Thursday, March 5, 2026 3/5/2026

Mechanism of white matter pathology in Alzheimer's disease

Award Number: R01AG076051
ORGANIZATION: NATIONAL INSTITUTE ON AGING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2022
PERIOD OF PERFORMANCE END DATE: 11/30/2026

Group Awards By:

View Award Description

Mechanism of white matter pathology in Alzheimer's disease - PROJECT SUMMARY Myelin degeneration and white matter loss that result from oligodendrocyte (OL) death are early events in Alzheimer’s disease (AD) that lead to cognitive deficits and correlate with disease status. The loss of OLs, accompanied by a reduction of myelin density, axonal loss, and astrogliosis, are major changes in white matter that occur in the brains in both AD patients and animal models of AD. OLs are the most abundant glial cell type in the brain but the least studied cell population in the context of neurodegeneration, despite their vital role in myelin maintenance and neuronal support. Recent genome-wide association studies and large-scale single- cell transcriptomics of AD patient brains emphasized the crucial role of OLs in the development of AD. The underlying mechanisms of OL dysfunction and its contribution to the initiation and progression of AD remain unknown. Our recent work reports, for the first time, that mature OLs in AD patients and AD mice exhibit NLRP3 inflammasome-associated inflammatory injury, concomitant with demyelination and axonal degeneration. Unbiased proteomic analysis further suggests that the hexokinase 1 (HK1)-dependent glycolysis pathway is most suppressed in AD mouse white matter. Mature OLs rely heavily on glycolysis for energy production, even in the presence of oxygen. HK is the rate-limiting enzyme that initiates the first step of glycolysis by the phosphorylation of glucose. OLs specifically express a brain HK isoform, HK1. HK1 localizes to the mitochondrial outer membrane, and the dissociation of HK1 from mitochondria decreases its enzymatic activity, which is sufficient to inhibit glycolysis and induce NLRP3 inflammasome activation. We found that HK1 immunodensity and enzyme activity significantly decreased in OLs in AD patients and AD mice. In mature OLs in AD, the HK1 mitochondrial association is disrupted by overactivation of the mitochondrial fission protein dynamin-related protein 1 (Drp1), and Drp1 and HK1 synergistically elicit NLRP3 inflammasome activation and the release of interleukin-1β, triggering inflammation. The mature OL-specific heterozygous knockout of Drp1 in AD mice restores HK1-dependent glycolysis, abolishes NLRP3 inflammasome activation, corrects myelin loss, reduces neuroinflammation and axonal degeneration, and improves cognitive function in animals. These findings support the scientific premise of the proposed project that glycolytic deficiency in OLs, driven by the Drp1-HK1 molecular switch, induces OL metabolic dysregulation and inflammation and causes white matter degeneration, AD pathology, and cognitive impairment. Successful completion of the proposed studies will support the hypothesis that OL metabolic deficiency is a key pathological process that induces inflammation, demyelination, white matter loss, and AD-associated neuropathology and cognitive deficits. These studies are crucial to further reveal the role of the novel Drp1-HK1 OL pathway in AD and determine whether this pathological pathway is a plausible treatment target 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: 2026 ( Subtotal = $607,498 )
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	000	5	12/26/2025	NON-COMPETING CONTINUATION	$546,748
2026	2026	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	001	5	2/23/2026	NON-COMPETING CONTINUATION	$60,750
														Subtotal = $607,498

Issue Date FY: 2025 ( Subtotal = $595,347 )
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	000	4	11/28/2024	NON-COMPETING CONTINUATION	$546,748
2025	2025	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	001	4	8/11/2025	NON-COMPETING CONTINUATION	$48,599
														Subtotal = $595,347

Issue Date FY: 2024 ( Subtotal = $607,498 )
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	001	3	5/2/2024	NON-COMPETING CONTINUATION	$60,750
2024	2024	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	000	3	11/3/2023	NON-COMPETING CONTINUATION	$546,748
														Subtotal = $607,498

Issue Date FY: 2023 ( Subtotal = $607,498 )
2023	2023	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	000	2	1/5/2023	NON-COMPETING CONTINUATION	$607,498
														Subtotal = $607,498

Issue Date FY: 2022 ( Subtotal = $607,498 )
2022	2022	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Aging Research	000	1	1/20/2022	NEW	$607,498
														Subtotal = $607,498

Grand Total All Awards = $3,025,339

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mechanism of white matter pathology in Alzheimer's disease

Award Number: R01AG076051

ORGANIZATION: NATIONAL INSTITUTE ON AGING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2022

PERIOD OF PERFORMANCE END DATE: 11/30/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer