Modeling effects of cadmium exposure on Alzheimer’s Disease pathology and neurodegeneration - Project Summary/Abstract Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the pathological accumulation of the tau protein and amyloid beta (Aβ) peptide. Tau pathology is also present in several other neurodegenerative disorders known as tauopathies. Most cases of these disorders have no clear genetic cause and the disease etiology remains poorly understood. There is growing interest in identifying how exposure to toxic elements in the environment, including heavy metals like cadmium, might help initiate and promote progression of these diseases. The typical human exposure route for cadmium occurs through eating contaminated food or smoking and up to 20% of Americans have elevated levels beyond what is considered safe. Increased cadmium levels are associated with increased risk of AD, lower levels of cognition, and increased levels of AD biomarkers. Multiple studies in transgenic amyloid models identified decreased cognitive performance and increased Aβ pathology. However, no studies to date have tested the effects of cadmium exposure on tau protein. Investigators hypothesize that Cd exposure promotes progression of disease pathologies and will enhance neurotoxicity through synergistic pathogenesis. This multi-PI application takes advantage of the relative strengths of the C. elegans nematode model organism and multiple transgenic rodent models of disease to answer specific questions about these interactions through three specific aims. Aim 1 is designed to identify mechanisms by which cadmium exposure alters Aβ and tau-induced neurodegeneration in worms. Novel worm strains expressing tau and Aβ in cholinergic neurons through inducible promoters will be used as controllable models to measure cadmium’s effect on cognition, pathology development, and neurodegeneration and determine the individual contributions of tau and Aβ. Aim 2 uses two different mouse lines to model the complex system of human non-AD tauopathy. The PS19 line expresses a mutant form of tau that aggressively develops tau pathology and neurodegeneration while the MAPT KI line is a human tau knock-in that is phenotypically normal. Orally treating these mice with cadmium will test how exposure affects tau pathology and neurodegeneration progression in a developing familial tauopathy and the ability to induce a sporadic tauopathy. Aim 3 uses the TgF344-AD rats that have mutations in APP and PS1 to model Aβ and late-stage tau pathology of AD. We will repeat the experimental paradigm from Aim 2 to determine cadmium’s effects in the presence of both Aβ and tau. Through these experiments it will identified how environmental exposure to cadmium, a neurotoxic heavy metal, alters tau pathology and tau-induced neurodegeneration for the first time. This will further our understanding of interactions between toxic environmental exposures and the etiology of AD and tauopathies as well as the underlying mechanisms of disease progression and neurodegeneration which is critical for developing effective therapeutics to counteract them.
