Impact of toxic metal exposures in novel genetic mouse models of late-onset alzheimer's disease - late-onset alzheimer's disease (load) is the leading cause of dementia and a major contributor to…

Impact of toxic metal exposures in novel genetic mouse models of late-onset alzheimer's disease - late-onset alzheimer's disease (load) is the leading cause of dementia and a major contributor to morbidity, mortality, and healthcare costs. Cardinal hallmarks of load brain pathology include age-related accumulation of amyloid-SS (ASS) plaques and neurofibrillary tangles (hyperphosphorylated TAU protein). Genetic susceptibility factors (e.g., APOE4) contribute to load pathology and phenotype but account for only 30-70% of load risk. Research indicates that load complexity and heterogeneity, as well as individual risk and health outcomes, are modulated by interactions between genetics and environmental factors such as high-FAT diet, sedentary behavior, and life exposure ("exposome") to environmental toxicants, including lead (PB), cadmium (CD), and arsenic (as). PB, CD, and as exposure is common, especially in disadvantaged populations (urban, rural), raising concern about load risk disparities, socioeconomic/racial inequities, and environmental justice. While PB, CD, and as are neurotoxins with known load association, the molecular mechanisms by which these environmental toxicants mediate gene-exposome interactions and modulate load pathobiology are unknown and potentially modifiable. This project will use innovative new mouse models created by the NIA-funded model-ad consortium (model-ad, U54-AG054345) with human-relevant phenotyping to investigate how chronic exposure to three ubiquitous environmental neurotoxicants (PB, CD, as) affect brain aging and load risk. This project is responsive to a new NIA initiative ("precision environmental health approach to ad/adrd treatment and risk prevention") to support preclinical research targeting mechanisms that mediate gene-environmental toxicant exposure effects ("exposome") on ad/adrd pathogenesis and leverages NIA-funded ad/adrd resources (boston university adrc, P30-AG072978; center for biometallomics; model-ad mouse models, systems biology analytics, jackson laboratory). We will test our hypothesis that chronic exposure to PB, CD, or as in drinking water: (i) induces accumulation of toxic metal/metalloid in brain, (II) modulates load-relevant pathologies/phenotypes (ATN: ASS, TAU proteinopathy, neurodegeneration, cognitive deficits; blood-brain barrier, microvascular dysfunction, neuroinflammation, brain biometal (CU, ZN, FE) dyshomeostasis); and (III) interacts with polygenic variants relevant to load. In aim 1, we will investigate effects of early-/mid-life exposures PB, CD, as on ad/adrd pathologies, phenotypes, and biomarkers in the new innovative LOAD3 mouse model (triple homozygous for humanized ASS (hass), mapt (htau), HAPOE4). In aim 2, we will identify load-relevant genes, proteomic networks, and molecular pathways modulated by PB, CD, as exposures (per aim 1). In aim 3, we investigate specific load genetic risk factors, (variants in ABCA7, PLCG2, mthfr) that data suggest will differentially interact with toxicant metabolism to modulate load risk. Results will identify mechanisms by which common metal/metalloid neurotoxicant exposures increase risk for ad/adrds and prioritize novel strategies for risk reduction, disease prevention, toxicant mitigation, and therapeutic intervention for load and adrds.