| First Author | Kanekiyo T | Year | 2013 |
| Journal | J Neurosci | Volume | 33 |
| Issue | 49 | Pages | 19276-83 |
| PubMed ID | 24305823 | Mgi Jnum | J:204149 |
| Mgi Id | MGI:5529723 | Doi | 10.1523/JNEUROSCI.3487-13.2013 |
| Citation | Kanekiyo T, et al. (2013) Neuronal clearance of amyloid-beta by endocytic receptor LRP1. J Neurosci 33(49):19276-83 |
| abstractText | Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population. Accumulation, aggregation, and deposition of amyloid-beta (Abeta) peptides generated through proteolytic cleavage of amyloid precursor protein (APP) are likely initiating events in the pathogenesis of AD. While Abeta production is accelerated in familial AD, increasing evidence indicates that impaired clearance of Abeta is responsible for late-onset AD. Because Abeta is mainly generated in neurons, these cells are predicted to have the highest risk of encountering Abeta among all cell types in the brain. However, it is still unclear whether they are also involved in Abeta clearance. Here we show that receptor-mediated endocytosis in neurons by the low-density lipoprotein receptor-related protein 1 (LRP1) plays a critical role in brain Abeta clearance. LRP1 is known to be an endocytic receptor for multiple ligands including Abeta. Conditional knock-out of Lrp1 in mouse forebrain neurons leads to increased brain Abeta levels and exacerbated amyloid plaque deposition selectively in the cortex of amyloid model APP/PS1 mice without affecting Abeta production. In vivo microdialysis studies demonstrated that Abeta clearance in brain interstitial fluid is impaired in neuronal Lrp1 knock-out mice. Because the neuronal LRP1-deletion did not affect the mRNA levels of major Abeta degrading enzymes, neprilysin and insulin-degrading enzyme, the disturbed Abeta clearance is likely due to the suppression of LRP1-mediated neuronal Abeta uptake and degradation. Together, our results demonstrate that LRP1 plays an important role in receptor-mediated clearance of Abeta and indicate that neurons not only produce but also clear Abeta. |
