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

Abstract

Carrying the apolipoprotein E (ApoE) Ɛ4 allele is associated with an increased risk of cerebral amyloidosis and late-onset Alzheimer’s disease, 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 E4 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 particles (s-HDL-P), which we have previously shown to be correlated with CSF Aβ42 levels and measures of cognitive function. Desialylation of apoE purified from CSF showed reduced Aβ42 degradation in microglia with E4 > E3 and 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 Oglycosylation disrupting protein localization and trafficking, in turn indicating excessive APP O-glycosylation alters processing by secretases [59].…”

New insight into protein glycosylation in the development of Alzheimer’s disease

“…Changes in glycosylation levels may affect the ability of APOE to aid in Aβ clearance and degradation through receptor-mediated transcytosis and endocytosis by affecting their binding to HDL. This provides new ideas on how APOE affects the pathogenesis of AD [ 97 ].…”