TY - JOUR T1 - Alzheimer’s disease pathogenesis is dependent on neuronal receptor PTPσ JF - bioRxiv DO - 10.1101/079806 SP - 079806 AU - Yuanzheng Gu AU - Yaoling Shu AU - Angela W. Corona AU - Kui Xu AU - Allen F. Yi AU - Shannon Chen AU - Man Luo AU - Michel L. Tremblay AU - Gary E. Landreth AU - Randy J. Nelson AU - Jerry Silver AU - Yingjie Shen Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/10/07/079806.abstract N2 - 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 PTPσ mediates both β-amyloid and Tau pathogenesis in two mouse models. In the brain, PTPσ binds to β-amyloid precursor protein (APP). Depletion of PTPσ reduces the affinity between APP and β-secretase, diminishing APP 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 PTPσ. 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. ER -