Differential regulation of amyloid-尾 endocytic trafficking and lysosomal degradation by apolipoprotein E isoforms
Li, Jie ,
LaDu, Mary Jo
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Aggregation of amyloid-尾 (A尾) peptides leads to synaptic disruption and neurodegeneration in Alzheimer disease (AD). A major A尾 clearance pathway in the brain is cellular uptake and degradation. However, how A尾 traffics through the endocytic pathway and how AD risk factors regulate this event is unclear. Here we show that the majority of endocytosed A尾 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尾 endocytic trafficking to the lysosomes. We also found that a portion of endocytosed A尾 traffics through Rab11-positive recycling vesicles. A blockage of this A尾 recycling pathway with a constitutively active Rab11 mutant significantly accelerates cellular A尾 accumulation. Inhibition of lysosomal enzymes results in A尾 accumulation and aggregation. Importantly, apolipoprotein E (apoE) accelerates neuronal A尾 uptake, lysosomal trafficking, and degradation in an isoform-dependent manner with apoE3 more efficiently facilitating A尾 trafficking and degradation than apoE4, a risk factor for AD. Taken together, our results demonstrate that A尾 endocytic trafficking to lysosomes for degradation is a major A尾 clearance pathway that is differentially regulated by apoE isoforms. A disturbance of this pathway can lead to accumulation and aggregation of cellular A尾 capable of causing neurotoxicity and seeding amyloid. 漏 2012 by The American Society for Biochemistry and Molecular Biology, Inc.