Liu S, Lau L, Wei J, Zhu D, Zou S, Sun HS, Fu Y, Liu F, Lu Y.
Expression of Ca(2+)-permeable AMPA receptor channels primes cell death in transient forebrain ischemia.
Neuron. 2004 Jul 8;43(1):43-55.
PubMed.
A previous study from Dr. YouMing Lu and colleagues reported that Cdk5 activation after ischemia leads to activation of the NMDA receptor via Ser1232 phosphorylation of NR2A (Wang et al., 2003). The authors further demonstrated that calpain activation and p25 production following ischemia was prevented by the AMPA receptor antagonist NBQX. In this study, Lu and colleagues provide additional evidence for the role of AMPA receptors during ischemia. Previously it was suggested that ischemia reduces GluR2 levels in CA1, which indicates that AMPA receptors become more permeable to Ca++ influx. This increased permeability may lead to neuronal death. This is the so-called GluR2 hypothesis (Pellegrini-Giampietro et al., 1997).
This study experimentally addresses the GluR2 hypothesis in ischemia by using Semliki Forest Virus (SFV) to mutagenize synaptic AMPA receptor channels in the hippocampus (Liu et al., 2004). The whole-cell patch-clamp recordings elegantly show that reduced GluR2 expression following ischemia induces Ca++ increases in vulnerable neurons. Furthermore, normally insensitive granule neurons in the hippocampus are rendered vulnerable to ischemia by expressing functional Ca++ permeable GluR2. This validates the GluR2 hypothesis for ischemia and fully supports the mechanism put forth in the previous paper that Ca++ influx through AMPA receptors leads to calpain activation and, ultimately, p35 to p25 conversion.
Intriguingly, several of these findings are recapitulated in Alzheimer’s disease (AD). First, GluR2 levels are decreased prior to NFT formation (Ikonomovic et al., 1997). Furthermore, calpain activity is increased in AD (Saito et al., 1993; Grynspan et al., 1997). Finally, p25 is increased in AD (Patrick et al., 1999; Tseng et al., 2002). This strongly suggests that the GluR2 hypothesis may also be relevant for AD. Therefore, the players in this pathway are all potential therapeutic targets for AD.
References:
Grynspan F, Griffin WR, Cataldo A, Katayama S, Nixon RA.
Active site-directed antibodies identify calpain II as an early-appearing and pervasive component of neurofibrillary pathology in Alzheimer's disease.
Brain Res. 1997 Jul 25;763(2):145-58.
PubMed.
Ikonomovic MD, Mizukami K, Davies P, Hamilton R, Sheffield R, Armstrong DM.
The loss of GluR2(3) immunoreactivity precedes neurofibrillary tangle formation in the entorhinal cortex and hippocampus of Alzheimer brains.
J Neuropathol Exp Neurol. 1997 Sep;56(9):1018-27.
PubMed.
Liu S, Lau L, Wei J, Zhu D, Zou S, Sun HS, Fu Y, Liu F, Lu Y.
Expression of Ca(2+)-permeable AMPA receptor channels primes cell death in transient forebrain ischemia.
Neuron. 2004 Jul 8;43(1):43-55.
PubMed.
Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH.
Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration.
Nature. 1999 Dec 9;402(6762):615-22.
PubMed.
Pellegrini-Giampietro DE, Gorter JA, Bennett MV, Zukin RS.
The GluR2 (GluR-B) hypothesis: Ca(2+)-permeable AMPA receptors in neurological disorders.
Trends Neurosci. 1997 Oct;20(10):464-70.
PubMed.
Saito K, Elce JS, Hamos JE, Nixon RA.
Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration.
Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2628-32.
PubMed.
Wang J, Liu S, Fu Y, Wang JH, Lu Y.
Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors.
Nat Neurosci. 2003 Oct;6(10):1039-47.
PubMed.
