Hidden Aggregation Hot-Spots on Human Apolipoprotein E: A Structural Study

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.

The Interplay of Apoes with Syndecans in Influencing Key Cellular Events of Amyloid Pathology

“…Fibrillation studies also revealed ApoE4 s propensity to form fibrillar aggregates; however, the size of ApoE4-based fibrils was markedly smaller than those of Aβ1-42. Regardless, these studies further confirmed that due its the intrinsic aggregation-prone regions, ApoE4 (and to a lesser extent, ApoE3) self-assembles into amyloid fibrils in vitro, further triggering (and stabilizing) the fibrillation of Aβ1-42 [55]. Utilizing these very basic SDC-focused cellular assays not only helped to reveal the intricate effect ApoEs exert on Aβ1-42, but also expanded our knowledge of the SDC3-mediated effects of amyloid pathology.…”

“…These effects of ApoE2 and 4 were rather striking on SDC3-overexpressing SH-SY5Y cells, where ApoE2 reduced the number of aggregates, while ApoE4 further increased them. Recent studies have explored small regions with amyloidogenic properties in the amino acid sequences of apoE3 and 4, showing that these aggregation hot spots would drive the self-assembly of amyloid-like fibrils [55]. Thus, we also examined the fibrillation of ApoEs isoforms in the absence of Aβ1-42.…”

Apolipoprotein E Proteinopathy Is a Major Dementia-Associated Pathologic Biomarker in Individuals with or without the APOE Epsilon 4 Allele

“…56e58 Importantly, aggregation-prone regions were previously identified in the central region of ApoE. 59 The APOE ε4 allele has been associated clinically with increased dementia risk and pathologically with increased Ab plaque load. 16,60e65 Our results emphasized the relevance of the ApoE protein as a particularly important protein aggregate constituent in itself and not only as an "upstream" genetic risk factor.…”

Complement Activation in the Central Nervous System: A Biophysical Model for Immune Dysregulation in the Disease State

“…It has been shown that Aβ binds to receptors such as LDLR in the absence of ApoE, and it is known that ApoE facilitates the earliest steps in Aβ self-association as it forms large aggregates. The influence of ApoE may not be from direct physical contact with Aβ (Cho et al, 2001 ; Kara et al, 2018 ; Tsiolaki et al, 2019 ). A CR1+7S: C3b 2 : Factor I: ApoE: Aβ complex is entirely possible from the perspective of biophysical chemistry.…”