RT Journal Article
SR Electronic
T1 Alzheimer’s disease pathogenesis is dependent on neuronal receptor PTPσ
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 079806
DO 10.1101/079806
A1 Gu, Yuanzheng
A1 Shu, Yaoling
A1 Corona, Angela W.
A1 Xu, Kui
A1 Yi, Allen F.
A1 Chen, Shannon
A1 Luo, Man
A1 Flanagan, John G.
A1 Tremblay, Michel L.
A1 Landreth, Gary E.
A1 Nelson, Randy J.
A1 Silver, Jerry
A1 Shen, Yingjie
YR 2016
UL http://biorxiv.org/content/early/2016/12/06/079806.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 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.