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

作者：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 · 发表于：Journal of Neuroscience · 年份：2016 · DOI：10.1523/jneurosci.2258-16.2016 · 被引用次数：51 · 研究领域：Alzheimer's disease research and treatments、Neuroscience and Neuropharmacology Research、Cholinesterase and Neurodegenerative Diseases

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.