Abstract
BackgroundThe amyloid-β (Aβ) peptide is the primary component of the extracellular senile plaques characteristic of Alzheimer's disease (AD). The metals hypothesis implicates redox-active copper ions in the pathogenesis of AD and the Cu2+ coordination of various Aβ peptides has been widely studied. A number of disease-associated modifications involving the first 3 residues are known, including isomerisation, mutation, truncation and cyclisation, but are yet to be characterised in detail. In particular, Aβ in plaques contain a significant amount of truncated pyroglutamate species, which appear to correlate with disease progression.Methodology/Principal FindingsWe previously characterised three Cu2+/Aβ1–16 coordination modes in the physiological pH range that involve the first two residues. Based upon our finding that the carbonyl of Ala2 is a Cu2+ ligand, here we speculate on a hypothetical Cu2+-mediated intramolecular cleavage mechanism as a source of truncations beginning at residue 3. Using EPR spectroscopy and site-specific isotopic labelling, we have also examined four Aβ peptides with biologically relevant N-terminal modifications, Aβ1[isoAsp]–16, Aβ1–16(A2V), Aβ3–16 and Aβ3[pE]–16. The recessive A2V mutation preserved the first coordination sphere of Cu2+/Aβ, but altered the outer coordination sphere. Isomerisation of Asp1 produced a single dominant species involving a stable 5-membered Cu2+ chelate at the amino terminus. The Aβ3–16 and Aβ3[pE]–16 peptides both exhibited an equilibrium between two Cu2+ coordination modes between pH 6–9 with nominally the same first coordination sphere, but with a dramatically different pH dependence arising from differences in H-bonding interactions at the N-terminus.Conclusions/SignificanceN-terminal modifications significantly influence the Cu2+ coordination of Aβ, which may be critical for alterations in aggregation propensity, redox-activity, resistance to degradation and the generation of the Aβ3–× (× = 40/42) precursor of disease-associated Aβ3[pE]–x species.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by progressive cognitive and memory impairment [1]
Isomerisation of Asp1 inhibits component II coordination by forming a stable 5-membered chelate X-band CW-electron paramagnetic resonance (EPR) of Cu2+/Ab1[isoAsp]–16 indicated the presence of only a single coordination mode with only subtle variation in linewidth between pH 6–8 (Figure 1), possibly due to pH-dependent structural changes beyond the first coordination sphere
The above observations can be explained if Cu2+/Ab1[isoAsp]–16 forms a stable 5-membered ring via the amino terminus and the carboxylate of isoAsp1 (Figure 2a), similar to the 5-membered chelate adopted by oxidised glutathione, in which the first residue of the tripeptide is isomerised glutamate [43]
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder characterised by progressive cognitive and memory impairment [1]. Amyloid plaques, comprising of extracellular cerebral deposits of insoluble Ab, are the pathological hallmark of AD [1,2]. Within these plaques, copper is found in high concentrations [2,3] and growing evidence suggests that copper ions play an important role in the pathogenesis of AD by inducing protein misfolding and generating reactive oxygen species [4,5,6,7,8,9]. The amyloid-b (Ab) peptide is the primary component of the extracellular senile plaques characteristic of Alzheimer’s disease (AD). Ab in plaques contain a significant amount of truncated pyroglutamate species, which appear to correlate with disease progression
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