WEKO3
アイテム
Selective autophagy in neurons and its involvement in the tau pathogenesis
https://repo.qst.go.jp/records/70926
https://repo.qst.go.jp/records/70926ece05527-eddd-41ae-9146-4b94c43e4504
| Item type | 会議発表用資料 / Presentation(1) | |||||
|---|---|---|---|---|---|---|
| 公開日 | 2012-10-04 | |||||
| タイトル | ||||||
| タイトル | Selective autophagy in neurons and its involvement in the tau pathogenesis | |||||
| 言語 | ||||||
| 言語 | eng | |||||
| 資源タイプ | ||||||
| 資源タイプ識別子 | http://purl.org/coar/resource_type/c_c94f | |||||
| 資源タイプ | conference object | |||||
| アクセス権 | ||||||
| アクセス権 | metadata only access | |||||
| アクセス権URI | http://purl.org/coar/access_right/c_14cb | |||||
| 著者 |
Ono, Maiko
× Ono, Maiko× Ki, Hin× Tokunaga, Masaki× Minamihisamatsu, Takeharu× Maruyama, Masahiro× Maeda, Jun× Suhara, Tetsuya× Higuchi, Makoto× 小野 麻衣子× 季 斌× 徳永 正希× 南久松 丈晴× 丸山 将浩× 前田 純× 須原 哲也× 樋口 真人 |
|||||
| 抄録 | ||||||
| 内容記述タイプ | Abstract | |||||
| 内容記述 | Background It is hypothesized that packaging of abnormal tau into neurofibrillary tangles (NFTs) protects neurons against tau-induced neurodegeneration, while molecular mediators of NFT formation versus accumulation of neurotoxic, low-order tau assemblies remain unidentified. p62 promotes autophagic degradation of ubiquitinated proteins, and sequesters them by forming an inclusion body. In mice transgenic for mutant human P301S tau protein (P301S mice), NFTs are abundantly developed in the brainstem but are accompanied by only modest neuronal loss in these area. By contrast, massive neuron death without deposition of NFTs occurs in the hippocampus. \nMethods Here, we investigated regional differences in levels of p62 and their association with tau lesions between the brainstem and hippocampus of P301S mice to analyze roles of p62 in the tau pathogenesis. Furthermore, we crossbred p62-knockout mice with P301S mice to investigate the influence of p62 deficiency on tau pathologies. \nResults Immunoreactivity for p62 was found in the brainstem neurons of wild-type mice, and this immunolabeling was markedly intensified with accumulation of phosphorylated tau (P-tau) in P301S mice, indicating recruitment of p62 to packaging of P-tau. Meanwhile, p62 was barely detectable in somas of hippocampal pyramidal neurons in both wild-type and P301S mice. In the hippocampus of aged P301S mice, p62 abundantly accumulated in aggresomes with ubiquitinated organelle but not with P-tau. Autophagic activities were higher in the hippocampus than in the brainstem in younger animals, and this regional difference was attenuated with aging in P301S mice. Sequential protein extraction of samples from these transgenics demonstrated a marked increase of relatively insoluble p62 and ubiquitin particularly in the hippocampus, but P-tau was observed primarily in a distinct solubility fraction. Genetic inactivation of p62 in P301S mice led to early accumulation of P-tau in the hippocampus and brainstem, and caused accelerated neuroinflammation and neuron loss in the hippocampus. \nConclusions Our findings support the view that p62 exerts neuroprtective effects against tau pathologies, and indicate that ubiquitinated substrates of p62 undergoing constitutive autophagy are abundant in the hippocampus under a normal physiological condition, leading to insufficient reserve capacity of autophagic clearance of P-tau and its segregation into inclusions. |
|||||
| 会議概要（会議名, 開催地, 会期, 主催者等） | ||||||
| 内容記述タイプ | Other | |||||
| 内容記述 | Alzheimer’s Association International Conference | |||||
| 発表年月日 | ||||||
| 日付 | 2012-07-19 | |||||
| 日付タイプ | Issued | |||||
