Beta-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 PTPsigma; mediates both beta-amyloid and Tau pathogenesis in two mouse models. In the brain, PTPsigma binds to beta-amyloid precursor protein (APP). Depletion of PTPsigma reduces the affinity between APP and beta-secretase, diminishing APP proteolytic products by beta- and gamma-cleavage without affecting other major substrates of the secretases, suggesting a specificity of beta-amyloidogenic regulation. In human APP transgenic mice during aging, the progression of beta-amyloidosis, Tau aggregation, neuroinflammation, synaptic loss, as well as behavioral deficits, all show unambiguous dependency on the expression of PTPsigma. 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 PTPsigma upstream of the degenerative pathogenesis, indicating a potential for this neuronal receptor as a drug target for Alzheimer's disease.