High ability of apolipoprotein E4 to stabilize amyloid-β peptide oligomers, the pathological entities responsible for Alzheimer's disease.
Nowadays, the emerging role of amyloid-β peptide (Aβ) oligomers in Alzheimer's disease (AD) is widely accepted, putting aside the old idea that fibrils are the primary entities responsible for the onset of the disease. Besides, carrying the E4 isoform of apolipoprotein E (apoE) represents the highest risk of developing AD. Nevertheless, the involvement of apoE4 in AD remains confusing. The goal of this study was to bring new insights into the role of apoE4 in Aβ aggregation. We used infrared spectroscopy, thioflavin T fluorescence, and Western blots to evaluate the influence of apoE isoforms on Aβ aggregation in vitro. Comparing Aβ controls with Aβ incubated either with the apoE3 or apoE4 isoform, we report a 30% reduction of the Aβ fibrillar content, whereas the oligomeric content is 2 times higher on incubation with the pathological isoform apoE4. ApoE4 would bind and block Aβ in its oligomeric conformation, inhibiting further formation of less toxic fibrillar forms of Aβ. While previous studies mostly correlated E4 with fibrils, our report underlines a link between apoE4 and Aβ oligomers and therefore reconciles apoE4 with the new amyloid cascade hypothesis. Our observations suggest that apoE4 strongly stabilizes Aβ oligomers, the pathological species responsible for Alzheimer's disease.
Structure and Function of Biological Membranes, Center for Structural Biology and Bioinformatics, Université Libre de Bruxelles, Brussels, Belgium.
Emilie
E
Cerf
Adelin
A
Gustot
Erik
E
Goormaghtigh
Jean-Marie
JM
Ruysschaert
Vincent
V
Raussens
D000544:Alzheimer Disease / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism*; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D052160:Benzothiazoles; D015153:Blotting, Western; D004586:Electrophoresis; D006801:Humans; D013055:Spectrophotometry, Infrared; D017550:Spectroscopy, Fourier Transform Infrared; D013844:Thiazoles / Q000378:metabolism
D016229:Amyloid beta-Peptides; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4; D052160:Benzothiazoles; D013844:Thiazoles; C009462:thioflavin T