Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer’s disease
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Oxford University Press
2019-07-01
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| Series: | Protein & Cell |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1007/s13238-019-0641-0 |
| _version_ | 1797713308288024576 |
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| author | Wenjuan Wu Shuwen Du Wei Shi Yunlong Liu Ying Hu Zuolei Xie Xinsheng Yao Zhenyu Liu Weiwei Ma Lin Xu Chao Ma Yi Zhong |
| author_facet | Wenjuan Wu Shuwen Du Wei Shi Yunlong Liu Ying Hu Zuolei Xie Xinsheng Yao Zhenyu Liu Weiwei Ma Lin Xu Chao Ma Yi Zhong |
| author_sort | Wenjuan Wu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-12T07:34:29Z |
| format | Article |
| id | doaj.art-cfe28ce16c0c4710bb54b87843a79f43 |
| institution | Directory Open Access Journal |
| issn | 1674-800X 1674-8018 |
| language | English |
| last_indexed | 2024-03-12T07:34:29Z |
| publishDate | 2019-07-01 |
| publisher | Oxford University Press |
| record_format | Article |
| series | Protein & Cell |
| spelling | doaj.art-cfe28ce16c0c4710bb54b87843a79f432023-09-02T21:36:04ZengOxford University PressProtein & Cell1674-800X1674-80182019-07-01101074575910.1007/s13238-019-0641-0Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer’s diseaseWenjuan Wu0Shuwen Du1Wei Shi2Yunlong Liu3Ying Hu4Zuolei Xie5Xinsheng Yao6Zhenyu Liu7Weiwei Ma8Lin Xu9Chao Ma10Yi Zhong11Tsinghua-Peking Center for Life Science, IDG/McGovern Institutes for Brain Research, MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua UniversityTsinghua-Peking Center for Life Science, IDG/McGovern Institutes for Brain Research, MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua UniversityTsinghua-Peking Center for Life Science, IDG/McGovern Institutes for Brain Research, MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua UniversityTsinghua-Peking Center for Life Science, IDG/McGovern Institutes for Brain Research, MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua UniversityTsinghua-Peking Center for Life Science, IDG/McGovern Institutes for Brain Research, MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua UniversityJoeKai Biotech. LLCInstitute of Traditional Chinese Medicine and Natural Products, College of Pharmacy, Jinan UniversityJoeKai Biotech. LLCTsinghua-Peking Center for Life Science, IDG/McGovern Institutes for Brain Research, MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua UniversityKey Lab of Animal Models and Human Disease Mechanisms, Kunming Institute of Zoology, Chinese Academy of SciencesInstitute 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 CollegeTsinghua-Peking Center for Life Science, IDG/McGovern Institutes for Brain Research, MOE Key Laboratory of Protein Science, School of Life Sciences, Tsinghua UniversityAbstract 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.http://link.springer.com/article/10.1007/s13238-019-0641-0Alzheimer’s diseaseRac1forgettingmemory losshippocampus |
| spellingShingle | Wenjuan Wu Shuwen Du Wei Shi Yunlong Liu Ying Hu Zuolei Xie Xinsheng Yao Zhenyu Liu Weiwei Ma Lin Xu Chao Ma Yi Zhong Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer’s disease Protein & Cell Alzheimer’s disease Rac1 forgetting memory loss hippocampus |
| title | Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer’s disease |
| title_full | Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer’s disease |
| title_fullStr | Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer’s disease |
| title_full_unstemmed | Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer’s disease |
| title_short | Inhibition of Rac1-dependent forgetting alleviates memory deficits in animal models of Alzheimer’s disease |
| title_sort | inhibition of rac1 dependent forgetting alleviates memory deficits in animal models of alzheimer s disease |
| topic | Alzheimer’s disease Rac1 forgetting memory loss hippocampus |
| url | http://link.springer.com/article/10.1007/s13238-019-0641-0 |
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