and the cancer-associated Pyruvate Kinase M2 (PKM2) splice variant emerged as a key player that compromises mature neuronal metabolism and neuronal identity. PKM2 promotes neuronal vulnerability and de-differentiation via metabolic changes in the cytoplasm, and via epigenetic processes in the nucleus, but the relative contribution of the two mechanisms remains elusive and might differ substantially between cancer cells and post-mitotic neurons. To understand PKM2 in AD, and to develop PKM-directed therapeutics, more knowledge regarding (1) the relationship between neuronal PKM2 and hallmarks of AD in the human brain, (2) the fundamental cell biological functions of PKM2 in aged human neurons, and (3) the crosstalk between PKM-compromised neurons and their glial environment is needed. This project will challenge the importance of shared pathogenic pathways between cancer and AD, and assess age-dependently compromised neurons in the context of AD. First, the team will study the relationship between cancer-related PKM2-positive neurons and AD pathology in the post-mortem human brain. Second, the mechanistic impact of PKM2 imbalance on the metabolic state and neuronal fate stability of patient-specific iNs will be assessed by transgene- and genome editing-based approaches. Third, pharmacological compounds from the cancer field as a basis for developing PKM2-targeted therapeutics for AD will be leveraged. Fourth, using a novel human iN-based three-dimensional multicellular model, the team will study neuron-astrocyte coupling in the context of metabolically challenged iNs and their metabolic crosstalk with human astrocytes. The ultimate goals of these four aims are to gain insight into the roles of the well- established cancer protein PKM2 in age-related neurodegeneration and to exploit this knowledge to develop therapeutic strategies against 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 = $1,009,134 )
2025	2025	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	7	9/18/2025	EXTENSION WITH OR WITHOUT FUNDS	$1,009,134
														Subtotal = $1,009,134

Issue Date FY: 2024 ( Subtotal = $375,805 )
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	001	6	8/22/2024	SUPPLEMENT FOR EXPANSION	$266,000
2024	2024	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	6	8/7/2024	SUPPLEMENT FOR EXPANSION	$109,805
2024	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	002	6	8/29/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $375,805

Issue Date FY: 2023 ( Subtotal = $212,663 )
2023	2023	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	6	8/14/2023	SUPPLEMENT FOR EXPANSION	$212,663
														Subtotal = $212,663

Issue Date FY: 2022 ( Subtotal = $1,169,591 )
2022	2022	SALK INSTITUTE FOR BIOLOGICAL STUDIES, SAN DIEGO, CALIFORNIA, THE	10010 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Aging Research	000	6	8/19/2022	COMPETING CONTINUATION	$1,169,591
														Subtotal = $1,169,591

Grand Total All Awards = $2,767,193

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Assessing cellular aging in old and rejuvenated neurons from Alzheimer patients

Award Number: RF1AG056306

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2017

PERIOD OF PERFORMANCE END DATE: 08/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer