Alzheimer-related pathogenesis is dependent on neuronal receptor PTPσ.

Due to limited understanding of disease mechanisms and the lack of molecular targets, translational research for Alzheimer disease has not been fruitful hitherto. Here we report findings that indicate neuronal receptor phosphatase PTP{sigma} as a potential therapeutic target for this dementia. In two TgAPP mouse models, a spectrum of Alzheimer-related pathologies, including aged-induced progression of {beta}-amyloidosis, Tau aggregation, neuroinflammation, synaptic loss, as well as behavioral deficits, all show unambiguous dependency on PTP{sigma}. APP amyloidogenic metabolites diminish upon PTP{sigma} genetic depletion or pharmacological inhibition. Binding to APP in the brain, PTP{sigma} regulates APP proteolytic metabolism via its phosphatase activity, likely through downstream signaling that modulates APP membrane localization and affinity to the {beta}-secretase, in a specific manner that does not broadly affect {beta}- and {gamma}-secretase processing of other major substrates. Together, these findings unveil a gatekeeping role of PTP{sigma} upstream in Alzheimer-like pathogenic pathway.