Mechanisms of trans-synaptic pathological tau spreading in the human brain

PROJECT SUMMARY The incidence of Alzheimer’s disease (AD) is on the rise, and we are in dire need of effective treatments. In AD, the spatiotemporal progression of tau pathology within the CNS remains the strongest neuropathological correlate of cognitive impairment, thus constituting a likely effective treatment target (long- term goal). Compelling evidence supports a trans-synaptic framework for pathological tau spreading, driven primarily by the propagation of toxic soluble tau oligomer (tauO) conformers between functionally connected brain regions. Numerous investigations further postulate the influence of amyloid-beta (Aβ) on trans- neuronal pathological tau spreading, while emerging evaluations of primary tauopathies (e.g. Primary Age Related Tauopathy—PART), which lack Aβ, observe limited regional tau spreading alongside little-to-no amnestic changes. Within the trans-synaptic spreading framework, however, the precise mechanisms by which tauO engage human synapses, and the role of Aβ in this process, remain unknown. We thus hypothesize that Aβ modulates pathological tau spreading by increasing oligomeric tau binding to vulnerable synapses. To support this hypothesis, we provide novel preliminary evidence for two (i.e. bivalent) tauO binding sites in human synapses and further show that synaptic tauO binding is significantly increased in the presence of soluble Aβ oligomers. In Aim 1, we will characterize the molecular mechanisms underlying bivalent tauO binding, as a function of AβO, in healthy human synapses. In In Aim 2, we will evaluate how AβO, or lack thereof, influences synaptic tauO binding as a function of regional (i.e. hippocampus vs. neocortex) and clinical (PART vs. AD) resilience status. To execute these aims, we have developed an innovative and translationally relevant approach to interrogate mechanisms of tau binding directly in human synapses isolated from post-mortem autopsy specimen using an array of biochemical techniques. At the completion of this project, we expect to document previously unappreciated mechanisms that modulate synaptic tauO binding—a key component of pathological tau spreading. In addition to advancing our understanding of human tauopathies, I also look forward to sharpening my understanding of human synapse biology, learning to integrate molecular biology research techniques with clinical neuropathology, and planning and executing translationally relevant research objectives. A uniquely qualified team of established research and clinical mentors at The University of Texas Medical Branch have been assembled to effectively guide my training through this project, bringing together expertise in AD molecular neurobiology (Dr. Taglialatela), amyloid biochemistry (Dr. Kayed), human synaptic physiology (Dr. Limon), neurology (Dr. Fang), and neuropathology (Dr. Felicella). The comprehensive training plan outlined herein will provide essential technical, intellectual, and professional skills to help me achieve my long-term career goals as an academician and physician-scientist.