Selective Degeneration of Entorhinal-CA1 Synapses in Alzheimer's Disease via Activation of DAPK1

Shu Shu; Houze Zhu; Na Tang; Wenting Chen; Xinyan Li; Hao Li; Lei Pei; Dan Liu; Yangling Mu; Qing Tian; Ling-Qiang Zhu; Youming Lu

doi:10.1523/JNEUROSCI.2258-16.2016

Selective Degeneration of Entorhinal-CA1 Synapses in Alzheimer's Disease via Activation of DAPK1

J Neurosci. 2016 Oct 19;36(42):10843-10852. doi: 10.1523/JNEUROSCI.2258-16.2016.

Authors

Shu Shu^{1

2}, Houze Zhu^{1

2}, Na Tang^{1

2}, Wenting Chen^{1

2}, Xinyan Li^{1

2}, Hao Li^{1

2}, Lei Pei^{3

2}, Dan Liu^{4

2}, Yangling Mu^{1

2}, Qing Tian^{5

2}, Ling-Qiang Zhu^{6

2}, Youming Lu^{7

2}

Affiliations

¹ Department of Physiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
² Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan 430030, China.
³ Department of Neurobiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
⁴ Department of Genetics, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
⁵ Department of Pathophysiology, School of Basic Medicine and Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China, and.
⁶ 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.
⁷ 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.

Abstract

Excitatory pyramidal neurons in the entorhinal cortical layer II region (ECII_PN) form functional excitatory synapses with CA1 parvalbumin inhibitory neurons (CA1_PV) 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 ECII_PN of AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECII_PN-CA1_PV synaptic loss and improves spatial learning and memory in AD mice. This study demonstrates that activation of DAPK1 in ECII_PN contributes to a memory loss in AD and hence warrants a promising target for the treatment of AD.

Significance statement: Our recent study reported that excitatory pyramidal neurons in the entorhinal cortical layer II region (ECII_PN) target to CA1 parvalbumin-type inhibitory neurons (CA1_PV) 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 ECII_PN of AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECII_PN-CA1_PV synaptic 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.

Keywords: Alzheimers’ disease; DAPK1; learning and memory; synaptic degeneration.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activation, Metabolic
Alzheimer Disease / genetics*
Alzheimer Disease / physiopathology*
Alzheimer Disease / psychology
Animals
CA1 Region, Hippocampal / physiopathology*
Death-Associated Protein Kinases / genetics*
Electrophysiological Phenomena
Entorhinal Cortex / physiopathology*
Humans
Male
Maze Learning
Memory
Mice
Mice, Transgenic
Motor Activity / genetics
Parvalbumins / metabolism
Postural Balance / genetics
Pyramidal Cells / physiology
Synapses*

Substances

Parvalbumins
DAPK1 protein, human
Death-Associated Protein Kinases