Apolipoprotein-E increases cell-associated amyloid-β through a heparan sulfate-dependent pathway
(English)Manuscript (preprint) (Other academic)
The increased risk of Alzheimer’s disease (AD) associated with specific apolipoprotein E (ApoE) isoforms appears to relate to altered amyloid-β (Aβ) homeostasis. The efficiency of Aβ clearance from the brain is reduced in the presence of the AD-associated ApoE4 isoform, which may explain the accumulation of Aβ deposits in the parenchyma and vasculature. The low density lipoprotein receptor-related protein 1 (LRP1) and heparan sulfate proteoglycans (HSPGs) are involved in Aβ uptake, with LRP1 further implicated in Aβ transcytosis across the blood brain barrier. However, both are also established ApoE receptors and function co-operatively to mediate cell interactions with lipoproteins and Aβ. Here we determined that HS, ApoE and LRP1 co-occur in Aβ40-positive microvessels of AD brain, establishing the relevance of studying interactions between these molecules. Using Chinese hamster ovary (CHO) cells deficient in HS or LRP1 we found that ApoE increases the levels of cell-associated Aβ in primarily a HSPG-dependent manner. Furthermore, in this model we found that ApoE is alternatively processed in the absence of cell surface HS, supporting a role for HSPGs in ApoE metabolism. The findings presented here raise the possibility that ApoE can increase Aβ associations with HSPGs and LRP1 in the vasculature. This may facilitate clearance, but if unbalanced could contribute to Aβ accumulation and the pathogenesis of AD.
Cell and Molecular Biology
IdentifiersURN: urn:nbn:se:uu:diva-159926OAI: oai:DiVA.org:uu-159926DiVA: diva2:447491