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Alzheimers Dement. 2018 Oct;14(10):1302-1312. doi: 10.1016/j.jalz.2018.05.017. Epub 2018 Jul 4.

N-methyl-D-aspartate receptor-mediated calcium influx connects amyloid-β oligomers to ectopic neuronal cell cycle reentry in Alzheimer's disease.

Author information

1
Department of Biology, University of Virginia, Charlottesville, VA, USA. Electronic address: ejk7tj@virginia.edu.
2
Department of Biology, University of Virginia, Charlottesville, VA, USA.
3
Departamento de Biofisica de la Facultad de Medicina, Universidad de la República, Monetivideo, Uruguay.
4
Department of Biology, University of Virginia, Charlottesville, VA, USA; Department of Cell Biology, University of Virginia, Charlottesville, VA, USA; Department of Neuroscience, University of Virginia, Charlottesville, VA, USA. Electronic address: gsb4g@virginia.edu.

Abstract

INTRODUCTION:

Alzheimer's disease (AD) symptoms reflect synaptic dysfunction and neuron death. Amyloid-β oligomers (AβOs) induce excess calcium entry into neurons via N-methyl-D-aspartate receptors (NMDARs), contributing to synaptic dysfunction. The study described here tested the hypothesis that AβO-stimulated calcium entry also drives neuronal cell cycle reentry (CCR), a prelude to neuron death in AD.

METHODS:

Pharmacologic modulators of calcium entry and gene expression knockdown were used in cultured neurons and AD model mice.

RESULTS:

In cultured neurons, AβO-stimulated CCR was blocked by NMDAR antagonists, total calcium chelation with 1,2-Bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM), or knockdown of the NMDAR subunit, NR1. NMDAR antagonists also blocked the activation of calcium-calmodulin-dependent protein kinase II and treatment of Tg2576 AD model mice with the NMDAR antagonist, memantine, prevented CCR.

DISCUSSION:

This study demonstrates a role for AβO-stimulated calcium influx via NMDAR and CCR in AD and suggests the use of memantine as a disease-modifying therapy for presymptomatic AD.

KEYWORDS:

Alzheimer's disease; Amyloid-β oligomers; Calcium; NMDA receptor; Neuronal cell cycle reentry; Tau

PMID:
30293574
DOI:
10.1016/j.jalz.2018.05.017

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