The P's and Q's of cellular PrP-Aβ interactions.

Prion disease research has opened up the "black-box" of neurodegeneration, defining a key role for protein misfolding wherein a predominantly alpha-helical precursor protein, PrP (C), is converted to a disease-associated, β-sheet enriched isoform called PrP (Sc). In Alzheimer disease (AD) the Aβ peptide derived from the β-amyloid precuror protein APP folds in β-sheet amyloid. Early thoughts along the lines of overlap may have been on target, (1) but were eclipsed by a simultaneous (but now anachronistic) controversy over the role of PrP (Sc) in prion diseases. (2) (,) (3) Nonetheless, as prion diseases such as Creutzfeldt-Jakob Disease (CJD) are themselves rare and can include an overt infectious mode of transmission, and as familial prion diseases and familial AD involve different genes, an observer might reasonably have concluded that prion research could occasionally catalyze ideas in AD, but could never provide concrete overlaps at the mechanistic level. Surprisingly, albeit a decade or three down the road, several prion/AD commonalities can be found within the contemporary literature. One important prion/AD overlap concerns seeded spread of Aβ aggregates by intracerebral inoculation much like prions, (4) and, with a neuron-to-neuron 'spreading' also reported for pathologic forms of other misfolded proteins, Tau (5) (,) (6) and α-synuclein in the case of Parkinson Disease. (7) (,) (8) The concept of seeded spread has been discussed extensively elsewhere, sometimes under the rubric of "prionoids" (9), and lies outside the scope of this particular review where we will focus upon PrP (C). From this point the story can now be subdivided into four strands of investigation: (1) pathologic effects of Aβ can be mediated by binding to PrP (C), (10) (2) the positioning of endoproteolytic processing events of APP by pathologic (β-cleavage + γ-cleavage) and non-pathologic (α-cleavage + γ-cleavage) secretase pathways is paralleled by seemingly analogous α- and β-like cleavage of PrP (C) (Fig. 1) (3) similar lipid raft environments for PrP (C) and APP processing machinery, (11) (-) (13) and perhaps in consequence, overlaps in repertoire of the PrP (C) and APP protein interactors ("interactomes"), (14) (,) (15) and (4) rare kindreds with mixed AD and prion pathologies. (16) Here we discuss confounds, consensus and conflict associated with parameters that apply to these experimental settings.