title: Diabetes mellitus accelerates Aβ pathology in brain accompanied by enhanced GAβ generation in nonhuman primates.
abstract: Growing evidence suggests that diabetes mellitus (DM) is one of the strongest risk factors for developing Alzheimer's disease (AD). However, it remains unclear why DM accelerates AD pathology. In cynomolgus monkeys older than 25 years, senile plaques (SPs) are spontaneously and consistently observed in their brains, and neurofibrillary tangles are present at 32 years of age and older. In laboratory-housed monkeys, obesity is occasionally observed and frequently leads to development of type 2 DM. In the present study, we performed histopathological and biochemical analyses of brain tissue in cynomolgus monkeys with type 2 DM to clarify the relationship between DM and AD pathology. Here, we provide the evidence that DM accelerates Aβ pathology in vivo in nonhuman primates who had not undergone any genetic manipulation. In DM-affected monkey brains, SPs were observed in frontal and temporal lobe cortices, even in monkeys younger than 20 years. Biochemical analyses of brain revealed that the amount of GM1-ganglioside-bound Aβ (GAβ)--the endogenous seed for Aβ fibril formation in the brain--was clearly elevated in DM-affected monkeys. Furthermore, the level of Rab GTPases was also significantly increased in the brains of adult monkeys with DM, almost to the same levels as in aged monkeys. Intraneuronal accumulation of enlarged endosomes was also observed in DM-affected monkeys, suggesting that exacerbated endocytic disturbance may underlie the acceleration of Aβ pathology due to DM.
authors: Tsukuba Primate Research Center, National Institute of Biomedical Innovation, 1-1 Hachimandai, Tsukuba-shi, Ibaraki, 305-0843, Japan; The Corporation for Production and Research of Laboratory Primates, 1-1 Hachimandai, Tsukuba-shi, Ibaraki, 305-0843, Japan.
authors: Sachi
authors: S
authors: Okabayashi
authors: Tsukuba Primate Research Center, National Institute of Biomedical Innovation, 1-1 Hachimandai, Tsukuba-shi, Ibaraki, 305-0843, Japan.
authors: Nobuhiro
authors: N
authors: Shimozawa
authors: Tsukuba Primate Research Center, National Institute of Biomedical Innovation, 1-1 Hachimandai, Tsukuba-shi, Ibaraki, 305-0843, Japan.
authors: Yasuhiro
authors: Y
authors: Yasutomi
authors: 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 (NCGG), Gengo 35, Moriika, Obu, Aichi, 474-8511, Japan.
authors: Katsuhiko
authors: K
authors: Yanagisawa
authors: Tsukuba Primate Research Center, National Institute of Biomedical Innovation, 1-1 Hachimandai, Tsukuba-shi, Ibaraki, 305-0843, Japan; 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 (NCGG), Gengo 35, Moriika, Obu, Aichi, 474-8511, Japan.
authors: Nobuyuki
authors: N
authors: Kimura
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology*; D002402:Cathepsin D / Q000378:metabolism; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism / Q000473:pathology; D003920:Diabetes Mellitus / Q000378:metabolism* / Q000473:pathology; D003924:Diabetes Mellitus, Type 2 / Q000150:complications; D004195:Disease Models, Animal; D004705:Endocytosis; D005260:Female; D005677:G(M1) Ganglioside / Q000378:metabolism*; D007150:Immunohistochemistry; D008252:Macaca fascicularis; D010588:Phagosomes / Q000378:metabolism; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D020691:rab GTP-Binding Proteins / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D005677:G(M1) Ganglioside; D002402:Cathepsin D; D020691:rab GTP-Binding Proteins