PROJECT SUMMARY/ABSTRACT There is ample scientific evidence that toxic oligomers of A and tau, considered the major neuropathological factors in Alzheimer’s disease (AD) lead to synaptic failure and dementia, but is also well recognized that some individuals can accumulate significant AD neuropathology without clinical manifestations. The established existence of these non-demented with high pathology (NDAN) individuals, suggests that if binding of A oligomers to specific AMPA and NMDA receptors trigger Ca2+ disruption and synaptic failure in AD, then modifications in the pharmacology or abundance of these receptors may underlie synaptic protection in NDAN individuals. However, little is known about the pharmacological sensitivity of human native glutamate receptors to A and tau oligomers in AD, or their role in resilience, as information primarily has come from studies in animal models of AD or protein expression systems. Here we will fill in this critical gap of our current knowledge by identifying the synaptic proteins involved in glutamatergic signaling and Ca2+ dysregulation in AD, evaluating whether modifications of these proteins correlate with metrics of synaptic preservation in NDAN individuals, and determining whether A and tau oligomers differentially activate human native synaptic receptors in NDAN individuals compared to those in AD and controls. The present proposal will test the hypothesis that differences in the regional abundance of Ca2+-permeable glutamate receptors and/or their pharmacodynamics profile in response to oligomeric species distinguishes NDAN from AD and control subjects. We will test our hypothesis in a rigorously characterized cohort of postmortem NDAN, AD, and age-matched normal cognitive control brains, using two unique and innovative approaches: Microtransplantation of Synaptic Membranes (MSM) to evaluate receptor electrical activity of native receptors complexes isolated from autopsy human brain, and Electrophysiologically-anchored Dataset Analysis (EDA) to identify proteins that correlate with receptors’ activity. The rationale for this project is that determining the pharmacological sensitivity of the natural targets of toxic oligomers is likely to offer a strong framework whereby novel strategies to AD therapy can be developed. Two complementary aims are proposed. Aim 1 will identify the impact of gene expression modifications on the abundance and function of Ca2+ permeable human native glutamate receptors in NDAN compared to AD and control cases, and aim 2 will evaluate the efficacy of A and tau oligomers to activate human native synaptic glutamate receptors from NDAN, AD and control cases. At the end of the proposed research we expect to have defined the mechanisms whereby oligomers trigger synaptic Ca2+ dysregulation in AD but not in NDAN subjects. These results will lay the foundations for the future development of innovative target-directed pharmacologic interventions to promote synaptic resilien...