title: Dynein dysfunction disrupts intracellular vesicle trafficking bidirectionally and perturbs synaptic vesicle docking via endocytic disturbances a potential mechanism underlying age-dependent impairment of cognitive function.
abstract: Although genetic studies have demonstrated that β-amyloid protein (Aβ) plays a pivotal role in Alzheimer's disease (AD) pathogenesis, how aging contributes to AD onset remains unclear. Moreover, growing evidence suggests that Aβ-independent mechanisms, such as altered intracellular signaling cascades and impaired neurotransmitter release, also are likely involved in this process. Cytoplasmic dynein, a microtubule-based motor protein, mediates minus end-directed vesicle transport via interactions with dynactin, another microtubule-associated protein. We previously showed that normal aging attenuates the interaction between dynein-dynactin complexes in monkey brain and that dynein dysfunction reproduces age-dependent endocytic disturbances, resulting in intracellular Aβ accumulation. In this study, we report that dynein dysfunction disrupts not only retrograde transport of neurotrophic receptors but also anterograde transport of synaptic vesicles, which occurs concomitantly with an increase in Rab3 GTPase levels. Additionally, synaptic vesicle docking was perturbed via enhanced endocytosis. Dynein dysfunction also induced neuritic swelling, which is accompanied by a significant accumulation of neurofilaments. Moreover, we also confirmed that the dynein dysfunction-related disturbances are associated with aging in monkey brains and that age-dependent endocytic disturbances precede Aβ abnormality. These findings suggest that dynein dysfunction can alter neuronal activity via endocytic disturbances and may underlie age-dependent impairment of cognitive function. Moreover, in the presence of other risk factors, such as intracellular Aβ accumulation, dynein dysfunction may contribute to the development of AD.
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: Sachi
authors.initials: S
authors.lastname: Okabayashi
authors.forename: Fumiko
authors.initials: F
authors.lastname: Ono
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000367:Age Factors; D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D001923:Brain Chemistry / Q000502:physiology; D002540:Cerebral Cortex / Q000378:metabolism; D003072:Cognition Disorders / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D000072159:Dynactin Complex; D004398:Dyneins / Q000502:physiology*; D004705:Endocytosis / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D008252:Macaca fascicularis; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D016900:Neurofilament Proteins / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D020813:Receptor, trkB / Q000378:metabolism; D013572:Synaptic Vesicles / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D000072159:Dynactin Complex; D004791:Enzyme Inhibitors; D008869:Microtubule-Associated Proteins; D016900:Neurofilament Proteins; C010192:9-(2-hydroxy-3-nonyl)adenine; D020813:Receptor, trkB; D004398:Dyneins; D020691:rab GTP-Binding Proteins; D000225:Adenine