Differential Regulation of Amyloid-β Endocytic Trafficking and Lysosomal Degradation by Apolipoprotein E Isoforms

• DOI: 10.1074/jbc.m112.420224
• Publication Date: 2012-11-07T22:49:04Z
• Authors: Jie Li; Takahisa Kanekiyo; Mitsuru Shinohara; Yunwu Zhang; Mary Jo LaDu; Huaxi Xu; Guojun Bu
• Keywords: CLEARANCE; 571; Apolipoprotein E4; Apolipoprotein E3; PROTEIN; Endosomes; IDENTIFIES VARIANTS; Mice; 03 medical and health sciences; OLIGOMERS; Alzheimer Disease; Cell Line, Tumor; Animals; Humans; PEPTIDE; Recycling; DOWN-SYNDROME; GENOME-WIDE ASSOCIATION; DEPOSITION; Cells, Cultured; Glycoproteins; rab5 GTP-Binding Proteins; Neurons; 0303 health sciences; Amyloid beta-Peptides; rab7 GTP-Binding Proteins; Endocytosis; Mice, Inbred C57BL; Enzyme inhibition; Protein Transport; rab GTP-Binding Proteins; Proteolysis; Lysosomes; SOLUBLE A-BETA; SPORADIC ALZHEIMERS-DISEASE

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