Human apolipoprotein E glycosylation and sialylation: from structure to function

Area of Science:

• Neuroscience
• Biochemistry
• Genetics

Background:

• Human apolipoprotein E (ApoE) isoforms (ApoE2, ApoE3, ApoE4) have distinct genetic associations with late-onset sporadic Alzheimer's disease (sAD).
• ApoE4 confers the highest genetic risk for sAD, whereas ApoE2 provides neuroprotection.
• The molecular basis for these opposing effects, despite minimal amino acid differences, remains a significant mystery.

Purpose of the Study:

• To explore the hypothesis that post-translational sialoglycan modification of ApoE isoforms critically influences their distinct roles in sAD etiology.
• To review current knowledge on ApoE glycosylation, particularly sialylation, in the brain and cerebrospinal fluid (CSF).
• To present recent findings on differential sialylation of ApoE isoforms and its potential role in modulating amyloid-beta (Aβ) interactions and pathogenesis.

Main Methods:

• Review of existing literature on ApoE structure, function, and post-translational modifications.
• Analysis of species-, tissue-, and cell-specific glycosylation patterns of ApoE.
• Examination of sialic acid modification (sialylation) in human ApoE from brain, CSF, and plasma.
• Investigation of the relationship between ApoE sialylation levels and interaction with amyloid-beta (Aβ).

Main Results:

• Human ApoE undergoes tissue-specific O-linked glycosylation, with significant sialylation observed in brain and CSF.
• ApoE2 exhibits the highest degree of sialylation, ApoE4 the least, and ApoE3 intermediate levels.
• Sialic acid moieties on ApoE may critically modulate ApoE's interaction with Aβ and subsequent Aβ pathogenesis.

Conclusions:

• Differential sialylation of ApoE isoforms is a novel mechanism potentially explaining their opposing effects on sAD risk.
• Sialylation of ApoE, particularly in the brain, may serve as a key modulator of Aβ pathology in Alzheimer's disease.
• Further research into ApoE sialylation offers promising avenues for understanding sAD and developing therapeutic strategies.