RT Journal Article SR Electronic T1 Alzheimer’s disease pathogenesis is dependent on neuronal receptor ΡΤΡσ JF bioRxiv FD Cold Spring Harbor Laboratory SP 079806 DO 10.1101/079806 A1 Yuanzheng Gu A1 Yaoling Shu A1 Angela W Corona A1 Kui Xu A1 Allen F. Yi A1 Shannon Chen A1 Man Luo A1 John G. Flanagan A1 Michel L. Tremblay A1 Gary E. Landreth A1 Randy J. Nelson A1 Jerry Silver A1 Yingjie Shen YR 2016 UL http://biorxiv.org/content/early/2016/12/01/079806.abstract AB β-amyloid accumulation and Tau aggregation are hallmarks of Alzheimer’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’s disease.