| First Author | Kanekiyo T | Year | 2011 |
| Journal | J Neurosci | Volume | 31 |
| Issue | 5 | Pages | 1644-51 |
| PubMed ID | 21289173 | Mgi Jnum | J:241063 |
| Mgi Id | MGI:5897551 | Doi | 10.1523/JNEUROSCI.5491-10.2011 |
| Citation | Kanekiyo T, et al. (2011) Heparan sulphate proteoglycan and the low-density lipoprotein receptor-related protein 1 constitute major pathways for neuronal amyloid-beta uptake. J Neurosci 31(5):1644-51 |
| abstractText | Alzheimer's disease (AD) is a progressive and irreversible neurodegenerative disorder in which the aggregation and deposition of amyloid-beta (Abeta) peptides in the brain are central to its pathogenesis. In healthy brains, Abeta is effectively metabolized with little accumulation. Cellular uptake and subsequent degradation of Abeta 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 Abeta 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 Abeta uptake. Fluorescence-activated cell sorter and confocal microscopy revealed that knockdown of LRP1 suppresses Abeta uptake, whereas overexpression of LRP1 enhances this process in neuronal cells. Heparin, which antagonizes HSPG, significantly inhibited cellular Abeta uptake. Importantly, treatment with heparin or heparinase blocked LRP1-mediated cellular uptake of Abeta. We further showed that HSPG is more important for the binding of Abeta to the cell surface than LRP1. The critical roles of HSPG in cellular Abeta 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 Abeta uptake in primary neurons. Our findings demonstrate that LRP1 and HSPG function in a cooperative manner to mediate cellular Abeta uptake and define a major pathway through which Abeta gains entry to neuronal cells. |
