Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-beta uptake.

ABSTRACT: Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder in which the aggregation and deposition of amyloid-? (A?) peptides in the brain are central to its pathogenesis. In healthy brains, A? is effectively metabolized with little accumulation. Cellular uptake and subsequent degradation of A? is one of the major pathways for its clearance in the brain. Increasing evidence has demonstrated significant roles for the low-density lipoprotein receptor-related protein 1 (LRP1) in the metabolism of A? in neurons, glia cells, and along the brain vasculatures. Heparan sulfate proteoglycan (HSPG) has also been implicated in several pathogenic features of AD, including its colocalization with amyloid plaques. Here, we demonstrate that HSPG and LRP1 cooperatively mediate cellular A? uptake. Fluorescence-activated cell sorter and confocal microscopy revealed that knockdown of LRP1 suppresses A? uptake, whereas overexpression of LRP1 enhances this process in neuronal cells. Heparin, which antagonizes HSPG, significantly inhibited cellular A? uptake. Importantly, treatment with heparin or heparinase blocked LRP1-mediated cellular uptake of A?. We further showed that HSPG is more important for the binding of A? to the cell surface than LRP1. The critical roles of HSPG in cellular A? binding and uptake were confirmed in Chinese hamster ovary cells genetically deficient in HSPG. We also showed that heparin and a neutralizing antibody to LRP1 suppressed A? uptake in primary neurons. Our findings demonstrate that LRP1 and HSPG function in a cooperative manner to mediate cellular A? uptake and define a major pathway through which A? gains entry to neuronal cells.

SUBMITTER: Kanekiyo T 

PROVIDER: S-EPMC3272839 | biostudies-literature | 2011 Feb

REPOSITORIES: biostudies-literature