Selective vulnerability and resilience to trans-synaptic pathological tau spreading in Alzheimers disease

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 (Aß) on trans-neuronal pathological tau spreading, while emerging evaluations of primary tauopathies (e.g. Primary Age Related Tauopathy—PART), which lack Aß, observe limited regional tau spreading alongside little-to-no amnestic changes. Within the trans-synaptic spreading framework, however, the precise mechanisms by which tauO selectively engage key synaptic subtypes (e.g. excitatory vs. inhibitory), and the role of Aß in this process, remain unknown. We thus hypothesize that Aß modulates pathological tau spreading by increasing oligomeric tau binding and internalization to vulnerable synapses. To support this hypothesis, we provide novel preliminary evidence for increased binding and internalization of toxic tauO binding in the presence of soluble Aß oligomers in human synapses. In Aim 1, we will determine the role of AßO in modulating synaptic tauO binding within a framework of cellular, regional and clinical resilience to pathological tau burden. In Aim 2, we will determine key synaptic proteins that modulate the binding and/or internalization of tauO in the presence and absence of AßO. 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 and internalization—a key component of pathological tau spreading.