title: Dynein Dysfunction Reproduces Age-Dependent Retromer Deficiency: Concomitant Disruption of Retrograde Trafficking Is Required for Alteration in β-Amyloid Precursor Protein Metabolism.
abstract: It is widely accepted that β-amyloid (Aβ) protein plays a pivotal role in Alzheimer disease pathogenesis, and accumulating evidence suggests that endocytic dysfunction is involved in Aβ pathology. Retromer, a conserved multisubunit complex, mediates the retrograde transport of numerous kinds of cargo from endosomes to the trans-Golgi network. Several studies have found that retromer deficiency enhances Aβ pathology both in vitro and in vivo. Cytoplasmic dynein, a microtubule-based motor protein, mediates minus-end-directed vesicle transport via interactions with dynactin, another microtubule-associated protein that also interacts with retromer. Aging attenuates the dynein-dynactin interaction, and dynein dysfunction reproduces age-dependent endocytic disturbance, resulting in the intracellular accumulation of beta-amyloid precursor protein (APP) and its β-cleavage products, including Aβ. Here, we report that aging itself affects retromer trafficking in cynomolgus monkey brains. In addition, dynein dysfunction reproduces this type of age-dependent retromer deficiency (ie, the endosomal accumulation of retromer-related proteins and APP. Moreover, we found that knockdown of Rab7, Rab9, or Rab11 did not alter endogenous APP metabolism, such as that observed in aged monkey brains and in dynein-depleted cells. These findings suggest that dynein dysfunction can cause retromer deficiency and that concomitant disruption of retrograde trafficking may be the key factor underlying age-dependent Aβ pathology.
authors.affiliation: Section of Cell Biology and Pathology, Department of Alzheimer's Disease Research, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Japan; The Corporation for Production and Research of Laboratory Primates, Tsukuba, Japan. Electronic address: kimura@ncgg.go.jp.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kimura
authors.affiliation: Tsukuba Primate Research Center, National Institute of Biomedical Innovation, Health and Nutrition, Tsukuba, Japan.
authors.forename: Eriko
authors.initials: E
authors.lastname: Samura
authors.affiliation: Section of Cell Biology and Pathology, Department of Alzheimer's Disease Research, Center for Development of Advanced Medicine for Dementia, National Center for Geriatrics and Gerontology, Obu, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Neurology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
authors.forename: Sachi
authors.initials: S
authors.lastname: Okabayashi
authors.affiliation: The Corporation for Production and Research of Laboratory Primates, Tsukuba, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Shimozawa
authors.affiliation: The Corporation for Production and Research of Laboratory Primates, Tsukuba, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Yasutomi
mesh_terms: D000375:Aging / Q000473:pathology* / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D004398:Dyneins / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D007150:Immunohistochemistry; D008252:Macaca fascicularis; D008297:Male; D046912:Multiprotein Complexes / Q000378:metabolism; D021381:Protein Transport; D034622:RNA Interference
chemical_list: D016564:Amyloid beta-Protein Precursor; D046912:Multiprotein Complexes; D004398:Dyneins