Comments
Picower Institute of MIT
A previous study from Dr. YouMing Lu and colleagues reported that Cdk5 activation after ischemia leads to activation of the NMDA receptor via Ser1232 phosphorylation of NR2A (Wang et al., 2003). The authors further demonstrated that calpain activation and p25 production following ischemia was prevented by the AMPA receptor antagonist NBQX. In this study, Lu and colleagues provide additional evidence for the role of AMPA receptors during ischemia. Previously it was suggested that ischemia reduces GluR2 levels in CA1, which indicates that AMPA receptors become more permeable to Ca++ influx. This increased permeability may lead to neuronal death. This is the so-called GluR2 hypothesis (Pellegrini-Giampietro et al., 1997).
This study experimentally addresses the GluR2 hypothesis in ischemia by using Semliki Forest Virus (SFV) to mutagenize synaptic AMPA receptor channels in the hippocampus (Liu et al., 2004). The whole-cell patch-clamp recordings elegantly show that reduced GluR2 expression following ischemia induces Ca++ increases in vulnerable neurons. Furthermore, normally insensitive granule neurons in the hippocampus are rendered vulnerable to ischemia by expressing functional Ca++ permeable GluR2. This validates the GluR2 hypothesis for ischemia and fully supports the mechanism put forth in the previous paper that Ca++ influx through AMPA receptors leads to calpain activation and, ultimately, p35 to p25 conversion.
Intriguingly, several of these findings are recapitulated in Alzheimer’s disease (AD). First, GluR2 levels are decreased prior to NFT formation (Ikonomovic et al., 1997). Furthermore, calpain activity is increased in AD (Saito et al., 1993; Grynspan et al., 1997). Finally, p25 is increased in AD (Patrick et al., 1999; Tseng et al., 2002). This strongly suggests that the GluR2 hypothesis may also be relevant for AD. Therefore, the players in this pathway are all potential therapeutic targets for AD.
References:
Grynspan F, Griffin WR, Cataldo A, Katayama S, Nixon RA. Active site-directed antibodies identify calpain II as an early-appearing and pervasive component of neurofibrillary pathology in Alzheimer's disease. Brain Res. 1997 Jul 25;763(2):145-58. PubMed.
Ikonomovic MD, Mizukami K, Davies P, Hamilton R, Sheffield R, Armstrong DM. The loss of GluR2(3) immunoreactivity precedes neurofibrillary tangle formation in the entorhinal cortex and hippocampus of Alzheimer brains. J Neuropathol Exp Neurol. 1997 Sep;56(9):1018-27. PubMed.
Liu S, Lau L, Wei J, Zhu D, Zou S, Sun HS, Fu Y, Liu F, Lu Y. Expression of Ca(2+)-permeable AMPA receptor channels primes cell death in transient forebrain ischemia. Neuron. 2004 Jul 8;43(1):43-55. PubMed.
Patrick GN, Zukerberg L, Nikolic M, de la Monte S, Dikkes P, Tsai LH. Conversion of p35 to p25 deregulates Cdk5 activity and promotes neurodegeneration. Nature. 1999 Dec 9;402(6762):615-22. PubMed.
Pellegrini-Giampietro DE, Gorter JA, Bennett MV, Zukin RS. The GluR2 (GluR-B) hypothesis: Ca(2+)-permeable AMPA receptors in neurological disorders. Trends Neurosci. 1997 Oct;20(10):464-70. PubMed.
Saito K, Elce JS, Hamos JE, Nixon RA. Widespread activation of calcium-activated neutral proteinase (calpain) in the brain in Alzheimer disease: a potential molecular basis for neuronal degeneration. Proc Natl Acad Sci U S A. 1993 Apr 1;90(7):2628-32. PubMed.
Wang J, Liu S, Fu Y, Wang JH, Lu Y. Cdk5 activation induces hippocampal CA1 cell death by directly phosphorylating NMDA receptors. Nat Neurosci. 2003 Oct;6(10):1039-47. PubMed.
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