GPCR-mediated clearance of tau in post-synaptic compartments attenuates tau pathology in vivo

Accumulation of pathological tau in synapses has been identified as an early pathogenic event in Alzheimer’s disease (AD) and correlates strongly with cognitive decline in patients with AD. Tau is a cytosolic, axonal protein. However, in the disease condition, tau accumulates in post-synaptic compartments and pre-synaptic terminals, either due to missorting within neurons, trans-synaptic transfer between neurons or due to failure of clearance systems in synapses. Using a sub-cellular fractionation assay, we show that progressive deposition of seed competent tau occurs predominantly in post-synaptic compartments in a tau transgenic mouse and in AD patient brain, making these neuronal structures particularly vulnerable to tau toxicity. Tau-mediated post-synaptic toxicity could be further exacerbated by impaired proteasome activity which we detected by measuring the levels of polyubiquitin chains that target proteins to proteasomal degradation. To combat the accumulation of tau and proteasome impairment at the subcellular level, we devised a therapeutic strategy of proteasome-mediated clearance of tau restricted to the post-synaptic compartment. Utilizing the pharmacology of GPCRs, we show that stimulation of the PAC1R receptor by its ligand can propagate intracellular PKA signaling leading to enhanced synaptic proteasome activity and reduced tau in the post-synaptic compartment. Over time, clearance of post-synaptic tau led to reduced tauopathy and cognitive decline in rTg4510 mice. Together, these results highlight a novel therapeutic strategy of targeting GPCRs that propagate cAMP/PKA signaling as a tool to activate proteolysis restricted to synapses to prevent the accumulation of tau in the early stages of AD.