Human apolipoprotein E isoforms are differentially sialylated and the sialic acid moiety in ApoE2 attenuates ApoE2-Aβ interaction and Aβ fibrillation

The APOE genotype is the most prominent genetic risk factor for the development of late-onset Alzheimer''s disease (LOAD); however, the underlying mechanisms remain unclear. In the present study, we found that the sialylation profiles of ApoE protein in the human brain are significantly different among the three isoforms, with ApoE2 exhibiting the most abundant sialic acid modification whereas ApoE4 had the least. We further observed that the sialic acid moiety in ApoE2 significantly affected the interaction between ApoE2 and A beta peptides. The removal of sialic acid in ApoE2 increased the ApoE2 binding affinity for the A beta 17-24 region of A beta and promoted A beta fibrillation. These findings provide a plausible explanation for the well-documented differential roles of ApoE isoforms in A beta pathogenesis. Specifically, compared to the other two isotypes, the higher expression of sialic acid in ApoE2 may contribute to the less potent interaction between ApoE2 and A beta and ultimately the slower rate of brain A beta deposition, a mechanism thought to underlie ApoE2-mediated decreased risk for AD. Future studies are warranted to determine whether the differential sialylation in ApoE isoforms may also contribute to some of their other distinct properties, such as their divergent preferences in associations with lipids and lipoproteins, as well as their potential impact on neuroinflammation through modulation of microglial Siglec activity. Overall, our findings lead to the insight that the sialic acid structure is an important posttranslational modification (PTM) that alters ApoE protein functions with relevance for AD.

Automated summary

APOE genotype is associated with the risk of late-onset Alzheimer's disease (LOAD). Sialic acid modification affects the function of ApoE protein and the interaction with Aβ peptides, providing a possible explanation for the differential roles of ApoE isoforms in Aβ pathology.