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-beta peptide (A beta) 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 A beta aggregation. We used infrared spectroscopy, thioflavin T fluorescence, and Western blots to evaluate the influence of apoE isoforms on A beta aggregation in vitro. Comparing A beta controls with A beta incubated either with the apoE3 or apoE4 isoform, we report a 30% reduction of the A beta fibrillar content, whereas the oligomeric content is 2 times higher on incubation with the pathological isoform apoE4. ApoE4 would bind and block A beta in its oligomeric conformation, inhibiting further formation of less toxic fibrillar forms of A beta. While previous studies mostly correlated E4 with fibrils, our report underlines a link between apoE4 and A beta oligomers and therefore reconciles apoE4 with the new amyloid cascade hypothesis. Our observations suggest that apoE4 strongly stabilizes A beta oligomers, the pathological species responsible for Alzheimer's disease.-Cerf, E., Gustot, A., Goormaghtigh, E., Ruysschaert, J.-M., Raussens, V. High ability of apolipoprotein E4 to stabilize amyloid-beta peptide oligomers, the pathological entities responsible for Alzheimer's disease. FASEB J. 25, 1585-1595 (2011). www.fasebj.org