期刊
JOURNAL OF NEUROSCIENCE
卷 33, 期 49, 页码 19276-19283出版社
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3487-13.2013
关键词
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资金
- National Institutes of Health (NIH) [P01NS074969, R01AG027924, R01AG035355, P01AG030128, R01AG042513, R37AG13956]
- NIH Mayo Clinic ADRC pilot grant [P50AG16574]
- Mayo Clinic CRM Career Developmental Award
Alzheimer's disease (AD) is the most prevalent form of dementia in the elderly population. Accumulation, aggregation, and deposition of amyloid-beta (A beta) peptides generated through proteolytic cleavage of amyloid precursor protein (APP) are likely initiating events in the pathogenesis of AD. While A beta production is accelerated in familial AD, increasing evidence indicates that impaired clearance of A beta is responsible for late-onset AD. Because A beta is mainly generated in neurons, these cells are predicted to have the highest risk of encountering A beta among all cell types in the brain. However, it is still unclear whether they are also involved in A beta 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 A beta clearance. LRP1 is known to be an endocytic receptor for multiple ligands including A beta. Conditional knock-out of Lrp1 in mouse forebrain neurons leads to increased brain A beta levels and exacerbated amyloid plaque deposition selectively in the cortex of amyloid model APP/PS1 mice without affecting A beta production. In vivo microdialysis studies demonstrated that A beta 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 A beta degrading enzymes, neprilysin and insulin-degrading enzyme, the disturbed A beta clearance is likely due to the suppression of LRP1-mediated neuronal A beta uptake and degradation. Together, our results demonstrate that LRP1 plays an important role in receptor-mediated clearance of A beta and indicate that neurons not only produce but also clear A beta.
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