ADAM10- and Presenilin 1/γ-Secretase-Dependent Cleavage of PTPRT Mitigates Neurodegeneration of Alzheimer’s Disease

Background: PTPRT (receptor-type tyrosine-protein phosphatase T), as a brain-specific type 1 transmembrane protein, plays an important function in neurodevelopment and synapse formation. However, whether PTPRT-dependent signaling is involved in Alzheimer’s disease (AD) remains elusive.MethodsHere, we first applied biochemistry methods and bioinformatic analysis to test and quantify the processing and expression of PTPRT in both human and mouse models. AAV delivery, primary culture system, electrophysiology, behavior tests were also used in this study.ResultsWe identified that PTPRT intracellular domain (PICD), which was released from ADAM10- and presenilin 1-/g-secretase-dependent cleavage of PTPRT, efficiently translocated to the nucleus via a conserved nuclear localization signal. Inhibition of Ptprt led to accumulation of phosphorylated signal transducer and activator of transcription 3 (pSTAT3), which is a substrate of PTPRT and eventually resulted in neurodegeneration. Consistently, RNA sequencing reveals that expression of the PICD alone can profoundly alter the expression of genes associated with synapse function and dephosphorylation, phosphatase and cell adhesion. Unexpectedly, the downregulated levels of Ptprt mRNA and protein were found in both human and mouse AD brains. Finally, overexpression of PICD alone not only significantly decreases the level of phosph-STAT3 Y705 and Ab deposition in the hippocampus of APP/PS1 mice, but also improves synaptic function and behavioral deficits in APP/PS1 mice.ConclusionOur findings suggest that a novel role of the ADAM 10- and presenilin 1-/g-secretase-dependent cleavage of PTPRT in the events can mitigate neurodegeneration of AD and moderate Alzheimer’s pathogenesis.