Are N- and C-terminally truncated Aβ 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 (Aβ peptides) that are produced by sequential cleavages of Aβ precursor protein (βAPP) by β- and γ-secretases. The amyloid cascade hypothesis proposes a key role for the full-length Aβ42 and the Aβ40/42 ratio in AD etiology, in which soluble Aβ 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 Aβ42 production or neutralizing it by immunotherapy have failed to reduce or even stabilize AD-related decline. Thus, the Aβ peptide (Aβ40/42)-centric hypothesis is probably a simplified view of a much more complex situation involving a multiplicity of APP fragments and Aβ catabolites. Indeed, biochemical analyses of AD brain deposits and fluids have unraveled an Aβ peptidome consisting of additional Aβ-related species. Such Aβ catabolites could be due to either primary enzymatic cleavages of βAPP or secondary processing of Aβ itself by exopeptidases. Here, we review the diversity of N- and C-terminally truncated Aβ peptides and their biosynthesis and outline their potential function/toxicity. We also highlight their potential as new pharmaceutical targets and biomarkers.

Rivastigmine modifies the α-secretase pathway and potentially early Alzheimer’s disease

“…A hypothesis for AD pathogenesis posits a shift in the processing of APP towards the amyloidogenic route or a decline in Aβ brain clearance that causes excessive accumulation of Aβ, and/or a shift in the ratio of Aβ species to favor the Aβ42 form 55 , although further truncated forms of Aβ may also play a role 56,57 . The reported upregulation of BACE1 during aging and AD may partly underlie this brain change [58][59][60] .…”

Proamyloidogenic effects of membrane type 1 matrix metalloproteinase involve MMP‐2 and BACE‐1 activities, and the modulation of APP trafficking

“…Overall, MMPs have been considered as Ab-degrading enzymes (55,56); for instance, MMP-2 and MMP-9 produced by reactive astrocytes may degrade extracellular Ab (57), and overexpressed MMP-2 in HEKswe cells shows similar effects (17). Consequently, it is conceivable that MMPs, and in particular MMP-2, could display a dual Abdegrading and Ab-promoting features at the plasma membrane and intracellular compartments, respectively.…”

Apolipoprotein E impairs amyloid‐β fibril elongation and maturation

“…The clinical manifestations are observed as a progressive dementia characterized by neuroinflammation, synapse loss, and nerve degeneration. Aβ is a 38‐ to 43‐residue peptide fragment derived from the membrane‐bound β‐amyloid precursor protein via sequential proteolytic cleavages by β‐ and γ‐secretase enzyme activities . Aβ 1–40 and Aβ 1–42 are the most abundant variants in vivo and are frequently considered to be the clinically most relevant species.…”