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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.
MedLine Citation:
PMID:  22182700     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
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:
Nobuyuki Kimura; Sachi Okabayashi; Fumiko Ono
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2011-12-16
Journal Detail:
Title:  The American journal of pathology     Volume:  -     ISSN:  1525-2191     ISO Abbreviation:  -     Publication Date:  2011 Dec 
Date Detail:
Created Date:  2011-12-20     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0370502     Medline TA:  Am J Pathol     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
Affiliation:
Laboratory of Disease Control, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Ibaraki, Japan.
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