The vacuolar protein sorting 35 (VPS35) is a major component of the retromer recognition core complex which regulates intracellular protein sorting and trafficking. Deficiency in VPS35 by altering APP/Aβ metabolism has been linked to late-onset Alzheimer’s disease. Here we report that VPS35 is significantly reduced in Progressive Supra-nuclear Palsy and Picks’ disease, two distinct primary tauopathies. In vitro studies show that overexpression of VPS35 leads to a reduction of pathological tau in neuronal cells, whereas genetic silencing of VPS35 results in its accumulation. Mechanistically the availability of active cathepsin D mediates the effect of VPS35 on pathological tau accumulation. Moreover, in a relevant transgenic mouse model of tauopathy, down-regulation of VPS35 results in an exacerbation of motor and learning impairments as well as accumulation of pathological tau and loss of synaptic integrity. Taken together, our data identify VPS35 as a novel critical player in tau metabolism and neuropathology, and a new therapeutic target for human tauopathies.
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Domenico Praticó is the Scott Richards North Star Charitable Foundation Chair for Alzheimer’s research. We would like to thank the patients and the families who have donated the brain tissues together with the University of Maryland Brain and Tissue Bank, the Human Brain and Spinal Fluid Resource Center (UCLA, Los Angeles, CA), and Harvard Brain Tissue Resource Center, McLean Hospital for providing post-mortem tissue through NIH NeuroBioBank. We would also like to thank Peter Davies for supplying the MC-1 antibody. This study was supported in part by grants from the National Institute of Health (AG055707, and AG056689).
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Vagnozzi, A.N., Li, JG., Chiu, J. et al. VPS35 regulates tau phosphorylation and neuropathology in tauopathy. Mol Psychiatry (2019). https://doi.org/10.1038/s41380-019-0453-x
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