Neuronal Clearance of Amyloid-beta by Endocytic Receptor LRP1

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	Neuronal Clearance of Amyloid-beta by Endocytic Receptor LRP1
	Kanekiyo, Takahisa ; Cirrito, John R. ; Liu, Chia-Chen ; Shinohara, Mitsuru ; Li, Jie ; Schuler, Dorothy R. ; Shinohara, Motoko ; Holtzman, David M. ; Bu, Guojun ; Bu GJ(卜国军)
刊名	http://dx.doi.org/10.1523/JNEUROSCI.3487-13.2013
	2013
关键词	CENTRAL-NERVOUS-SYSTEM ALZHEIMERS-DISEASE TRANSGENIC MICE APOLIPOPROTEIN-E PRECURSOR PROTEIN IN-VIVO A-BETA INTERSTITIAL FLUID BRAIN DEPOSITION
英文摘要	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.
语种	英语
出版者	SOC NEUROSCIENCE
内容类型	期刊论文
源URL	[http://dspace.xmu.edu.cn/handle/2288/93421]
专题	医学院－已发表论文
推荐引用方式 GB/T 7714	Kanekiyo, Takahisa,Cirrito, John R.,Liu, Chia-Chen,et al. Neuronal Clearance of Amyloid-beta by Endocytic Receptor LRP1[J]. http://dx.doi.org/10.1523/JNEUROSCI.3487-13.2013,2013.
APA	Kanekiyo, Takahisa.,Cirrito, John R..,Liu, Chia-Chen.,Shinohara, Mitsuru.,Li, Jie.,...&卜国军.(2013).Neuronal Clearance of Amyloid-beta by Endocytic Receptor LRP1.http://dx.doi.org/10.1523/JNEUROSCI.3487-13.2013.
MLA	Kanekiyo, Takahisa,et al."Neuronal Clearance of Amyloid-beta by Endocytic Receptor LRP1".http://dx.doi.org/10.1523/JNEUROSCI.3487-13.2013 (2013).