PROJECT SUMMARY Alzheimer’s disease (AD) currently affects an estimated 5.8 million individuals in the United States, a number that is expected to grow to 7 million by 2050. In the US AD is the sixth leading cause of death overall and the fifth leading cause of death in individuals 65 and older. There are currently no disease modifying therapies known to slow or halt AD progression, thus a better understanding of AD pathogenesis is essential to address an impeding global health crisis. While it is understood that amyloid beta (Aβ) leads to progressive synapse loss and is a major contributing feature of AD, it is not well-understood how Aβ signaling triggers tau pathology. Studies designed to reveal how Aβ contributes to this second equally critical component of the disease are critical. Multiple genome wide association studies have identified Pyk2 (PTK2B) as a genetic risk factor for late- onset Alzheimer’s disease, which comprises a vast majority of AD cases. Pyk2 is both activated by Aβ signaling and is required for the presentation of a number of Aβ associated phenotypes including synapse loss and memory impairment. However, preliminary data I have gathered suggests that Pyk2, which has been demonstrated to interact both directly and indirectly with tau, is protective against tau-mediated neuronal dysfunction. The Aims of this proposal will determine how Pyk2 functions to protect neurons from tau-mediated damage and how Aβ may modulate that function in a way that diminishes this protective capacity. Aim 1 will investigate the role of Pyk2 in protecting neurons against tau-mediated synaptic dysfunction and toxicity. Experiment 1a will use an electrophysiological approach to determine whether Pyk2 expression is protective against tau-mediated impairments of synaptic transmission and plasticity in a well-described tauopathy animal model. Experiment 1b and Experiment 1c will determine whether Pyk2 expression modulates tau-associated synaptic disorganization in vitro and in vivo, respectively. Aim 2 will investigate Pyk2’s role in regulating Aβ-induced tau dysfunction and how that role is modulated by Aβ. Experiment 2a will determine whether Pyk2 expression is protective against Aβ-induced tau hyperphosphorylation and dendritic mislocalization in human neurons. Experiment 2b will assess how Aβ signaling modulates the expression and localization of Pyk2. Experiment 2c will determine how Pyk2 protein binding partners are modulated by Aβ signaling. To the best of our knowledge, these experiments represent the first attempts to understand Pyk2’s role in protecting synapses against tau-mediated damage and how that might be perturbed in the presence of Aβ. These experiments will yield critical information regarding the link between Aβ and tau and will likely reveal novel protein targets for future AD therapies.