Aging-induced Akt activation involves in aging-related pathologies and Aβ-induced toxicity

被引：30

作者：

Chen, Yu-Ru ^{[1
]}

Li, Yu-Hsuan ^{[1
]}

Hsieh, Tsung-Chi ^{[2
]}

Wang, Chih-Ming ^{[3
]}

Cheng, Kuan-Chung ^{[1
,2
]}

Wang, Lei ^{[4
]}

Lin, Tzu-Yu ^{[2
]}

Cheung, Chun Hei Antonio ^{[1
,2
]}

Wu, Chia-Lin ^{[5
,6
,7
]}

Chiang, HsuehCheng ^{[1
,2
]}

机构：

[1] Natl Cheng Kung Univ, Dept Pharmacol, Tainan, Taiwan

[2] Natl Cheng Kung Univ, Inst Basic Med Sci, Coll Med, Tainan, Taiwan

[3] Natl Cheng Kung Univ, Sch Pharm, Coll Med, Tainan, Taiwan

[4] Beijing Univ Chem Technol, Coll Life Sci & Technol, Beijing, Peoples R China

[5] Chang Gung Univ, Dept Biochem, Coll Med, Taoyuan, Taiwan

[6] Chang Gung Univ, Grad Inst Biomed Sci, Coll Med, Taoyuan, Taiwan

[7] Chang Gung Mem Hosp, Dept Neurol, Linkou, Taiwan

来源：

AGING CELL | 2019年 / 18卷 / 04期

关键词：

gamma-secretase; aging; Akt; Alzheimer's disease; neuron; LIFE-SPAN; ALZHEIMERS-DISEASE; GAMMA-SECRETASE; DROSOPHILA; BRAIN; PHOSPHORYLATION; RECEPTOR; IMPAIRMENT; DISORDERS; ERK1/2;

D O I：

10.1111/acel.12989

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Multicellular signals are altered in the processes of both aging and neurodegenerative diseases, including Alzheimer's disease (AD). Similarities in behavioral and cellular functional changes suggest a common regulator between aging and AD that remains undetermined. Our genetics and behavioral approaches revealed the regulatory role of Akt in both aging and AD pathogenesis. In this study, we found that the activity of Akt is upregulated during aging through epidermal growth factor receptor activation by using the fruit fly as an in vivo model. Downregulation of Akt in neurons improved cell survival, locomotor activity, and starvation challenge in both aged and A beta 42-expressing flies. Interestingly, increased cAMP levels attenuated both Akt activation-induced early death and A beta 42-induced learning deficit in flies. At the molecular level, overexpression of Akt promoted Notch cleavage, suggesting that Akt is an endogenous activity regulator of gamma-secretase. Taken together, this study revealed that Akt is involved in the aging process and A beta toxicity, and manipulating Akt can restore both neuronal functions and improve behavioral activity during the processes of aging and AD pathogenesis.

引用

页数：11

共 47 条

[1] Extended longevity in mice lacking the insulin receptor in adipose tissue [J].