Objective: To investigate whether apolipoprotein E (ApoE) isoforms directly interact with α-synuclein and determine how these interactions influence aggregation dynamics and cellular uptake.

Background: The accumulation of aggregated α-synuclein is a central pathological feature of Parkinson’s disease. Clinical observations indicate that individuals carrying the APOE4 allele are more likely to develop cognitive impairment and exhibit a wider distribution of α-synuclein pathology across brain regions, independently of β-amyloid pathology. Although experimental studies support a relationship between ApoE and α-synuclein pathology, the molecular basis of this interaction remains poorly understood.

Method: Single-molecule approaches were used to examine interactions between unlipidated ApoE isoforms (ApoE2, ApoE3, ApoE4) and α-synuclein and to quantify their effects on aggregation kinetics. ApoE was tested across concentrations ranging from 0.1 to 0.4 µM. Two-color fluorescence cross-correlation spectroscopy was employed to assess co-localization between ApoE and α-synuclein species. Cellular uptake of aggregates generated in the presence of different ApoE isoforms was evaluated using SH-SY5Y neuroblastoma cells.

Results: Unlipidated ApoE was found to associate directly with α-synuclein at the single-molecule level and to influence aggregation behavior in an isoform-dependent manner. The presence of ApoE slowed fibril formation, with the magnitude of the effect following the order ApoE4 > ApoE3 > ApoE2, and increasing ApoE concentrations enhanced this delay. ApoE promoted the stabilization of intermediate α-synuclein assemblies, with the strongest retention observed for ApoE4. Two-color fluorescence cross-correlation analysis confirmed that ApoE and α-synuclein co-localized within these intermediate complexes. In cellular assays, α-synuclein species generated in the presence of ApoE4 were internalized more efficiently by SH-SY5Y cells than those formed with ApoE2 or ApoE3.

Conclusion: These findings demonstrate that ApoE isoforms differentially influence both the aggregation pathway and cellular uptake of α-synuclein. ApoE4 favors the persistence of intermediate co-aggregated species and enhances their internalization by cells. This mechanism may contribute to the elevated risk of dementia observed in APOE4 carriers with Parkinson’s disease.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/role-of-apoe-in-%ce%b1-synuclein-pathology/