The Interplay of Apoes with Syndecans in Influencing Key Cellular Events of Amyloid Pathology

Hudák, Anett and Jósvay, Katalin and Racskóné Domonkos, Ildikó and Letoha, Annamaria and Szilák, László (2021) The Interplay of Apoes with Syndecans in Influencing Key Cellular Events of Amyloid Pathology. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, 22 (13). ISSN 1661-6596

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Abstract

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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