Contribution of syndecans to cellular internalization and fibrillation of amyloid-β(1–42)

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.

Contribution of syndecans to the cellular entry of SARS-CoV-2

“…Our related studies with non-viral drug delivery agents, including cell-penetrating peptides (CPPs) and cationic liposomes, contributed to the understanding of SDCs' capacity to deliver bioactive macromolecules into the cells 43,44,64 . Moreover, we also revealed that SDCs contribute to the seeding and prion-like spreading of pathological protein aggregates, the major molecular culprits responsible for the onset of neurodegenerative disorders 45,46 . During these endeavors, we have been developing several SDC speci c assays and constructs, enabling thorough analyses of SDCs' interactions with potential ligands.…”

“…SDCs share a similar structure: a one-span and highly conserved transmembrane domain (TM) and a relatively short cytoplasmic domain (CD) 43,44 . The extracellular domain (ectodomain) of SDCs is more diverse, containing HS attachment sites with glycosaminoglycan (GAG) side chains 45,46 .…”

“…Through their highly sulfated GAG chains, SDCs interact with a myriad of extracellular ligands, hence transmitting extracellular signals intracellularly 40,[45][46][47][48] . Besides cell signaling, SDCs also mediate the intracellular transport of ligands [45][46][47] .…”

“…Through their highly sulfated GAG chains, SDCs interact with a myriad of extracellular ligands, hence transmitting extracellular signals intracellularly 40,[45][46][47][48] . Besides cell signaling, SDCs also mediate the intracellular transport of ligands [45][46][47] . During SDC-mediated endocytosis, ligand-mediated clustering of SDCs induces the redistribution of SDCs to lipid rafts and stimulation of a lipid raft-dependent, but clathrin-and caveolae-independent endocytosis of the SDC-ligand complex 46,47,49 .…”

“…Besides cell signaling, SDCs also mediate the intracellular transport of ligands [45][46][47] . During SDC-mediated endocytosis, ligand-mediated clustering of SDCs induces the redistribution of SDCs to lipid rafts and stimulation of a lipid raft-dependent, but clathrin-and caveolae-independent endocytosis of the SDC-ligand complex 46,47,49 . As ligands internalized through SDC-mediated endocytosis can avoid lysosomal degradation, several parasites, including viruses and bacteria, utilize SDCs as shuttles to enter the cells [50][51][52][53][54][55][56] .…”