title: Amyloid β peptide promotes lysosomal degradation of clusterin via sortilin in hippocampal primary neurons.
abstract: Progressive accumulation of amyloid-β peptide (Aβ) in the brain is implicated as the central event in the development of Alzheimer's disease (AD). It is thought that extracellular Aβ triggers toxic signals leading to neurodegeneration. The events downstream of Aβ however are not entirely clear. Clusterin (Apo J) is one of the major risk factors for sporadic form of AD. Clusterin binds to Aβ and prevents Aβ aggregation. In addition, clusterin promotes Aβ degradation and accelerates Aβ clearance from the brain. Clusterin thus protects neurons from Aβ and loss of clusterin level in the brain is implicated as promoting AD pathology. In this study, we found that the level of clusterin protein but not mRNA is reduced in the brains of 3xTg-AD mice. When rat hippocampal primary neurons were treated with Aβ1-42, level of clusterin protein but not mRNA was downregulated. Aβ1-42-induced downregulation of clusterin was blocked by lysosome inhibitors bafilomycin A1 and ammonium chloride. In neurons, Aβ1-42 induced expression of sortilin, a lysosomal sorting protein that targets proteins to lysosome for degradation. In BE(2) M17 human neuroblastoma cells, clusterin bound to sortilin and when sortilin expression was silenced, Aβ1-42-induced clusterin downregulation was almost completely blocked. Our data demonstrate that in neurons, Aβ1-42 promotes lysosomal degradation of clusterin by inducing expression of sortilin and provide a novel mechanism by which Aβ promotes AD pathogenesis.
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec H4H 1R3, Canada.
authors.forename: Yunling
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec H4H 1R3, Canada.
authors.forename: Xike
authors.initials: X
authors.lastname: Qin
authors.affiliation: Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec H4H 1R3, Canada; Department of Neurology and Neurosurgery, McGill University, Montreal, Quebec H4H 1R3, Canada. Electronic address: hemant.paudel@mcgill.ca.
authors.forename: Hemant K
authors.initials: HK
authors.lastname: Paudel
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002478:Cells, Cultured; D051152:Clusterin / Q000378:metabolism*; D005260:Female; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010446:Peptide Fragments / Q000633:toxicity*; D051381:Rats; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D016229:Amyloid beta-Peptides; D051152:Clusterin; D010446:Peptide Fragments; D000099183:Sortilin; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer's disease; Amyloid-β; Clusterin; Lysosomal degradation; Sortilin