The Binding of Apolipoprotein E to Oligomers and Fibrils of Amyloid-β Alters the Kinetics of Amyloid Aggregation

Abstract

Deposition of amyloid-β (Aβ) in Alzheimer’s disease (AD) is strongly correlated with the APOE genotype. However, the role of apolipoprotein E (apoE) in Aβ aggregation has remained unclear. Here we have used different apoE preparations, such as recombinant protein or protein isolated from cultured astrocytes, to examine the effect of apoE on the aggregation of both Aβ1–40 and Aβ1–42. The kinetics of aggregation, measured by the loss of fluorescence of tetramethylrhodamine-labeled Aβ, is shown to be dramatically slowed by the presence of substoichiometric concentrations of apoE. Using these concentrations, we conclude that apoE binds primarily to and affects the growth of oligomers that lead to the nuclei required for fibril growth. At higher apoE concentrations, the protein also binds to Aβ fibrils, resulting in fibril stabilization and a slower rate of fibril growth. The aggregation of Aβ1–40 is dependent on the apoE isoform, being the most dramatic for apoE4 and less so for apoE3 and apoE2. Our results indicate that the detrimental role of apoE4 in AD could be related to apoE-induced stabilization of the soluble but cytotoxic oligomeric forms and intermediates of Aβ, as well as fibril stabilization.

Apolipoprotein E and Alzheimer's disease: the influence of apolipoprotein E on amyloid-β and other amyloidogenic proteins

“…On the contrary, other studies suggest that apoE isoforms can also inhibit A aggregation, with apoE4 being least effective (63)(64)(65)(66). These seemingly contradicting findings may be explained by the variable experimental conditions, such as the species and source of A used (67) (A40 versus A42, recombinant versus synthetic) and, especially, the preparation and the (resulting) lipidation state of apoE.…”

Label-free detection of ApoE4-mediated β-amyloid aggregation on single nanoparticle uncovering Alzheimer's disease

“…Fig. 4A shows that according to concentration-based LSPR the shift increased from 5 nM to 9 nM and was saturated from 10 nM to 20 nM, which indicated that higher ApoE4 concentration inhibits the growth kinetics of fibrils via a mediation of the interaction between ApoE4 and Aβ fibrils and then stabilization of fibrils (Garai et al, 2014).…”

Helical structure, stability, and dynamics in human apolipoprotein E3 and E4 by hydrogen exchange and mass spectrometry

“…As summarized in the introductory paragraphs, the physiological functions of the apoE molecule involve various binding events that are mediated by amphipathic α-helices located in the N-and C-terminal domains. After dissociation of apoE tetramers [such as occur in plasma HDL-LpE (35)] to the monomeric state (15,47), the C-terminal helical domain initiates hydrophobic interactions such as binding to lipid and lipoprotein surfaces (7,44), and to amyloid-β (13,48). The present HX results prove that the amphipathic α-helix organization in the C-terminal domains of tetrameric WT apoE3 and apoE4 is different and suggest the following explanation for the molecular basis of the enhanced binding of apoE4 in such situations.…”

“…Therefore, at the same apoE expression level, progression down the lipolysis cascade will be relatively limited (8), leading to higher plasma cholesterol levels and, potentially, the increased incidence of cardiovascular disease associated with apoE4 (6). Second, in the brain, the enhanced binding of apoE4 to amyloid-β oligomers can alter the kinetics of aggregation by inhibiting growth and nucleation on the pathway to forming fibrils (13). This effect may promote pathogenesis by, for example, leading to greater accumulation of the cytotoxic oligomeric forms of amyloid-β.…”

“…ApoE4 leads to reduced clearance of extracellular amyloid plaque deposits in the brain (10), increases neuronal degeneration (11), and reduces longevity (12). It is known that apoE can bind to amyloid-β peptide (13), but further mechanistic detail is lacking.…”