title: Dynein dysfunction induces endocytic pathology accompanied by an increase in Rab GTPases: a potential mechanism underlying age-dependent endocytic dysfunction.
abstract: Growing evidence suggests that endocytic dysfunction is intimately involved in early stage Alzheimer disease pathology, such as the accumulation of beta-amyloid precursor protein in enlarged early endosomes. However, it remains unclear how endocytic dysfunction is induced in an age-dependent manner. Cytoplasmic dynein, a microtubule-based motor protein, interacts with another microtubule-associated protein, dynactin. The resulting dynein-dynactin complex mediates minus end-directed vesicle transport, including endosome trafficking. We have previously shown that the interaction between dynein-dynactin complexes is clearly attenuated in aged monkey brains, suggesting that dynein-mediated transport dysfunction exists in aged brains. Our immunohistochemical analyses revealed that age-dependent endocytic pathology was accompanied by an increase in Rab GTPases in aged monkey brains. Here, we demonstrated that siRNA-induced dynein dysfunction reproduced the endocytic pathology accompanied by increased Rab GTPases seen in aged monkey brains and significantly disrupted exosome release. Moreover, it also resulted in endosomal beta-amyloid precursor protein accumulation characterized by increased beta-site cleavage. These findings suggest that dynein dysfunction may underlie age-dependent endocytic dysfunction via the up-regulation of Rab GTPases. In addition, this vicious circle may worsen endocytic dysfunction, ultimately leading to Alzheimer disease pathology.
authors.affiliation: Laboratory of Disease Control, Tsukuba Primate Research Center, National Institute of Biomedical Innovation, 1-1 Hachimandai, Tsukuba-shi, Ibaraki 305-0843, Japan. kimura@nibio.go.jp
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kimura
authors.forename: Makoto
authors.initials: M
authors.lastname: Inoue
authors.forename: Sachi
authors.initials: S
authors.lastname: Okabayashi
authors.forename: Fumiko
authors.initials: F
authors.lastname: Ono
authors.forename: Takayuki
authors.initials: T
authors.lastname: Negishi
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology*; D000818:Animals; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D000072159:Dynactin Complex; D004398:Dyneins / Q000235:genetics / Q000378:metabolism*; D004705:Endocytosis; D011992:Endosomes / Q000378:metabolism; D006801:Humans; D008252:Macaca fascicularis; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D020691:rab GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000072159:Dynactin Complex; D008869:Microtubule-Associated Proteins; D004398:Dyneins; D020691:rab GTP-Binding Proteins