期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 22, 期 13, 页码 -出版社
MDPI
DOI: 10.3390/ijms22137070
关键词
ApoE; amyloid beta; syndecans; protein aggregation; endocytosis; neurodegeneration
资金
- Innovative Medicines Initiative 2 Joint Undertaking [807015]
- European Union's Horizon 2020 research and innovation programme
- EFPIA
- European Union's Horizon 2020 Research and Innovation Programme under Future and Emerging Technologies [863214]
- National Research, Development and Innovation Office, Hungary [GINOP-2.1.2-8-1-4-16-2017-00234, EUREKA_16-1-20170018, 2019-2.1.1-EUREKA-2019-00007, 2017-2.3.6-TET-CN-2018-00023]
The interaction between different isoforms of Apolipoprotein E and syndecans plays a role in the pathogenesis of Alzheimer's disease, with ApoE2 preventing intracellular aggregation of A beta while ApoE4 facilitates extracellular plaque formation. This study reveals new insights into the cellular biology of ApoE and enhances our understanding of the ApoE-dependent mechanism of A beta pathology.
Apolipoprotein E (ApoE) isoforms exert intricate effects on cellular physiology beyond lipid transport and metabolism. ApoEs influence the onset of Alzheimer's disease (AD) in an isoform-dependent manner: ApoE4 increases AD risk, while ApoE2 decreases it. Previously we demonstrated that syndecans, a transmembrane proteoglycan family with increased expression in AD, trigger the aggregation and modulate the cellular uptake of amyloid beta (A beta). Utilizing our previously established syndecan-overexpressing cellular assays, we now explore how the interplay of ApoEs with syndecans contributes to key events, namely uptake and aggregation, in A beta pathology. The interaction of ApoEs with syndecans indicates isoform-specific characteristics arising beyond the frequently studied ApoE-heparan sulfate interactions. Syndecans, and among them the neuronal syndecan-3, increased the cellular uptake of ApoEs, especially ApoE2 and ApoE3, while ApoEs exerted opposing effects on syndecan-3-mediated A beta uptake and aggregation. ApoE2 increased the cellular internalization of monomeric A beta, hence preventing its extracellular aggregation, while ApoE4 decreased it, thus helping the buildup of extracellular plaques. The contrary effects of ApoE2 and ApoE4 remained once A beta aggregated: while ApoE2 reduced the uptake of A beta aggregates, ApoE4 facilitated it. Fibrillation studies also revealed ApoE4 ' s tendency to form fibrillar aggregates. Our results uncover yet unknown details of ApoE cellular biology and deepen our molecular understanding of the ApoE-dependent mechanism of A beta pathology.
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