Alzheimer disease A tale of two prions

Alzheimer disease (AD) has traditionally been thought to involve the misfolding and aggregation of two different factors that contribute in parallel to pathogenesis: amyloid-beta (A beta) peptides, which represent proteolytic fragments of the transmembrane amyloid precursor protein, and tau, which normally functions as a neuronally enriched, microtubule-associated protein that predominantly accumulates in axons. Recent evidence has challenged this model, however, by revealing numerous functional interactions between A beta and tau in the context of pathogenic mechanisms for AD. Moreover, the propagation of toxic, misfolded A beta and tau bears a striking resemblance to the propagation of toxic, misfolded forms of the canonical prion protein, PrP, and misfolded A beta has been shown to induce tau misfolding in vitro through direct, intermolecular interaction. In this review we discuss evidence for the prion-like properties of both A beta and tau individually, as well as the intriguing possibility that misfolded A beta acts as a template for tau misfolding in vivo.