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N‐methyl‐D‐aspartate receptor–mediated calcium influx connects amyloid‐β oligomers to ectopic neuronal cell cycle reentry in Alzheimer's disease
Author(s) -
Kodis Erin J.,
Choi Sophie,
Swanson Eric,
Ferreira Gonzalo,
Bloom George S.
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.05.017
Subject(s) - memantine , nmda receptor , bapta , calcium , gene knockdown , neuron , chemistry , microbiology and biotechnology , neuroscience , pharmacology , medicine , receptor , biology , biochemistry , apoptosis
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.