title: Inhibition of clathrin-mediated endocytosis prevents amyloid β-induced axonal damage.
abstract: Amyloid β (Aβ)-induced axonal degeneration is a major cause of Alzheimer's disease (AD) pathology. However, the critical target to prevent Aβ-induced axonal degeneration remains unknown. Here, we analyzed growth cone collapse elicited by Aβ, a putative early Aβ-induced event in axons. Although no study has yet shown influence of Aβ on the growth cone, we first visualized Aβ-initiated growth cone collapse in cultured neurons. Furthermore, we determined that the collapse was triggered by clathrin-mediated endocytosis probably via Aβ-Ca(2+) signaling. The inhibition of clathrin-mediated endocytosis prevented Aβ-induced axonal loss both in vitro and in vivo and prevented memory impairment in an AD mouse model. Our results clarified the important role of clathrin-mediated endocytosis in Aβ-induced collapse of growth cone that leads to axonal degeneration and memory impairment.
authors.affiliation: Division of Neuromedical Science, Institute of Natural Medicine, University of Toyama, Toyama, Japan. Electronic address: kuboyama@inm.u-toyama.ac.jp.
authors.forename: Tomoharu
authors.initials: T
authors.lastname: Kuboyama
authors.affiliation: Division of Neuromedical Science, Institute of Natural Medicine, University of Toyama, Toyama, Japan; Department of Food Science and Nutrition, Catholic University of Daegu, Gyeongsan, Republic of Korea.
authors.forename: Young-A
authors.initials: YA
authors.lastname: Lee
authors.affiliation: Division of Neuromedical Science, Institute of Natural Medicine, University of Toyama, Toyama, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Nishiko
authors.affiliation: Division of Neuromedical Science, Institute of Natural Medicine, University of Toyama, Toyama, Japan.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Tohda
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000009:adverse effects* / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000378:metabolism* / Q000473:pathology*; D020013:Calcium Signaling / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D002966:Clathrin / Q000502:physiology; D004195:Disease Models, Animal; D004705:Endocytosis / Q000502:physiology*; D020439:Growth Cones / Q000378:metabolism / Q000473:pathology; D008569:Memory Disorders / Q000209:etiology; D008815:Mice, Inbred Strains; D009410:Nerve Degeneration / Q000209:etiology*; D009474:Neurons
chemical_list: D016229:Amyloid beta-Peptides; D002966:Clathrin
keywords: Amyloid β (Aβ); Axonal degeneration; Clathrin-mediated endocytosis; Growth cone collapse; Memory impairment