Alzheimer's disease (AD) is characterized by the presence of amyloid plaques 
mainly consisting of hydrophobic β-amyloid peptide (Aβ) aggregates and 
neurofibrillary tangles (NFTs) composed principally of hyperphosphorylated tau. 
Aβ oligomers have been described as the earliest effectors to negatively affect 
synaptic structure and plasticity in the affected brains, and cellular prion 
protein (PrP(C)) has been proposed as receptor for these oligomers. The most 
widely accepted theory holds that the toxic effects of Aβ are upstream of change 
in tau, a neuronal microtubule-associated protein that promotes the 
polymerization and stabilization of microtubules. However, tau is considered 
decisive for the progression of neurodegeneration, and, indeed, tau pathology 
correlates well with clinical symptoms such as dementia. Different pathways can 
lead to abnormal phosphorylation, and, as a consequence, tau aggregates into 
paired helical filaments (PHF) and later on into NFTs. Reported data suggest a 
regulatory tendency of PrP(C) expression in the development of AD, and a 
putative relationship between PrP(C) and tau processing is emerging. However, 
the role of tau/PrP(C) interaction in AD is poorly understood. In this study, we 
show increased susceptibility to Aβ-derived diffusible ligands (ADDLs) in 
neuronal primary cultures from PrP(C) knockout mice, compared to wild-type, 
which correlates with increased tau expression. Moreover, we found increased 
PrP(C) expression that paralleled with tau at early ages in an AD murine model 
and in early Braak stages of AD in affected individuals. Taken together, these 
results suggest a protective role for PrP(C) in AD by downregulating tau 
expression, and they point to this protein as being crucial in the molecular 
events that lead to neurodegeneration in AD.