2024-03-28T22:46:11Z
https://niigata-u.repo.nii.ac.jp/oai
oai:niigata-u.repo.nii.ac.jp:00010518
2022-12-15T03:46:23Z
453:456
471:537:538:972
インスリンシグナル伝達障害がアルツハイマー病に及ぼす影響
インスリンシグナル伝達障害がアルツハイマー病に及ぼす影響
Impaired Insulin Signal Transduction Promotes Alzheimer's Disease Pathology
春日, 健作
Alzheimer's disease (AD)
Insulin signal transduction
Presenilin 1 (PS1)
β-Amyloid (Aβ)
phosphorylated tau
Alzheimer's disease (AD) is by far the most common form of dementia, and its prevalence is increasing all over the world. The pathology of AD is characterized by senile plaque and neurofibrillar tangle, which consist of β-amyloid (Aβ) and hyperphosphorylated tan, respectively. Although amyloid hypothesis in AD pathogenesis is widely accepted, the mechanisms how Aβ deposition leads to abnormal accumulation of hyperphosphorylated tau remain unclear. Recent epidemiological studies have suggested that there is a close association between AD and type 2 diabetes mellitus (T2DM). In this study, I investigated the molecular regulatory mechanisms of insulin signal transduction with special reference to AD pathology. When neuroblastoma-derived Neuro2a cells were treated with various concentrations of insulin, insulin receptor (IR) was proteolytically processed and extracellular Aβ was accumulated in a dose-dependent manner. Treating with high concentration of insulin resulted in impaired responses of phosphorylation of Akt and glycogen synthase kinase 3β (GSK3β) upon insulin stimulation, which is reminiscent of insulin resistance in T2DM. Interestingly, Neuro2a cells producing a large amount of intracellular Aβ showed the similar insulin resistance. Furthermore, when cells stably expressing human tau were coincubated with cells producing a large amount of Aβ, the levels of phosphorylated tau detected with the AT8 antibody were increased. These results suggest that Aβ accumulation might cause abnormal tau phosphorylation through impaired insulin signal transduction and that improvement of insulin signal transduction could be a new therapeutic target of AD treatment.
新潟医学会
2009-12
jpn
departmental bulletin paper
http://hdl.handle.net/10191/28591
https://niigata-u.repo.nii.ac.jp/records/10518
AN00182415
00290440
新潟医学会雑誌
新潟医学会雑誌
123
12
618
630
https://niigata-u.repo.nii.ac.jp/record/10518/files/123(12)_618-630.pdf
application/pdf
1.9 MB
2019-08-06