期刊论文详细信息
Protein & Cell
Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer’s disease
Chao Ma1  Xinsheng Yao2  Zuolei Xie3  Zhenyu Liu3  Lin Xu4  Wei Shi5  Shuwen Du5  Weiwei Ma5  Ying Hu5  Yunlong Liu5  Wenjuan Wu5  Yi Zhong5 
[1] Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, Department of Human Anatomy, Histology and Embryology, Neuroscience Center, Joint Laboratory of Anesthesia and Pain, School of Basic Medicine, Peking Union Medical College;Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University;JoeKai Biotech. LLC;Key Lab of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences;Tsinghua-Peking Center for Life Science, IDG/McGovern Institutes for Brain Research, MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University;
关键词: Alzheimer’s disease;    Rac1;    forgetting;    memory loss;    hippocampus;   
DOI  :  10.1007/s13238-019-0641-0
来源: DOAJ
【 摘 要 】

Abstract Accelerated forgetting has been identified as a feature of Alzheimer’s disease (AD), but the therapeutic efficacy of the manipulation of biological mechanisms of forgetting has not been assessed in AD animal models. Ras-related C3 botulinum toxin substrate 1 (Rac1), a small GTPase, has been shown to regulate active forgetting in Drosophila and mice. Here, we showed that Rac1 activity is aberrantly elevated in the hippocampal tissues of AD patients and AD animal models. Moreover, amyloid-beta 42 could induce Rac1 activation in cultured cells. The elevation of Rac1 activity not only accelerated 6-hour spatial memory decay in 3-month-old APP/PS1 mice, but also significantly contributed to severe memory loss in aged APP/PS1 mice. A similar age-dependent Rac1 activity-based memory loss was also observed in an AD fly model. Moreover, inhibition of Rac1 activity could ameliorate cognitive defects and synaptic plasticity in AD animal models. Finally, two novel compounds, identified through behavioral screening of a randomly selected pool of brain permeable small molecules for their positive effect in rescuing memory loss in both fly and mouse models, were found to be capable of inhibiting Rac1 activity. Thus, multiple lines of evidence corroborate in supporting the idea that inhibition of Rac1 activity is effective for treating AD-related memory loss.

【 授权许可】

Unknown   

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