Abstract
Beta (β)-amyloid (Aβ) is a causative protein of Alzheimer’s disease (AD). In the pathogenesis of AD, the apolipoprotein (apo) A-I and high-density lipoprotein (HDL) metabolism is essential for the clearance of Aβ. In this study, recombinant Aβ42 was expressed and purified via the pET-30a expression vector and E.coli production system to elucidate the physiological effects of Aβ on HDL metabolism. The recombinant human Aβ protein (51 aa) was purified to at least 95% purity and characterized in either the lipid-free and lipid-bound states with apoA-I. Aβ was incorporated into the reconstituted HDL (rHDL) (molar ratio 95:5:1, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC):cholesterol:apoA-I) with various apoA-I:Aβ ratios from 1:0 to 1:0.5, 1:1 and 1:2. With an increasing molar ratio of Aβ, the α-helicity of apoA-I was decreased from 62% to 36% with a red shift of the Trp wavelength maximum fluorescence from 337 to 340 nm in apoA-I. The glycation reaction of apoA-I was accelerated further by the addition of Aβ. The treatment of fructose and Aβ caused more multimerization of apoA-I in the lipid-free state and in HDL. The phospholipid-binding ability of apoA-I was impaired severely by the addition of Aβ in a dose-dependent manner. The phagocytosis of LDL into macrophages was accelerated more by the presence of Aβ with the production of more oxidized species. Aβ severely impaired tissue regeneration, and a microinjection of Aβ enhanced embryotoxicity. In conclusion, the beneficial functions of apoA-I and HDL were severely impaired by the addition of Aβ via its detrimental effect on secondary structure. The impairment of HDL functionality occurred more synergistically by means of the co-addition of fructose and Aβ.
Highlights
Mild cognitive impairment (MCI), Alzheimer’s disease, and dementia are related to low serum high-density lipoprotein (HDL)-C levels, in middle age [1]
These results suggest that the additioninof the reconstituted HDL (rHDL)
These results suggest that the addition of amyloid β (Aβ) to the apoA-I-rHDL impaired the stabilization of apoA-I in rHDL
Summary
Mild cognitive impairment (MCI), Alzheimer’s disease, and dementia are related to low serum HDL-C levels, in middle age [1]. The functionality of HDL is very important for suppressing the incidence of diabetes, cardiovascular disease, and stroke. Many cardiovascular risk factors, such as hypertension, diabetes mellitus, and dyslipidemia, are important risk factors of Alzheimer’s disease and vascular dementia [5]. Dysfunctional HDL and low serum apoA-I levels are a hallmark of diabetes, inflammation, and CVD [8]. A higher serum level of apoA-I and enhanced HDL functionality are critical for suppressing the incidence of CVD [9,10]. Glycated apolipoproteins are associated with a higher incidence of diabetes and Alzheimer’s disease [12], even though the mechanism has not been fully elucidated. The physiological functionality of apoA-I and the toxicity of the Aβ were evaluated using human macrophage cells, zebrafish embryos, and a wound-healing model of zebrafish
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