High ability of ApoE4 to interfere with Aβ aggregation

The aggregation of the highly hydrophobic amyloid-beta peptide (Aβ) is most probably the early event in Alzheimer's disease (AD) that subsequently leads to amyloid plaques deposition in the brain, synapses degeneration and eventually neuronal death. The ∊4 allele of apolipoprotein E (ApoE) gene is the major known genetic risk factor in late onset AD as people carrying one ∊4 allele have significantly higher chances to develop AD. A few mechanisms underlying this pathogenic nature have been identified. Nevertheless, none of them have been completely elucidated. Our group has shown that infrared spectroscopy (Attenuated Total Reflection-Fourier Transform IR) could discriminate between Aβ(1-42) oligomers and fibrils from a structural point of view. Indeed, oligomers display anti-parallel β-sheet spectral components while fibrils are characterized by a parallel β-sheet organization. Using those structural features to characterize the oligomeric content of our samples, we studied the influence of lipid-free ApoE on Aβ(1-42) αγγρ∊γατιoν. The data we collected from our IR experiments as well as Thioflavin T fluorescence measurements and western blots, led us to the conclusion that the presence of ApoE4 prevents the formation of insoluble fibrils and decreases Aβ aggregation rate by stabilizing the oligomeric forms of Aβ. Nevertheless, the phenomenon seems to concern all kinds of oligomeric species present in the sample rather than specifically targeting some oligomers in particular. Although Aβ aggregation pathway still remains unclear, it is now well-established that soluble oligomers exhibit an enhanced toxicity in comparison to monomers or insoluble fibrils. This ability of ApoE4 to stabilize the most toxic species of Aβ could therefore explain its impact on AD.