Aβ(31–35) and Aβ(25–35) fragments of amyloid beta‐protein induce cellular death through apoptotic signals: Role of the redox state of methionine‐35

Abstract

In order to clarify the basis of neuronal toxicity exerted by the shortest active peptides of amyloid beta-protein (Ab), the toxic effects of Ab(31-35) and Ab(25-35) peptides on isolated rat brain mitochondria were investigated. The results show that exposure of isolated rat brain mitochondria to and Ab(25-35) peptides determines: (i) release of cytochrome c; (ii) mitochondrial swelling and (iii) a significant reduction in mitochondrial oxygen consumption. In contrast, the amplitude of these events resulted attenuated in isolated brain mitochondria exposed to the Ab(31-35)Met35 OX in which methionine-35 was oxidized to methionine sulfoxide. The Ab peptide derivative with norleucine substituting Met-35, i.e., Ab(31-35)Nle-35, had not effect on any of the biochemical parameters tested. We have further characterized the action of Ab(31-35) and Ab(25-35) peptides on neuronal cells.Taken together our result indicate that Ab(31-35) and Ab(25-35) peptides in non-aggregated form, i.e., predominantly monomeric, are strongly neurotoxic, having the ability to enter within the cells, determining mitochondrial damage with an evident trigger of apoptotic signals. Such a mechanism of toxicity seems to be dependent by the redox state of methionine-35.

Interactions between Amyloid-β and Tau Fragments Promote Aberrant Aggregates: Implications for Amyloid Toxicity

“…28−33 Aβ(25–35) is an amphipathic peptide with similar aggregation propensity and toxicity to the full length Aβ(1–42). 34,35 Takashima et al 27 have shown that embryonic rat hippocampal neurons undergo progressive degeneration and that Tau phosphorylation is enhanced after exposure to Aβ(25–35), similar to the result obtained with Aβ(1–40) by Busciglio and co-workers. 25 Tau(273–284) is in the second repeat (R2) of MTBR and encompasses the PHF6* hexapeptide (VQIINK), one of the two hexapeptides known to play an important role in Tau aggregation.…”

A Comparative Study of β-Amyloid Peptides Aβ1-42 and Aβ25-35 Toxicity in Organotypic Hippocampal Slice Cultures

“…Among the Ab fragments studied so far, the Ab25-35 peptide represents the shortest fragment of Ab processed in vivo by brain proteases [15]. Therefore, this peptide exhibits significant levels of molecular aggregation, retaining the toxicity of the fulllength peptide, although it is lacking of the metal binding sites [16]. It has been proposed that Ab25-35 peptide represents the biologically active region of Ab1-42 [17].…”

Sequence‐based modeling of Aβ42 soluble oligomers

“…78 It is well known that the oxidation state of this methionine strongly modifies the properties of A. 79,80 It significantly impairs the rate of amyloid formation, alters the fibril morphology, and modifies the neurotoxic features of A. As the oxidation of Met35 modifies A42 oligomerization, 81 it was concluded that Met35 is directly involved in formation of A42 paranuclei, probably through an intermolecular interaction between Met35 and Ile41.…”