PROJECT SUMMARY/ABSTRACT Finding a resolving cure for Alzheimer's Disease (AD) is an urgent critical need and there is ample consensus that successful treatments should target early disease events. Among these, synaptic dysfunction induced by soluble oligomers of tau (TauO) is recognized as one of the earliest key events in AD and related disorders, where disease-specific TauO conformers (strains) may drive the diverse clinical presentations. Thus, blocking synaptic demise induced by TauO conformers is a highly desirable therapeutic strategy, its potential effectiveness supported by the existence of resilient individuals who remain Non-Demented despite the CNS presence of late-stage Braak AD Neuropathology (here termed NDAN) that present with functional synapses devoid of TauO. Notably, late Braak stage pathology paralleled by intact synapses in NDAN suggests the novel concept that trans-synaptic spreading of tau and tau-driven synaptic toxicity are two distinct phenomena that coexist in AD and other symptomatic tauopathies but not in NDAN, where the toxic impact of TauO on synapses (but not spreading) is curbed. While such evidence indicates that rejecting synaptic tau toxic impact as a protective mechanism can be effectively enabled in the human brain despite the spread of AD neuropathology, a therapeutic strategy to achieve such a game-changing goal remains missing. Filling this critical knowledge gap by laying the molecular foundations for the development of such therapeutic strategy is the overall objective of the present project. Our central hypothesis is that dysfunctional engagement of synapses by TauO is determined by the type of tau strain and its binding to LRP1 (a synaptic receptor essential for tau uptake and spreading), which differentially affects LRP1-containing protein complexes in vulnerable vs. resilient synapses. We will test our central hypothesis by evaluating binding dynamic and functional impact of disease-specific brain-derived TauO conformers on human synapses as a function of LRP1-mediated toxicity (Aim 1) and by evaluating the functional response of human synapses from different tauopathies (AD, PSP) and resilience status (NDAN, PART) to TauO as a function of the synaptic LRP1 (Aim 2). At the completion of the proposed studies, we expect to have documented a previously unappreciated mechanism of synaptic interaction of TauO conformers as well as a phenomenon of synaptic resistance modulated by LRP1. This discovery will have a significant impact in the development of an innovative treatment concept for AD centered on sustaining synaptic resistance to toxic oligomers, a strategy expected effective as demonstrated by NDAN subjects. A uniquely qualified investigative team has been assembled to successfully accomplish this project, bringing together expertise in AD molecular neurobiology (Taglialatela), human synaptic physiology (Limon) and function (Krishnan) and biochemistry of tau oligomers (Kayed).