Amyloid-β 1–24 C-terminal truncated fragment promotes amyloid-β 1–42 aggregate formation in the healthy brain

Abstract

Substantial data indicate that amyloid-β (Aβ), the major component of senile plaques, plays a central role in Alzheimer’s Disease and indeed the assembly of naturally occurring amyloid peptides into cytotoxic aggregates is linked to the disease pathogenesis. Although Aβ42 is a highly aggregating form of Aβ, the co-occurrence of shorter Aβ peptides might affect the aggregation potential of the Aβ pool. In this study we aimed to assess whether the structural behavior of human Aβ42 peptide inside the brain is influenced by the concomitant presence of N-terminal fragments produced by the proteolytic activity of glial cells. We show that the occurrence of the human C-terminal truncated 1–24 Aβ fragment impairs Aβ42 clearance through blood brain barrier and promotes the formation of Aβ42 aggregates even in the healthy brain. By showing that Aβ1-24 has seeding properties for aggregate formation in intracranially injected wild type mice, our study provide the proof-of-concept that peptides produced upon Aβ42 cleavage by activated glial cells may cause phenotypic defects even in the absence of genetic mutations associated with Alzheimer’s Disease, possibly contributing to the development of the sporadic form of the pathology.

Are N- and C-terminally truncated Aβ species key pathological triggers in Alzheimer's disease?

“…This also indicates that cellular, genetic, or environmental cofactors may govern seeding formation and its acceleration in pathological conditions (75). Interestingly, this increased capability to induce full-length A␤ seeding has been described for several truncated A␤ variants such as A␤24 (43) and pE3A␤ (76).…”

“…However, it has been shown that intracranial injection of synthetic A␤24 in WT mice impairs full-length A␤42 clearance through the blood-brain barrier and promotes A␤42 aggregation via its seeding properties. Moreover, the synthetic A␤24 peptide tends to promote A␤42 aggregation, whereas the A␤24 peptide itself presents a lowaggregation propensity (43). The exact nature of the enzyme responsible for A␤24 production still remains unknown.…”

Alpha-synuclein fragments trigger distinct aggregation pathways

“…Moreover, truncation of αSyn seems to correlate with accelerated aggregation and pathology in cell and mouse models [13][14][15] . Remarkably, fragments are emerging as a potential common feature observed also for other neurodegeneration-related proteins, such as amyloid precursor protein and tau 16 .…”

Deuteron Solid‐State NMR Relaxation Measurements Reveal Two Distinct Conformational Exchange Processes in the Disordered N‐Terminal Domain of Amyloid‐β Fibrils

“…The N‐terminal domain is known to be extremely important in regulating the overall aggregation of Aβ . It contains the main binding and regulatory sites for interaction with metals as well as several regulatory sites that have recently been implicated to be controlled via post‐translational modifications.…”