Dietary and donepezil modulation of mTOR signaling and neuroinflammation in the brain

被引:24
作者
Dasuri, Kalavathi [1 ,2 ]
Zhang, Le [1 ,3 ]
Kim, Sun O. K. Fernandez [1 ]
Bruce-Keller, Annadora J. [1 ]
Keller, Jeffrey N. [1 ]
机构
[1] LSU Syst, Pennington Biomed Res Ctr, Baton Rouge, LA 70810 USA
[2] Tufts Univ, USDA, Human Nutr Res Ctr Aging, Boston, MA 02111 USA
[3] Huazhong Univ Sci & Technol, Tongji Hosp, Dept Geriatr, Inst Aging, Wuhan 430074, Peoples R China
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE | 2016年 / 1862卷 / 02期
基金
美国国家卫生研究院;
关键词
Brain; Aging; High fat diet; Obesity; Neurodegenerative disorders; mTOR pathway; Donepezil; Neuroinflammation; HIGH-FAT-DIET; INDUCED INSULIN-RESISTANCE; TAUOPATHY MOUSE MODEL; ALZHEIMERS-DISEASE; MAMMALIAN TARGET; ADIPOSE-TISSUE; GLUTAMATE NEUROTOXICITY; COGNITIVE IMPAIRMENT; METABOLIC SYNDROME; OXIDATIVE STRESS;
D O I
10.1016/j.bbadis.2015.11.002
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Recent clinical and laboratory evidences suggest that high fat diet (HFD) induced obesity and its associated metabolic syndrome conditions promotes neuropathology in aging and age-related neurological disorders. However, the effects of high fat diet on brain pathology are poorly understood, and the effective strategies to overcome these effects remain elusive. In the current study, we examined the effects of HFD on brain pathology and further evaluated whether donepezil, an AChE inhibitor with neuroprotective functions, could suppress the ongoing HFD induced pathological changes in the brain. Our data demonstrates that HFD induced obesity results in increased neuroinflammation and increased AChE activity in the brain when compared with the mice fed on low fat diet (LFD). HFD administration to mice activated mTOR pathway resulting in increased phosphorylation of mTORser2448, AKTthr3 8 and S6K proteins involved in the signaling. Interestingly, donepezil administration with HFD suppressed HFD induced increases in AChE activity, and partially reversed HFD effects on microglial reactivity and the levels of mTOR signaling proteins in the brain when compared to the mice on LFD alone. However, gross levels of synaptic proteins were not altered in the brain tissues of mice fed either diet with or without donepezil. In conclusion, these results present a new insight into the detrimental effects of HFD on brain via microglial activation and involvement of mTOR pathway, and further demonstrates the possible therapeutic role for donepezil in ameliorating the early effects of HFD that could help preserve the brain function in metabolic syndrome conditions. (C) 2015 Elsevier B.V. All rights reserved.
引用
收藏
页码:274 / 283
页数:10
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