Abstract
Human apolipoprotein E (apoE) is a major component of lipoprotein particles, and under physiological conditions, is involved in plasma cholesterol transport. Human apolipoprotein E found in three isoforms (E2; E3; E4) is a member of a family of apolipoproteins that under pathological conditions are detected in extracellular amyloid depositions in several amyloidoses. Interestingly, the lipid-free apoE form has been shown to be co-localized with the amyloidogenic Aβ peptide in amyloid plaques in Alzheimer’s disease, whereas in particular, the apoE4 isoform is a crucial risk factor for late-onset Alzheimer’s disease. Evidence at the experimental level proves that apoE self-assembles into amyloid fibrilsin vitro, although the misfolding mechanism has not been clarified yet. Here, we explored the mechanistic insights of apoE misfolding by testing short apoE stretches predicted as amyloidogenic determinants by AMYLPRED, and we computationally investigated the dynamics of apoE and an apoE–Αβ complex. Our in vitro biophysical results prove that apoE peptide–analogues may act as the driving force needed to trigger apoE aggregation and are supported by the computational apoE outcome. Additional computational work concerning the apoE–Αβ complex also designates apoE amyloidogenic regions as important binding sites for oligomeric Αβ; taking an important step forward in the field of Alzheimer’s anti-aggregation drug development.
Highlights
Human mature apolipoprotein E is a 299 amino acid glycoprotein [1,2], taking part in most lipoprotein classes, such as chylomicrons, very low-density lipoproteins (VLDL) and high-density lipoproteins (HDL) [3]
The purpose of this study was to investigate the poorly explored amyloidogenic properties of human apolipoprotein E [58,63], a protein closely associated with disorders with worldwide prevalence, such as Alzheimer’s disease [23,24]
Recently in vivo, causing rare forms of hereditary systemic amyloidosis [104,105]. These two newly identified fibril proteins expand the list of amyloidogenic apolipoproteins associated with amyloidoses [38] and draw attention to unknown aggregation properties of the apolipoprotein family
Summary
Human mature apolipoprotein E (apoE) is a 299 amino acid glycoprotein [1,2], taking part in most lipoprotein classes, such as chylomicrons, very low-density lipoproteins (VLDL) and high-density lipoproteins (HDL) [3]. It is a member of an apolipoprotein family, along with apoA-I, apoA-II, apoA-IV, ApoC-I, apoC-II, and apoC-III [4,5]. Each allele exhibits distinct frequencies among the human population, with APOE3 having the highest (approximately 78%) [19,20,21] The expression of these alleles results in three main forms of the protein, namely, apoE2, apoE3, and apoE4. The apoE4 isoform is of great importance, since it is reported to be involved in both hereditary and sporadic
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