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- Title
Neuronal Clearance of Amyloid-ß by Endocytic Receptor LRP1.
- Authors
Takahisa Kanekiyo; Cirrito, John R.; Chia-Chen Liu; Shinohara, Mitsuru; Jie Li; Schuler, Dorothy R.; Motoko Shinohara; Holtzman, David M.; Guojun Bu
- Abstract
Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population. Accumulation, aggregation, and deposition of amyloid-ß (Aß) peptides generated through proteolytic cleavage of amyloid precursor protein (APP) are likely initiating events in the pathogenesis of AD. While Aß production is accelerated in familial AD, increasing evidence indicates that impaired clearance of Aß is responsible for late-onset AD. Because Aß is mainly generated in neurons, these cells are predicted to have the highest risk of encoun-tering Aß among all cell types in the brain. However, it is still unclear whether they are also involved in Aß 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 Aß clearance. LRP1 is known to be an endocytic receptor for multiple ligands including Aß. Conditional knock-out of Lrpl in mouse forebrain neurons leads to increased brain Aß levels and exacerbated amyloid plaque deposition selectively in the cortex of amyloid model APP/PS1 mice without affectingAß production. In vivo microdialysis studies demonstrated that Aß clearance in brain interstitial fluid is impaired in neuronal Lrpl knock-out mice. Because the neuronal LRP1-deletion did not affect the mRNA levels of major Aß degrading enzymes, neprilysin and insulin-degrading enzyme, the disturbed Aß clearance is likely due to the suppression of LRP1-mediated neuronal Aß uptake and degradation. Together, our results demonstrate that LRP1 plays an important role in receptor-mediated clearance of Aß and indicate that neurons not only produce but also clear Aß.
- Subjects
ETIOLOGY of Alzheimer's disease; DEMENTIA patients; AMYLOID genetics; PROTEOLYTIC enzyme structure; BIOLOGICAL aggregation; ENDOCYTOSIS
- Publication
Journal of Neuroscience, 2013, Vol 33, Issue 49, p19276
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.3487-13.2013