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

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease / drug therapy
  • Alzheimer Disease / metabolism*
  • Alzheimer Disease / pathology
  • Amyloid beta-Peptides / metabolism*
  • Animals
  • Calcium / metabolism*
  • Cell Cycle / physiology*
  • Cells, Cultured
  • Disease Models, Animal
  • Excitatory Amino Acid Antagonists / pharmacology
  • HEK293 Cells
  • Humans
  • Intracellular Space / drug effects
  • Intracellular Space / metabolism
  • Memantine / pharmacology
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Neurons / drug effects
  • Neurons / metabolism*
  • Neurons / pathology
  • Receptors, N-Methyl-D-Aspartate / antagonists & inhibitors
  • Receptors, N-Methyl-D-Aspartate / genetics
  • Receptors, N-Methyl-D-Aspartate / metabolism*

Substances

  • Amyloid beta-Peptides
  • Excitatory Amino Acid Antagonists
  • Receptors, N-Methyl-D-Aspartate
  • Calcium
  • Memantine