Abstract
Previous studies suggested that the cellular prion protein (PrPc) plays a critical role in the pathogenesis of Alzheimer's disease (AD). Specifically, amyloid-β (Aβ) oligomers were proposed to cause synaptic and cognitive dysfunction by binding to PrPc. To test this hypothesis, we crossed human amyloid precursor protein (hAPP) transgenic mice from line J20 onto a PrPc-deficient background. Ablation of PrPc did not prevent the premature mortality and abnormal neural network activity typically seen in hAPPJ20 mice. Furthermore, hAPPJ20 mice with or without PrPc expression showed comparably robust abnormalities in learning and memory and in other behavioral domains at 6–8 months of age. Notably, these abnormalities are not refractory to therapeutic manipulations in general: they can be effectively prevented by interventions that prevent Aβ-dependent neuronal dysfunction also in other lines of hAPP transgenic mice. Thus, at least in this model, PrPc is not an important mediator of Aβ-induced neurological impairments.
