U01AG088557

Pre3BAD: Preclinical research on emerging environmental exposures, brain aging, and dementia - Environmental stressors may promote and/or accelerate neurodegenerative diseases.

The US population has been progressively aging, resulting in prolonged duration of environmental toxicant exposures and a potential for increased vulnerability to new environmental insults.

Consequently, there is a growing population at risk for Alzheimer’s disease (AD) and AD-related dementias (ADRDs).

Our appreciation of the effect of various pollutants, including wildfire smoke, microplastics, and heavy metals, on neurological conditions is still evolving.

Compelling new evidence shows that PM, and specifically wood smoke, can induce neuroinflammation and blood-brain barrier (BBB) deficits and also alter the brain metabolic profile and contribute to behavioral impairment, the effects of which are more persistent in advanced aging.

While limited research exists on microplastics and neurological outcomes, we have shown that orally delivered microplastics can accumulate in the brain and promote metabolomic changes, while another study suggests that micro- and nano-plastics may cross the BBB and induce mis-folding of proteins relevant to amyloidosis.

Lastly, numerous transition and heavy metals in our diet have been associated with neurodegenerative outcomes, including manganese, cadmium, lead, and copper.

We propose that early-life exposures are largely recoverable compared to later-life exposures and, furthermore, that intermittency of exposures circumvents adaptation mechanisms and promotes a sustained negative impact on ADRD-related phenotypes.

In Aim 1, we will assess the neuropathological impacts of emerging environmental contaminants across disparate temporal patterns in complementary mouse models of AD/ADRD.

Using established regimens of A) wildfire smoke, B) microplastics, and C) mixed heavy metals, we will expose WT (C57BL/6J) and APPNL-F and MAPT KI mouse model of amyloidosis and tauopathy to contrast ADRD resistant and vulnerable phenotypes.

Exposure designs will include I) early life, II) late-life, III) intermittent, and IV) continuous lifespan exposures.

Thorough molecular and histopathological assessment will be conducted at 18- and 24-mo of age to reflect early and late stages of AD/ADRD pathogenesis.

In Aim 2, we will comprehensively delineate multi-omic pathways perturbed by environmental exposures that augment AD/ADRD outcomes.

Multi-omic characterization will include metabolomic, lipidomic, proteomic, transcriptomic, high-dimensional flow cytometry, and epigenetic assessments, with computational integration to identify key pathway perturbations.

We identify those pathways activated or inhibited by environmental exposures and further refine the assessments to ascertain novel environmentally perturbed pathways that exacerbate AD/ADRD phenotypes and may help resolve uncertainty in AD/ADRD risk prediction.

This comprehensive preclinical program brings together major scientific resources from the University of New Mexico’s Brain and Behavioral Health Institute and the Center for Metals in Biology and Medicine, along with key collaborations from Arizona State and Texas Tech universities.

University Of New Mexico

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]

Albuquerque, New Mexico 871310001 United States

Single Zip Code

Preclinical Studies to Characterize the Impact of Toxicants on Brain Aging and Alzheimer's Disease (AD) and AD-Related Dementias (ADRD) (U01 Clinical Trial Not Allowed) (RFA-AG-24-023)

Amendment Since initial award the total obligations have increased 97% from $1,962,632 to $3,859,319.