title: Selective Degeneration of Entorhinal-CA1 Synapses in Alzheimer's Disease via Activation of DAPK1.
abstract: Excitatory pyramidal neurons in the entorhinal cortical layer II region (ECIIPN) form functional excitatory synapses with CA1 parvalbumin inhibitory neurons (CA1PV) and undergo selective degeneration in the early stages of Alzheimer's disease (AD). Here, we show that death-associated protein kinase 1 (DAPK1) is selectively activated in ECIIPNof AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECIIPN-CA1PVsynaptic loss and improves spatial learning and memory in AD mice. This study demonstrates that activation of DAPK1 in ECIIPNcontributes to a memory loss in AD and hence warrants a promising target for the treatment of AD.
  
  
  
  Our recent study reported that excitatory pyramidal neurons in the entorhinal cortical layer II region (ECIIPN) target to CA1 parvalbumin-type inhibitory neurons (CA1PV) at a direct pathway and are one of the most vulnerable brain cells that are selectively degenerated in the early stage of Alzheimer's disease (AD). Our present study shows that death-associated protein kinase 1 (DAPK1) is selectively activated in ECIIPNof AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECIIPN-CA1PVsynaptic loss and improves spatial learning and memory in the early stage of AD. These data not only demonstrate a crucial molecular event for synaptic degeneration but also provide a therapeutic target for the treatment of AD.
authors: Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.|Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Shu
authors: S
authors: Shu
authors: Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.|Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Houze
authors: H
authors: Zhu
authors: Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.|Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Na
authors: N
authors: Tang
authors: Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.|Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Wenting
authors: W
authors: Chen
authors: Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.|Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Xinyan
authors: X
authors: Li
authors: Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.|Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Hao
authors: 0000-0003-3559-8965
authors: H
authors: Li
authors: Department of Neurobiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.|Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Lei
authors: L
authors: Pei
authors: Department of Genetics, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.|Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Dan
authors: D
authors: Liu
authors: Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.|Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Yangling
authors: Y
authors: Mu
authors: Department of Pathophysiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China, and.|Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Qing
authors: Q
authors: Tian
authors: Department of Pathophysiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China, and zhulq@hust.edu.cn lym@hust.edu.cn.|Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Ling-Qiang
authors: LQ
authors: Zhu
authors: Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China, zhulq@hust.edu.cn lym@hust.edu.cn.|Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
authors: Youming
authors: 0000-0002-6754-4411
authors: Y
authors: Lu
mesh_terms: D065767:Activation, Metabolic; D000544:Alzheimer Disease / Q000235:genetics* / Q000503:physiopathology* / Q000523:psychology; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000503:physiopathology*; D064550:Death-Associated Protein Kinases / Q000235:genetics*; D055724:Electrophysiological Phenomena; D018728:Entorhinal Cortex / Q000503:physiopathology*; D006801:Humans; D008297:Male; D018782:Maze Learning; D008568:Memory; D051379:Mice; D008822:Mice, Transgenic; D009043:Motor Activity / Q000235:genetics; D010320:Parvalbumins / Q000378:metabolism; D004856:Postural Balance / Q000235:genetics; D017966:Pyramidal Cells / Q000502:physiology; D013569:Synapses
chemical_list: D010320:Parvalbumins; C579096:DAPK1 protein, human; D064550:Death-Associated Protein Kinases
keywords: Alzheimers’ disease; DAPK1; learning and memory; synaptic degeneration