The etiology and pathogenesis of Alzheimer’s disease (AD) are multifactorial including genetic, environmental and age-related factors that together drive neurodegeneration and cognitive and behavioral declines. Abnormal molecular mechanisms impacted by chronic manganese (Mn) overexposure have been associated with neurodegeneration and may directly contribute to and/or accelerate AD pathology and clinical dementia. Global profiling studies using state-of-the-art analysis tools will be used to define mechanisms of exposure-induced excitotoxity properties and to explore opportunities for intervention on altered pathways related to cognitive function and neuropathological change in cortex and striatum brain tissue. The primary goal of this project is to understand at the molecular level (metabolites and lipids) the biochemical mechanisms between chronic manganese exposure and AD neuropathology. Our focus is dysregulation of glutamatergic and dopaminergic neurotransmitter systems but the targeted and non-targeted approaches will identify multiple novel and targetable pathways. This knowledge will be used to determine which mechanisms may potentially be manipulated by nutrition or pharmacological interventions in order to slow cognitive decline. Our data will also identify changes that may relate more strongly to cognitive decline than the classical hallmark features of AD (β-Amyloid and neurofibrillary tangles). Our overarching hypothesis is that if key AD-relevant metabolic pathways are responsive to external exposures then they are malleable and targeting these pathways may provide new avenues to slow AD onset or progression in the brain. In the first of two independent Specific Aims we will identify metabolomic and lipidomic changes indicative of neuropathological and behavioral change in APP/PSEN1 mice exposed to low or high Mn through diet. We will use cortex and striatum (tissues available through R01 ES031401) to understand changes in two areas known to accumulate Mn, that are associated with different aspects of behavioral change. State-of-the-art chemical determination of metabolite and lipid profiles will be used to identify which pathways are most impacted by manganese exposure, and determine if there are differences in tissue type (striatum and cortex). Through Specific Aim 2 we will determine which members of the glutamate metabolism pathway are dysregulated by chronic Mn exposure via targeted LC- MS/MS analyses on the same tissues utilized in Aim 1. Specifically, these studies will allow us to determine which specific members of the canonical glutamate metabolism pathway, as well as redox homeostasis, the tricarboxylic (TCA) cycle and the alanine, and aspartate pathways are up- or down-regulated in response to chronic Mn exposure to further our understanding of Mn-induced excitotoxicity in AD and normal aging brains. All findings will be correlated with behavioral, neuropathological and biochemical data generated through the parent R01 t...