Abstract
Intraneuronal accumulation of amyloid-β(1–42) (Aβ1–42) is one of the earliest signs of Alzheimer’s disease (AD). Cell surface heparan sulfate proteoglycans (HSPGs) have profound influence on the cellular uptake of Aβ1–42 by mediating its attachment and subsequent internalization into the cells. Colocalization of amyloid plaques with members of the syndecan family of HSPGs, along with the increased expression of syndecan-3 and -4 have already been reported in postmortem AD brains. Considering the growing evidence on the involvement of syndecans in the pathogenesis of AD, we analyzed the contribution of syndecans to cellular uptake and fibrillation of Aβ1–42. Among syndecans, the neuron specific syndecan-3 isoform increased cellular uptake of Aβ1–42 the most. Kinetics of Aβ1–42 uptake also proved to be fairly different among SDC family members: syndecan-3 increased Aβ1–42 uptake from the earliest time points, while other syndecans facilitated Aβ1–42 internalization at a slower pace. Internalized Aβ1–42 colocalized with syndecans and flotillins, highlighting the role of lipid-rafts in syndecan-mediated uptake. Syndecan-3 and 4 also triggered fibrillation of Aβ1–42, further emphasizing the pathophysiological relevance of syndecans in plaque formation. Overall our data highlight syndecans, especially the neuron-specific syndecan-3 isoform, as important players in amyloid pathology and show that syndecans, regardless of cell type, facilitate key molecular events in neurodegeneration.
Highlights
Dementia is one of the most important health-care problems in ageing populations[1,2]
While cell surface heparan sulfate proteoglycans (HSPGs) have been already identified as key targets for the cellular attachment and internalization of Aβ1–42, the exact contribution of transmembrane SDCs to Aβ1–42 endocytosis has not been assessed yet
To enable the exact assessment of SDCs’ contribution to cellular uptake of Aβ1–42, while minimizing the interfering effects of other HSPGs or caveolae-mediated endocytosis, stable transfectants of SDCs were created in the K562 cells, a cell line with reportedly low HSPG and no syndecan or glypican expression, along with no detectable levels of caveolin-1, the main component of caveolae[61,62,63,64,65]
Summary
Dementia is one of the most important health-care problems in ageing populations[1,2]. Fibrillation of Aβ1–42 increases its interactions with HSPGs, such as syndecan-4 (SDC4), the universally expressed isoform of the syndecan (SDC) family of transmembrane proteoglycans[35]. SDC1-3 were found to be associated with the majority of senile plaques in AD brains[36] Due to their highly sulfated polyanionic glycosaminoglycan (GAG) chains, SDCs interact with myriad of extracellular cationic ligands and transmit signals from the extracellular space towards the cellular interior, influencing cellular metabolism, transport and information transfer[37,38,39]. SDCs share similar structure: a conserved short, one span transmembrane domain (TM) and the approximately 30 amino acid length cytoplasmic domain (CD) Through their CDs, SDCs effect a large number of signaling cascades[44]. Contrary to SDCs, the cell surface HSPG glypicans mediate internalization of their ligands primarily through caveolin-dependent endocytosis[52]
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