Alzheimer's disease(AD)is a progressive and degenerative disorder accompanied by cognitive decline,which could be promoted by mitochondrial dysfunction induced by mitochondrial Ca2+(mCa2+)homeostasis Mi-tochondrial calcium uniporter(MCU),a key channel of mCa2+uptake,may be a target for AD treatment.In the present study,we reveal for the first time that MCU knockdown in hippocampal neurons improves the memory performance of APP/PS1/tau mice through radial arm maze task.Western blot analysis,transmission electron microscopy(TEM),Golgi staining,immunohistochemistry(IHC)and ELISA results demonstrate that MCU knock-down in hippocampal neurons upregulates the levels of postsynaptic density protein 95(PSD95)and synaptophysin(SYP),and increases the numbers of synapses and dendritic spines.Meanwhile,MCU knockdown in hippocampal neurons decreases the neuroinflammatory response induced by astrogliosis and high levels of IL-1 β and TNF-α,and improves the PINK1-Parkin mitophagy signaling pathway and increases the level of Beclin-1 but decreases the level of P62.In addition,MCU knockdown in hippocampal neurons recovers the average volume and number of mi-tochondria.These data confirm that MCU knockdown in hippocampal neurons improves the memory performance of APP/PS1/tau mice through ameliorating the synapse structure and function,relieving the inflammation response and recovering mitophagy,indicating that MCU inhibition has the potential to be developed as a novel therapy for AD.

Hongyan Cai;Jing Qiao;Siru Chen;Junting Yang;Christian H?lscher;Zhaojun Wang;Jinshun Qi;Meina Wu

Department of Microbiology and Immunology,Shanxi Medical University,Taiyuan 030001,China;Key Laboratory of Cellular Physiology(Shanxi Medical University),Ministry of Education,Taiyuan 030001,China;Key Laboratory of Cellular Physiology,Shanxi Province,China;Department of Physiology,Shanxi Medical University,Taiyuan 030001,China;Academy of Chinese Medical Science,Henan University of Chinese Medicine,Zhengzhou 450046,China

生物化学与生物物理学报（英文版）

[1]Hongyan Cai;Jing Qiao;Siru Chen;Junting Yang;Christian H?lscher;Zhaojun Wang;Jinshun Qi;Meina Wu-.MCU knockdown in hippocampal neurons improves memory performance of an Alzheimer's disease mouse model)[J].生物化学与生物物理学报（英文版）,2022(10):1528-1539

mCa2+,uniporter,mCa2+uptake,astrogliosis,tochondria

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