Research ArticleAlzheimer’s Disease

PAC1 receptor–mediated clearance of tau in postsynaptic compartments attenuates tau pathology in mouse brain

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Science Translational Medicine  26 May 2021:
Vol. 13, Issue 595, eaba7394
DOI: 10.1126/scitranslmed.aba7394

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PACking toxic tau a punch

Tau is enriched in healthy axons, but in the early stages of Alzheimer’s disease (AD), tau becomes mislocalized to synapses. Using a mouse model of tauopathy and postmortem human brain tissue samples from patients with AD, Schaler et al. show that synaptic tau accumulated predominantly in postsynaptic compartments resulting in tau aggregation. To combat tau accumulation in postsynaptic compartments, the authors stimulated the PAC1 receptor expressed on the surface of dendrites using the receptor’s ligand PACAP. This resulted in increased PKA-dependent proteasome activity and tau clearance. Treatment with PACAP led to reduced synaptic tau, attenuated tauopathy, and improved cognitive performance in mice.

Abstract

Accumulation of pathological tau in synapses has been identified as an early event in Alzheimer’s disease (AD) and correlates with cognitive decline in patients with AD. Tau is a cytosolic axonal protein, but under disease conditions, tau accumulates in postsynaptic compartments and presynaptic terminals, due to missorting within neurons, transsynaptic transfer between neurons, or a failure of clearance pathways. Using subcellular fractionation of brain tissue from rTg4510 tau transgenic mice with tauopathy and human postmortem brain tissue from patients with AD, we found accumulation of seed-competent tau predominantly in postsynaptic compartments. Tau-mediated toxicity in postsynaptic compartments was exacerbated by impaired proteasome activity detected by measuring lysine-48 polyubiquitination of proteins targeted for proteasomal degradation. To combat the accumulation of tau and proteasome impairment in the postsynaptic compartments of rTg4510 mouse brain, we stimulated the pituitary adenylate cyclase–activating polypeptide (PACAP) type 1 receptor (PAC1R) with its ligand PACAP administered intracerebroventricularly to rTg4510 mice. We observed enhanced synaptic proteasome activity and reduced total tau in postsynaptic compartments in mouse brain after PACAP treatment. The clearance of tau from postsynaptic compartments correlated with attenuated tauopathy and improved cognitive performance of rTg4510 transgenic mice on two behavioral tests. These results suggest that activating PAC1R could prevent accumulation of aggregate-prone tau and indicate a potential therapeutic approach for AD and other tauopathies.

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