Differential Regulation of Amyloid-β Endocytic Trafficking and Lysosomal Degradation by Apolipoprotein E Isoforms
journal contributionposted on 2014-04-15, 00:00 authored by Jie Li, Takahisa Kanekiyo, Mitsuru Shinohara, Yunwu Zhang, Mary Jo LaDu, Huaxi Xu, Guojun Bu
Aggregation 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.
This 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.).
Publisher StatementThis 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 Biology
PublisherAmerican Society for Biochemistry and Molecular Biology