Amyloid beta (Aβ) oligomers are the primary neurotoxic species in Alzheimer’s disease (AD), with their levels strongly depending on APOE genotype. The APOE4 allele, a major genetic risk factor for AD, is associated with an increased level of Aβ oligomers, compared to APOE3 (WT) and protective APOE2. However, it remains unclear whether the differences are due to isoform-specific binding of ApoE or differential modulation of glial uptake. Here, we optimized protocols for the reproducible preparation of Aβ oligomers and measured their hydrodynamic radii alongside Aβ monomers and fibrils via fluorescence correlation spectroscopy (FCS). We then used fluorescence polarization to measure the dissociation constants between ApoE isoforms (lipidated or unlipidated) and Aβ in various aggregation states, and examined the impact of the interaction on Aβ uptake by human astrocytes. We observed that binding was dependent on both Aβ aggregation state and ApoE lipidation. While all isoforms of unlipidated ApoE equally bound Aβ oligomers, lipidated ApoE lost this ability. In contrast, both lipidated and unlipidated ApoE bound Aβ fibrils, and neither bound Aβ monomers. Functionally, ApoE’s effect on Aβ uptake was directly correlated with Aβ interaction. Unlipidated ApoE inhibited Aβ oligomer uptake more substantially compared to lipidated ApoE. Aβ monomer uptake was unaffected by either lipidated or unlipidated ApoE, while both had a similar inhibitory effect on Aβ fibrils. Our results suggest that APOE genotype-specific AD risks are driven by isoform-specific differences in lipidation in vivo, not by intrinsic isoform differences. We propose that ApoE4, which is known to be poorly lipidated in vivo, interacts with Aβ oligomers, leading to reduced glial uptake and subsequent cytotoxicity. Taken together, our work supports the existing therapeutic efforts aimed at increasing ApoE lipidation to alleviate AD pathology.
Nurmakova et al. (Sun,) studied this question.