U01AG088683

Leveraging novel mouse models to investigate toxic metal exposures on brain aging and Alzheimer's disease.

Alzheimer’s disease (AD) and AD-related dementias (ADRDs) are leading causes of cognitive decline and major contributors to morbidity, mortality, and healthcare costs.

Cardinal hallmarks of AD brain pathology include amyloid-β (Aβ) plaques, neurofibrillary tangles (hyperphosphorylated tau), neurodegeneration, cerebrovascular pathology, and neuroinflammation.

AD risk is modulated by interaction of genetics (e.g., APOE-ε4 allele) and environmental factors, including high-fat diet, sedentary lifestyle, and exposures to environmental toxicants (exposome).

Despite strong evidence for the role of environmental factors in AD/ADRD risk, the specific mechanisms driving the underlying biology remain elusive.

A major reason for this knowledge gap is the absence of resource-based studies to identify age-, sex-, and toxicant-dependent molecular processes that modulate AD/ADRD pathobiology.

This U01 preclinical project addresses this gap responsive to NIA exposome initiatives (RFA-AG-24-023) by leveraging a multidisciplinary collaborative team led by MPIs Lee Goldstein, MD, PhD (Boston University Alzheimer’s Disease Research Center, BU-ADRC), Gareth Howell, PhD (The Jackson Laboratory, JAX; MODEL-AD), Paul Territo, PhD (Indiana University, IU; MODEL-AD, TREAT-AD).

Collectively, our team brings broad expertise and decades of experience in AD/ADRD research and resource generation using advanced AD/ADRD mouse models to investigate brain health, AD pathobiology, gene by exposome (GxE) interactions, and biometallomics.

The project team includes: Dr. Greg Carter, PhD (JAX, MODEL-AD, TREAT-AD, MARMO-AD), David Aylor, PhD (North Carolina State University, NIEHS-TARGET), and Greg Crawford, PhD (Duke, TARGET).

This U01 project will generate resources to identify mechanisms by which AD-relevant genetic factors interact with exposures to ubiquitous neurotoxic metals/metalloid (lead, Pb; cadmium, Cd; arsenic, As) to modulate AD/ADRDs pathobiology.

We will expose male and female mice carrying humanized genetic risk factors (hAβ, hMAPT; APOE4 or APOE3; MODEL-AD) to Pb, Cd, or As in drinking water at human toxicant-relevant doses during two clinically-relevant exposure windows: (prenatal-early adult, developing brain; early adult-aged, mature brain).

Exposed mice and non-exposed controls will be assessed across the lifespan using an enhanced MODEL-AD phenotyping pipeline (behavior/cognition, PET/CT, BBB integrity, metallomic imaging MS brain mapping, multi-omics, epigenomics, neuropathology, blood-based biomarkers) following a combined longitudinal/cross-sectional study design.

Data will be integrated, aligned to human data resources, and made available to the scientific community via the AD Knowledge Portal (Sage Bionetworks).

Molecular processes predicted to drive toxicant/exposure-dependent effects relevant to AD/ADRD risk will be validated using JAX, MODEL-AD, BU-ADRC resources.

Strong links with MODEL-AD, AMP-AD, TREAT-AD, NIEHS-TARGET, ADRCs, and a network of interactions with other research teams (via companion RFAs) position our team to serve as a pivotal resource to address AD/ADRD risks posed by modifiable environmental exposures.

Trustees Of Boston 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]

Boston, Massachusetts 021182646 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 95% from $2,122,961 to $4,141,255.