Understanding of the mechanistic progess of Amyloid-β peptide (Aβ) aggregation is

Understanding of the mechanistic progess of Amyloid-β peptide (Aβ) aggregation is critical for elucidating the underlying pathogenesis of Alzheimer’s disease (AD). appropriate experimental conditions. The results suggest that the electrostatic interactions between Aβ40 and the charged vesicles can be of great importance in regulating Aβ40-vesicle interaction. Our results also indicate that the structural properties of the aggregates of the cholesterol derivatives including the surface charge and the size of the vesicles are critical in regulating the effects of these vesicles on Aβ40 aggregation kinetics. Abstract INTRODUCTION Anomalous protein aggregation and fibril formation is one of the dominant characteristics in the pathogenesis of a number of neurodegenerative diseases such as Alzheimer’s Parkinson’s and Creutzfeldt–Jakob diseases.1-3 In Alzheimer’s disease (AD) extensive genetic biochemical and pathological evidence links accumulation and amyloid fibril formation of amyloid-β (Aβ) peptides (e.g. the major components Aβ40 and Aβ42) produced by the β- and γ-secretase cleavage of the parental amyloid precursor protein (APP) to the AD phenotype.4 5 Aβ amyloid fibril contains a typical cross-β-sheet architecture extending Lapatinib (free base) in a direction parallel to the fibril axis identified by high resolution techniques such as solid-state NMR at the molecular level.6-8 Moreover recent evidences suggest that the oligomeric diffusible assemblies of Aβ peptides formed in the early stages of aggregation appear to be highly toxic species in AD.9-11 Although it has been reconciled that both Aβ oligomers and fibrillar plaques may play roles in the progressive degeneration of neurons 12 the fundamental mechanism by which the assembly process causes the toxicity leading to cell death is still unclear. A growing body of recent research highlights the importance of cellular membranes in mediating Aβ self-assembly and the consequent cellular toxicity.13-15 Cholesterol is an essential component of the eukaryotic plasma membrane necessary for Lapatinib (free base) Lapatinib (free base) membrane fluidity permeability and receptor function. Elevated levels of cholesterol have been recgonized as one important risk factor for AD and the role of cholesterol in APP processing and Aβ generation has been supported by recent studies.16-18 Sparks et al. reported a dose-dependent Aβ amyloid accumulation in the brain of rabbits fed with a high-cholesterol diet.19 Cerebral Aβ generation was reported to be cholesterol dependent 20 and guinea pigs treated with high doses of simvastatin a widely used cholesterol-lowering drug showed a strong and reversible reduction of cerebral Aβ levels in the cerebrospinal fluid and brain homogenate.21 Although the mechanism by which cholesterol modulate Aβ generation is unclear lipid rafts the cholesterol-rich membrane microdomains appear to promote β- and γ-secretase processing function.22 23 Furthermore increased free cholesterol in the cytoplasm has also been found to affect the aggregation of Aβ peptides into fibrils.24 25 These suggest that one of the possible roles for cholesterol in AD may be to directly interact with Aβ and consequently modulate the amyloidogenic process of Aβ. Lapatinib (free base) However most of the reports available so LRP1 far have mainly focused on cholesterol as the component in cellular membranes or lipid bilayer or monolayer model membranes 26 leaving the direct investigation of the effects of the pure form of cholesterol on Aβ amyloid formation largely neglected. Although increasing efforts have been provided to put insight into the interactions between cholesterol and Aβ peptides 30 a detailed mechanistic view of cholesterol-mediated Aβ fibrillogenesis is unclear. Cholesterol as a neutral and Lapatinib (free base) hydrophobic steroid molecule can be decorated to form a series of derivatives such as the oxidation metabolite 27-hydroxycholesterol and 24S-hydroxycholesterol. The effects of these derivatives in the pathology of AD have been suggested in recent studies.33 34 Cholesterol sulfate (cholesterol-SO4 Fig. 1) is one of the most important known sterol sulfates and has emerged as a significant lipid constituent in a variety of human tissues 35 with a concentration of ~110-170 μg/mL in human plasma.36 37 While its definite functions in human physiology remain poorly understood considering the potential use of the level of Aβ including the aggregated Aβ species in plasma as a biomarker for early diagnosis of AD 38 the effect of this cholesterol derivative on Aβ amyloidogenesis is of physiological.