Syndecan-4 exerts canonical heparan sulfate-dependent and noncanonical heparan sulfate-independent functions that regulate Aβ amyloid homeostasis
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Background
Heparan sulfate (HS) and heparan sulfate proteoglycans (HSPGs) are components of the amyloid deposits in Alzheimer’s disease (AD) and other amyloidoses. HS and HSPGs are canonically thought to facilitate amyloid deposition by accelerating the aggregation of amyloidogenic proteins and impairing their clearance in a HS-dependent manner.
Methods
Leveraging insights from large-scale proteomic data, we focused on Syndecan-4 (Sdc4), the most increased transmembrane HSPG in the AD brain and in the brain of Aβ amyloid depositing mice. We used proximity ligation assays (PLA) to evaluate the association of Sdc4 with Aβ in situ and assessed the impacts of the Sdc4 ectodomain on Aβ aggregation in vitro . Overexpression studies in cells, hiPSC-derived neurons, and mouse organotypic brain slice cultures (OBSCs) coupled with structure-function studies were used to investigate impacts on Aβ production and APP processing. Finally, effects of overexpression of Sdc4 in vivo in the CRND8 amyloid deposition model were evaluated.
Results
Consistent with canonical roles, PLA demonstrated a spatial association of Sdc4 with amyloid deposits, and in vitro , the Sdc4 ectodomain accelerated Aβ fibril formation in a HS-dependent manner. Unexpectedly, Sdc4 overexpression reduced Aβ production in CHO cells, hiPSC-derived neurons, and OBSCs. These effects were accompanied by dramatic decreases in the levels of sAPPα and C83 and increased immature APP in the cell. Sdc4 promoted altered APP localization into detergent resistant membrane domains and increased APP association with ATG5+/LC3+/Cathepsin D+ vesicles. Structure-function studies revealed that the transmembrane region mediates these effects in a glycosaminoglycan-independent manner. Sdc4 overexpression in the brain of APP mice significantly reduced amyloid deposition at an early age.
Conclusions
Sdc4 exerts paradoxical and mechanistically distinct effects that could impact AD pathogenesis differentially, potentially promoting Aβ fibrillization extracellularly while suppressing APP processing and Aβ production. Such data challenge the prevailing view that increased levels of HSPGs in AD are always pro-amyloidogenic and identify Sdc4 as a previously unrecognized regulator of amyloid homeostasis in AD.
