R01AG076051

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 of 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.

Case Western Reserve University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Cleveland, Ohio 44106 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 398% from $607,498 to $3,025,339.