Contribution of syndecans to cellular internalization and fibrillation of amyloid-ß(1-42).

ABSTRACT

Intraneuronal accumulation of amyloid-ß(1-42) (Aß1-42) 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 Aß1-42 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 Aß1-42. Among syndecans, the neuron specific syndecan-3 isoform increased cellular uptake of Aß1-42 the most. Kinetics of Aß1-42 uptake also proved to be fairly different among SDC family members syndecan-3 increased Aß1-42 uptake from the earliest time points, while other syndecans facilitated Aß1-42 internalization at a slower pace. Internalized Aß1-42 colocalized with syndecans and flotillins, highlighting the role of lipid-rafts in syndecan-mediated uptake. Syndecan-3 and 4 also triggered fibrillation of Aß1-42, 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.