title: Adaptive responses to alloxan-induced mild oxidative stress ameliorate certain tauopathy phenotypes.
abstract: Oxidative stress is considered to promote aging and age-related disorders such as tauopathy. Although recent reports suggest that oxidative stress under certain conditions possesses anti-aging properties, no such conditions have been reported to ameliorate protein-misfolding diseases. Here, we used neuronal and murine models that overexpress human tau to demonstrate that mild oxidative stress generated by alloxan suppresses several phenotypes of tauopathy. Alloxan treatment reduced HSP90 levels and promoted proteasomal degradation of tau, c-Jun N-amino terminal kinase, and histone deacetylase (HDAC) 6. Moreover, reduced soluble tau (phosphorylated tau) levels suppressed the formation of insoluble tau in tau transgenic mice, while reduced HDAC6 levels contributed to microtubule stability by increasing tubulin acetylation. Age-dependent decreases in HDAC2 and phospho-tau levels correlated with spatial memory enhancement in alloxan-injected tau mice. These results suggest that mild oxidative stress, through adaptive stress responses, operates counteractively against some of the tauopathy phenotypes.
authors: Laboratory for Alzheimer's Disease, RIKEN Brain Science Institute, Hirosawa, Wako-shi, Saitama, Japan. yyoshiik@ncgg.go.jp
authors: Yuji
authors: Y
authors: Yoshiike
authors: Shunji
authors: S
authors: Yamashita
authors: Tatsuya
authors: T
authors: Mizoroki
authors: Sumihiro
authors: S
authors: Maeda
authors: Miyuki
authors: M
authors: Murayama
authors: Tetsuya
authors: T
authors: Kimura
authors: Naruhiko
authors: N
authors: Sahara
authors: Yoshiyuki
authors: Y
authors: Soeda
authors: Akihiko
authors: A
authors: Takashima
mesh_terms: D000107:Acetylation; D000222:Adaptation, Physiological / Q000187:drug effects; D000375:Aging / Q000187:drug effects / Q000523:psychology*; D000496:Alloxan / Q000008:administration & dosage* / Q000627:therapeutic use; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D010641:Phenotype; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D024801:Tauopathies / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D014404:Tubulin / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D018841:HSP90 Heat-Shock Proteins; D014404:Tubulin; D016875:tau Proteins; D000496:Alloxan; D048031:JNK Mitogen-Activated Protein Kinases; D046988:Proteasome Endopeptidase Complex; C499033:Hdac6 protein, mouse; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases