Tau-containing neuronal inclusions are a prominent feature of Alzheimer’s disease (AD) and other disorders with tauopathy, implying a deficit in the cell’s ability to clear misfolded tau species either as a cause or a consequence of the disease process. Tau is a substrate of the ubiquitin proteasome system (UPS), thus elucidating a mechanism for how proteasome becomes dysfunctional in tauopathy may identify pathways that could be targeted therapeutically to halt disease progression. We have recently provided insight into a direct, negative effect of aggregated and oligomeric tau on proteasome function using in vivo and in vitro models. Additionally, we have shown that pharmacological activation of proteasome function by phosphorylation via cAMP/PKA pathway reduces levels of pathological tau and rescues cognitive decline. Presently, symptomatic treatment during the dementia stage cannot halt the disease progression. Therefore, identifying molecular mechanisms of the earliest stages of tauopathy will help in the development of effective therapies against AD. The early pathological hallmark of tauopathy disorders is abnormal missorting of tau into the somatodendritic compartments of neurons. In synapses, accumulated tau is polyubiquitinated, implying a defect in proteasome- mediated proteolysis, which can contribute to accelerated synaptotoxicity as proteasomes play an indispensable role in maintaining synaptic plasticity and transmission. The Career Development Proposal’s AIM 1 will investigate the effect of missorted synaptic tau on proteasome function in the pre and post -synaptic fractions. One of the pathways related to synaptic plasticity is the cAMP/PKA pathway, which is regulated by the intra and extra -cellular factors. AIM 2 will test the hypothesis that in AD, activity of PKA is downregulated as a consequence of reduced synaptic proteasome proteolysis (the intra-synaptic factor), and depleted levels of PACAP (pituitary adenylate cyclase–activating polypeptide) (the inter-synaptic factor). PACAP is an abundant neuropeptide that when released from pre-synaptic compartments, binds and stimulate its receptor (PAC1R), a GPCR subfamily receptor situated in the postsynaptic compartments which then leads to an increase in cAMP production and PKA activation in dendrites. As a therapeutic strategy, AIM 3 will investigate if PACAP administration restores PKA activity and activates proteasome function leading to tau clearance in dendrites and improved synaptic function. Finally, AIM 4 will make use of robotic technology to develop a new screening assay to test for proteasome activators and to assess if receptor-mediated proteolysis in synapses is applicable to other subfamily GPCRs. The data and insights generated during this award will identify a mechanism of post-synaptic proteasome dysfunction that can contribute to synaptotoxicity by dysregulating the PKA pathway. Moreover, application of a therapeutic strategy of receptor-stimulated proteolysis ...