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 (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.