Alzheimer’s disease (AD) is the most common type of senile dementia. AD is characterized by neurofibrillary tangles and senile plaques in the pathology of affected brains. Amyloid-β peptides (Aβ) are the major components of senile plaques and are generated by the sequential cleavage of the amyloid precursor protein (APP) by β- and γ-secretase [1]. Aβ40 (40-mer) and Aβ42 (42-mer) are the most common species of Aβ [2]. Aβ40 and Aβ42 share identical amino
Almorexant hydrochloride sequence except that Aβ42 has two extra residues (IA) at the C-terminus. However, Aβ42 aggregates much faster [3], [4], [5], [6] and [7] and is more toxic to neurons in cell culture than Aβ40 [5] and [8]. Although the mechanism of Aβ toxicity is not well understood, Aβ most likely executes its toxicity through oligomeric and/or fibril forms [9]. Therefore the enhanced toxicity of Aβ42 likely derives from its enhanced aggregation. Characterization of the dynamics of Aβ40 and Aβ42 monomers, which are the starting
molecules of aggregation, will provide important insights into the mechanism of Aβ aggregation, Aβ toxicity and the pathogenesis of Alzheimer’s disease. Previous studies of the backbone 15N dynamics on ps–ns time scales revealed that Aβ42 has a more rigid C-terminus than Aβ40 [10], [11] and [12]. It was hypothesized that the rigid C-terminus of Aβ42 may contribute to Aβ aggregation by serving as an internal seed for aggregation and by reducing the entropic cost of aggregation.
