Show simple item record

dc.contributor.authorLi, Jie
dc.contributor.authorKanekiyo, Takahisa
dc.contributor.authorShinohara, Mitsuru
dc.contributor.authorZhang, Yunwu
dc.contributor.authorLaDu, Mary Jo
dc.contributor.authorXu, Huaxi
dc.contributor.authorBu, Guojun
dc.date.accessioned2013-11-26T21:37:17Z
dc.date.available2014-04-15T09:30:45Z
dc.date.issued2012-12
dc.identifier.bibliographicCitationLi, J. Kanekiyo, T. Shinohara, M. Zhang, Y. W. LaDu, M. J. Xu, H. X. Bu, G. J.. Differential Regulation of Amyloid-beta Endocytic Trafficking and Lysosomal Degradation by Apolipoprotein E Isoforms. Journal of Biological Chemistry. Dec 2012;287(53):44593-44601. DOI: 10.1074/jbc.M112.420224en_US
dc.identifier.issn0021-9258
dc.identifier.urihttp://hdl.handle.net/10027/10680
dc.descriptionThis research was originally published in Journal of Biological Chemistry. Differential Regulation of Amyloid-beta Endocytic Trafficking and Lysosomal Degradation by Apolipoprotein E Isoforms. Journal of Biological Chemistry. Dec 2012;287(53):44593-44601. © the American Society for Biochemistry and Molecular Biologyen_US
dc.description.abstractAggregation of amyloid-beta (A beta) peptides leads to synaptic disruption and neurodegeneration in Alzheimer disease (AD). A major A beta clearance pathway in the brain is cellular uptake and degradation. However, how A beta traffics through the endocytic pathway and how AD risk factors regulate this event is unclear. Here we show that the majority of endocytosed A beta in neurons traffics through early and late endosomes to the lysosomes for degradation. Overexpression of Rab5 or Rab7, small GTPases that function in vesicle fusion for early and late endosomes, respectively, significantly accelerates A beta endocytic trafficking to the lysosomes. We also found that a portion of endocytosed A beta traffics through Rab11-positive recycling vesicles. A blockage of this A beta recycling pathway with a constitutively active Rab11 mutant significantly accelerates cellular A beta accumulation. Inhibition of lysosomal enzymes results in A beta accumulation and aggregation. Importantly, apolipoprotein E (apoE) accelerates neuronal A beta uptake, lysosomal trafficking, and degradation in an isoform-dependent manner with apoE3 more efficiently facilitating A beta trafficking and degradation than apoE4, a risk factor for AD. Taken together, our results demonstrate that A beta endocytic trafficking to lysosomes for degradation is a major A beta clearance pathway that is differentially regulated by apoE isoforms. A disturbance of this pathway can lead to accumulation and aggregation of cellular A beta capable of causing neurotoxicity and seeding amyloid.en_US
dc.description.sponsorshipThis work was supported by NIH grants R01AG027924, R01AG035355, P01AG030128, and P01 NS074969 (to G.B.), a grant from the Alzheimer's Association (to G.B.), and a NIH ADRC pilot grant P50AG16574 (to T.K.).en_US
dc.language.isoen_USen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biologyen_US
dc.subjectAlzheimer’s diseaseen_US
dc.subjectdegradationen_US
dc.subjectlysosomeen_US
dc.titleDifferential Regulation of Amyloid-β Endocytic Trafficking and Lysosomal Degradation by Apolipoprotein E Isoformsen_US
dc.typeArticleen_US


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record