An Association of CSF Apolipoprotein E glycosylation and amyloid-beta 42 in individuals who carry the APOE4 allele

Abstract

Carrying the Apolipoprotein E (apoE) ε4 allele is associated with an increased risk of cerebral amyloidosis, but the degree to which apoE glycosylation affects its development is not clear. In a previous pilot study, we identified distinct total and secondary isoform-specific cerebral spinal fluid (CSF) apoE glycosylation profiles, with the apoE4 isoform having the lowest glycosylation percentage (E2 > E3 > E4). In this work, we extend the analysis to a larger cohort of individuals (n = 106), utilizing matched plasma and CSF samples with clinical measures of AD biomarkers. The results confirm the isoform-specific glycosylation of apoE in CSF, resulting from secondary CSF apoE glycosylation patterns. CSF apoE glycosylation percentages positively correlated with CSF Aβ42 levels (r = 0.53, p < 0.0001). These correlations were not observed for plasma apoE glycosylation. CSF total and secondary apoE glycosylation percentages also correlated with the concentration of CSF small high-density lipoprotein (HDL) particles which we have previously shown to be correlated with CSF Aβ42 levels and measures of cognitive function. Desialylation of apoE3 purified from CSF showed increased binding affinity to heparin. These results indicate that apoE glycosylation has a new and important role in influencing brain Aβ metabolism and can be a potential target of treatment.

Distinct patterns of plaque and microglia glycosylation in Alzheimer's disease

“…But, sialylation of APOE is likely critical for proper APOE‐HDL association. Thus, one mechanism for APOE4 exacerbation of amyloid pathology in AD is caused by the decreased sialylation of APOE4 leading to issues with lipidation and ultimately preference for VLDL, reduced binding affinity inducing issues with amyloid beta clearance [ 57 , 58 ]. Additional O ‐glycosylation has been shown to disrupt amyloid precursor protein (APP) processing by reducing Aβ1‐40 generation with marginal impact on Aβ1‐42 generation, potentially because of O ‐glycosylation disrupting protein localization and trafficking, in turn indicating excessive APP O ‐glycosylation alters processing by secretases [ 59 ].…”