Alzheimer disease: a tale of two prions

Abstract

Alzheimer disease (AD) has traditionally been thought to involve the misfolding and aggregation of two different factors that contribute in parallel to pathogenesis: amyloid-β (Aβ) 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 Aβ and tau in the context of pathogenic mechanisms for AD. Moreover, the propagation of toxic, misfolded Aβ and tau bears a striking resemblance to the propagation of toxic, misfolded forms of the canonical prion protein, PrP, and misfolded Aβ 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 Aβ and tau individually, as well as the intriguing possibility that misfolded Aβ acts as a template for tau misfolding in vivo.

Keywords: Alzheimer disease; amyloid plaque; amyloid-β; neurodegeneration; neurofibrillary tangle; prion; tau.

Figure 1.

Prion-like mechanisms in Alzheimer disease. Amyloid-β (Aβ) peptides can form toxic oligomers that are able to propogate by a prion-like mechanism of template-mediated protein misfolding. Aβ oligomers can activate tau kinases, which then catalyze pathogenic phosphorylation of tau (pTau), and may also serve as prion-like seeds that induce tau to oligomerize. Tau oligomers also self-propogate by a prion-like mechanism, and along with pathogenically phosphorylated tau, drive the degeneration and death of neurons involved in memory and cognition. The temporal and functional relationships between pathogenic phosphorylation and oligomerization of tau remain to be determined.