Shuwen Du
Wei Shi
Yunlong Liu
Ying Hu
Zuolei Xie
Xinsheng Yao
Zhenyu Liu
Weiwei Ma
Lin Xu
Chao Ma
Yi Zhong
1 Tsinghua-Peking Center for Life Science, IDG/McGovern Institutes for Brain Research, MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua University, Beijing 100084, China;
2 Life Science Division, Graduate school at Shenzhen, Tsinghua University, Shenzhen 518055, China;
3 JoeKai Biotech. LLC, LianQiang International Building, Yongfeng Base, Beijing 100084, China;
4 Institute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan University, Guangzhou 510632, China;
5 Key Lab of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China;
6 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, Beijing 100005, China
Funds: This work was supported by the Beijing Municipal Science & Technology Commission[Nos. Z161100000216132 and Z16110000 2616010 (to Y, Z)]. This work was also supported by grants from the Beijing Municipal Science and Technology Commission (Z161100000216132/01, to Yi Zhong), the National Basic Research Project (973 program) of the Ministry of Science and Technology of China[2013cb835100 (to Y, Z)], the National Science Foundation of China[91332207 and 91632301 (to Y, Z)], the Tsinghua-Peking Joint Centre for Life Sciences (to Y, Z), the National Natural Science Foundation of China[NSFC #81271239, #81771205, #91632113 (to C, Ma)], the Natural Science Foundation and Major Basic Research Program of Shanghai[16JC1420500, 16JC1420502 (to C, Ma)], and the CAMS Innovation Fund for Medical Sciences[CIFMS #2017-I2M-3-008 (to C, Ma)].
Received Date: 2019-04-09
Rev Recd Date:2019-05-23
Abstract
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.Keywords: Alzheimer's disease,
Rac1,
forgetting,
memory loss,
hippocampus
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