PT  - JOURNAL ARTICLE
AU  - Gu, Yuanzheng
AU  - Shu, Yaoling
AU  - Corona, Angela W.
AU  - Xu, Kui
AU  - Yi, Allen F.
AU  - Chen, Shannon
AU  - Luo, Man
AU  - Flanagan, John G.
AU  - Tremblay, Michel L.
AU  - Landreth, Gary E.
AU  - Nelson, Randy J.
AU  - Silver, Jerry
AU  - Shen, Yingjie
TI  - Alzheimer’s disease pathogenesis is dependent on neuronal receptor PTPσ
AID  - 10.1101/079806
DP  - 2016 Jan 01
TA  - bioRxiv
PG  - 079806
4099  - http://biorxiv.org/content/early/2016/12/06/079806.short
4100  - http://biorxiv.org/content/early/2016/12/06/079806.full
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 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.