Abstract
Aging is a crucial cause of cognitive decline and a major risk factor for Alzheimer’s disease (AD); however, AD’s underlying molecular mechanisms remain unclear. Recently, tetraspanins have emerged as important modulators of synaptic function and memory. We demonstrate that the level of tetraspanin CD82 is upregulated in the brains of AD patients and middle-aged mice. In young adult mice, injection of AAV-CD82 to the hippocampus induced AD-like cognitive deficits and impairments in neuronal spine density. CD82 overexpression increased TRPM7 α-kinase cleavage via caspase-3 activation and induced Numb phosphorylation at Thr346 and Ser348 residues. CD82 overexpression promoted beta-amyloid peptide (Aβ) secretion which could be reversed by Numb T346S348 mutants. Importantly, hippocampus-related memory functions were improved in Cd82−/− mice. Taken together, our findings provide the evidence that links the elevated CD82-TRPM7-Numb signaling to age-related cognitive impairment.
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Acknowledgments
We thank Prof. Jiapei Dai from Chinese Brain Bank Center for providing human brain tissues, Prof. Jianzhi Wang from Key Laboratory of Ministry of Education for Neurological Disorders at Tongji Medical College of HUST for N2a/APP cell line, and Ms. Kathy Kyler of the University of Oklahoma Health Science Center for English editing.
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The current studies were supported by funding from the National Natural Science Foundation of China Grant No. 31800868 (to Dr. Yin Zhao).
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YZ, XL, AC, and XZ conceived and designed the project; YZ, TK, JD, LL, LZ, and XL performed the experiments; XZ, AC, ZU, and JS provided valuable advice, coordinated the studies, and/or conducted the data analysis; YZ, TK, and XZ wrote the manuscript with approval from all authors.
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All animal experiments were approved by the Ethics Committees for Animal Experimentation of Huazhong University of Science and Technology and the University of Oklahoma Health Sciences Center in strict accordance with the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health. Efforts were made to minimize animal suffering and to reduce the number of animals used. This study was performed in accordance with the principles of the Declaration of Helsinki and approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, HUST, China (2017-K-036).
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Zhao, Y., Kiss, T., DelFavero, J. et al. CD82-TRPM7-Numb signaling mediates age-related cognitive impairment. GeroScience 42, 595–611 (2020). https://doi.org/10.1007/s11357-020-00166-4
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DOI: https://doi.org/10.1007/s11357-020-00166-4