R01AG074489

Peroxynitrite is a molecular determinant of impaired microvascular energetics in Alzheimer's disease - Summary

Brain microvessels (BMVs) play an important role in the neurovascular coupling (NVC). Mitochondria are energy sensors of cells, and impaired mitochondrial respiratory function initiates critical signaling detrimental to NVC, leading to impaired cognitive function associated with Alzheimer's disease (AD).

Our recent technological breakthrough, utilizing Agilent Seahorse XFe extracellular flux analyzer, developed a mitochondrial respiration assay in BMVs. Using this novel method, we observed age-dependent impairment of mitochondrial respiration and bioenergetics in BMVs from male and female C57BL/6 mice. Notably, we found that BMVs from the APP NL-G-F knock-in model of AD display impaired mitochondrial respiration and accelerated senescence.

Furthermore, we observed that young and aged female mice display sex-dependent differences in microvascular energetics related to the relative contribution of oxidative phosphorylation and glycolysis to overall energy production. Finally, we found that peroxynitrite scavenger (FETMPYP) treatment enhanced non-mitochondrial respiration in young female mice but enhanced proton leak in young male mice, indicating that the differential peroxynitrite activity is sex-dependent.

Therefore, we hypothesize that peroxynitrite differentially regulates microvascular mitochondrial function sex-dependently and is the molecular determinant of exaggerated age-related impairment of NVC and cognitive function in AD. We will employ male and female AD and C57BL/6 mice of 8 months and 20 months age.

Aim 1 will determine the sex-dependent differential impact of peroxynitrite on the bioenergetics and enzyme activities (Krebs cycle, glycolysis, and antioxidants) in BMVs ex vivo. Aim 2 will determine the sex-dependent differential impact of peroxynitrite on in vivo NVC responses to whisker deflections by two-photon excitation microscopy in awake mice. Aim 3 will determine the sex-dependent differential impact of FETMPYP on cognitive function by assessing whisker-dependent perceptual learning using the novel texture discrimination task.

The results of this proposal would challenge the existing dogma and will demonstrate the sex-specific physiological role of peroxynitrite in regulating the microvascular bioenergetics and neurovascular unit. Furthermore, our results will firmly establish microvascular peroxynitrite as a potential therapeutic target in sex-dependent vulnerability and severity of AD and other neurodegenerative diseases.

The Administrators Of Tulane Educational Fund

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]

New Orleans, Louisiana 701122632 United States

Single Zip Code

Research on Current Topics in Alzheimer's Disease and Its Related Dementias (R01 Clinical Trial Optional) (PAR-19-070)

Amendment Since initial award the total obligations have increased 394% from $638,400 to $3,155,638.