@article {Gu079806, author = {Yuanzheng Gu and Yaoling Shu and Angela W Corona and Kui Xu and Allen F. Yi and Shannon Chen and Man Luo and John G. Flanagan and Michel L. Tremblay and Gary E. Landreth and Randy J. Nelson and Jerry Silver and Yingjie Shen}, title = {Alzheimer{\textquoteright}s disease pathogenesis is dependent on neuronal receptor ΡΤΡσ}, elocation-id = {079806}, year = {2016}, doi = {10.1101/079806}, publisher = {Cold Spring Harbor Laboratory}, abstract = {β-amyloid accumulation and Tau aggregation are hallmarks of Alzheimer{\textquoteright}s disease, yet their underlying molecular mechanisms remain obscure, hindering therapeutic advances. Here we report that neuronal receptor ΡΤΡσ mediates both β-amyloid and Tau pathogenesis in two mouse models. In the brain, ΡΤΡσ binds to β-amyloid precursor protein (APP). Depletion of ΡΤΡσ reduces the affinity between APP and β-secretase, diminishing ΑΡΡ proteolytic products by β- and γ-cleavage without affecting other major substrates of the secretases, suggesting a specificity of β-amyloidogenic regulation. In human APP transgenic mice during aging, the progression of β-amyloidosis, Tau aggregation, neuroinflammation, synaptic loss, as well as behavioral deficits, all show unambiguous dependency on the expression of ΡΤΡσ. Additionally, the aggregates of endogenous Tau are found in a distribution pattern similar to that of early stage neurofibrillary tangles in Alzheimer brains. Together, these findings unveil a gatekeeping role of PTPσ upstream of the degenerative pathogenesis, indicating a potential for this neuronal receptor as a drug target for Alzheimer{\textquoteright}s disease.}, URL = {https://www.biorxiv.org/content/early/2016/12/01/079806}, eprint = {https://www.biorxiv.org/content/early/2016/12/01/079806.full.pdf}, journal = {bioRxiv} }