April 15, 2021

ADAM10- and presenilin 1/γ-secretase-dependent cleavage of PTPRT mitigates neurodegeneration of Alzheimer’s disease

PTPRT (receptor-type tyrosine-protein phosphatase T), as a brain-specific type 1 transmembrane protein, plays an important function in neurodevelopment and synapse formation. Here, we identified that PTPRT is a novel substrate of ADAM10- and presenilin 1/{gamma}-secretase. The intracellular domain (PICD), which was released from the cleavage of PTPRT, translocated to the nucleus and dephosphorylated signal transducer and activator of transcription 3 (pSTAT3Y705). Overexpression of the PICD alone profoundly altered gene expression in neuronal cells. We further found that the downregulation of Ptprt expression was negatively correlated to the accumulation of pSTAT3Y705 in the brains of human Alzheimer’s disease (AD) and model mice. PICD alone not only decreased pSTAT3Y705 and A{beta} deposition but also markedly improved synaptic function and behavioral deficits in APP/PS1 mice. Our data demonstrate a distinct role of the ADAM 10- and presenilin 1/{gamma}-secretase-dependent cleavage of PTPRT in mitigating neurodegeneration of Alzheimer’s disease.

 bioRxiv Subject Collection: Neuroscience

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