title: Aging attenuates dynactin-dynein interaction: down-regulation of dynein causes accumulation of endogenous tau and amyloid precursor protein in human neuroblastoma cells.
abstract: Impaired axonal transport may promote pathogenesis in neurodegenerative disorders, such as Alzheimer's disease (AD). We previously showed that tau, amyloid precursor protein (APP), and intracellular amyloid beta-protein (Abeta) accumulate in the nerve-ending fraction of aged monkey brains, perhaps because of impaired axonal transport. In the present study, we assessed age-related changes of axonal transport motor proteins in aged monkey brains. Western blotting showed that kinesin, dynein, and dynactin (DYN) localizations dramatically changed with aging, and dynein level in nerve-ending fractions increased significantly. Coimmunoprecipitation analyses showed that DYN-dynein intermediate chain (DIC) interactions decreased, suggesting that age-related attenuation of this interaction may cause the impairment of dynein function. Moreover, RNAi-induced down-regulation of DIC in human neuroblastoma cells caused endogenous tau and APP to accumulate, and their subcellular localizations were also affected. Our findings suggest that aging attenuates DYN-DIC interaction, representing one of the risk factors for age-related impaired dynein function and even for accumulation of disease proteins.
authors.affiliation: Laboratory of Disease Control, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Ibaraki, Japan. kimura@nibio.go.jp
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kimura
authors.forename: Osamu
authors.initials: O
authors.lastname: Imamura
authors.forename: Fumiko
authors.initials: F
authors.lastname: Ono
authors.forename: Keiji
authors.initials: K
authors.lastname: Terao
mesh_terms: D000375:Aging / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology*; D000072159:Dynactin Complex; D004398:Dyneins / Q000502:physiology*; D000882:Haplorhini; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D009447:Neuroblastoma / Q000473:pathology; D034741:RNA, Small Interfering / Q000494:pharmacology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D016564:Amyloid beta-Protein Precursor; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D016875:tau Proteins; D004398:Dyneins