Are N- And C-terminally truncated A β species key pathological triggers in Alzheimer's disease?

Abstract

The histopathology of Alzheimer's disease (AD) is characterized by neuronal loss, neurofibrillary tangles, and senile plaque formation. The latter results from an exacerbated production (familial AD cases) or altered degradation (sporadic cases) of 40/42-amino acid-long β-amyloid peptides (A β peptides) that are produced by sequential cleavages of A β precursor protein (β APP) by β - And γ -secretases. The amyloid cascade hypothesis proposes a key role for the full-length A β 42 and the A β 40/42 ratio in AD etiology, in which soluble A β oligomers lead to neurotoxicity, tau hyperphosphorylation, aggregation, and, ultimately, cognitive defects. However, following this postulate, during the last decade, several clinical approaches aimed at decreasing full-length A β 42 production or neutralizing it by immunotherapy have failed to reduce or even stabilize AD-related decline. Thus, the A β peptide (A β 40/42)-centric hypothesis is probably a simplified view of a much more complex situation involving a multiplicity of APP fragments and A β catabolites. Indeed, biochemical analyses of AD brain deposits and fluids have unraveled an A β peptidome consisting of additional A β -related species. Such A β catabolites could be due to either primary enzymatic cleavages of β APP or secondary processing of A β itself by exopeptidases. Here, we review the diversity of N- And C-terminally truncated A β peptides and their biosynthesis and outline their potential function/toxicity. We also highlight their potential as new pharmaceutical targets and biomarkers.