Aging attenuates dynactin-dynein interaction: down-regulation of dynein causes accumulation of endogenous tau and amyloid precursor protein in human neuroblastoma cells.
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.
Kimura
Nobuyuki
N
Laboratory of Disease Control, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Ibaraki, Japan. kimura@nibio.go.jp
Imamura
Osamu
O
Ono
Fumiko
F
Terao
Keiji
K
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*
D016564:Amyloid beta-Protein Precursor; D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D016875:tau Proteins; D004398:Dyneins