Abstract
Alzheimer’s disease is the most common form of neurodegenerative disease. Beta-amyloid peptides (Aβ) are responsible for neuronal death both in vitro and in vivo. Previously, L17 and F19 residues were identified as playing key roles in the stabilization of the Aβ40 conformation and in the reduction of its neurotoxicity. In this study, the effects of L17A/F19A mutations on the neurotoxicity of Aβ genetic mutant Arctic-type Aβ40(E22G) were tested. The results showed that compared to Aβ40(E22G), Aβ40(L17A/F19A/E22G) reduced the rate of conformation conversion, aggregation, and cytotoxicity, suggesting that L17 and F19 are critical residues responsible for conformational changes which may trigger the neurotoxic cascade of Aβ. Aβ40(L17A/F19A/E22G) also had decreased damage due to reactive oxygen species. The results are consistent with the discordant helix hypothesis, and confirm that residues 17–25 are in the discordant helix region. Compared to Aβ40(L17A/F19A), reduction in aggregation of Aβ40(L17A/F19A/E22G) was less significantly decreased. This observation provides an explanation based on the discordant helix hypothesis that the mutation of E22 to G22 of Aβ40(E22G) alters the propensity of the discordant helix. Arctic-type Aβ40(E22G) aggregates more severely than wild-type Aβ40, with a consequential increase in toxicity.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly population [1,2,3]
From the Circular Dichroism (CD) spectra, it can be seen that both Ab40 and Arctic-type Ab40(E22G) peptides were converted from random coil to b-sheet after 48 hours
Conformational change is a key step in the Ab-aggregation cascade, during which the conformation of Ab undergoes a structural conversion from either a-helix or random coil to b-sheet [15,16]
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease in the elderly population [1,2,3]. SAD is predominantly diagnosed in people over 65 years of age, and less frequent FAD often occurs in patients under the age of 65 years [5,6]. In SPs, the main component is the b amyloid peptide (Ab), that is either 40 (Ab40) or 42 (Ab42) amino acids long, containing hydrophobic amino acid sequences at its C-termini. This peptide is the proteolytic product of the amyloid precursor protein (APP), which is sequentially cleaved first by b-secretase, by csecretase [8,9]
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