β-Amyloid-Induced Cholinergic Denervation Correlates with Enhanced Nitric Oxide Synthase Activity in Rat Cerebral Cortex: Reversal by NMDA Receptor Blockade

O’Mahony, Sheila; Harkany, Tibor; Rensink, Annemieke A.M.; Ábrahám, István M.; Jong, G.I. de; Varga, József; Zarándi, Márta; Penke, Botond; Nyakas, Csaba; Luiten, P.G.M.; Leonard, Brian E.

doi:10.1016/s0361-9230(97)00405-x

Cited by 44 publications

(36 citation statements)

References 25 publications

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“…Oxidative stress, or free radical generation, is one of the candidates for the cause of A␤-induced cytotoxicity. Previous reports have shown that A␤ stimulates NO production through Ca 2ϩ entry triggered by activated N-methyl-D-aspartate-gated channels (24). Other reports have suggested that A␤ inhibits glutamate uptake and causes extracellular glutamate increase (7).…”

Section: Discussionmentioning

confidence: 97%

α7 Nicotinic Receptor Transduces Signals to Phosphatidylinositol 3-Kinase to Block A β-Amyloid-induced Neurotoxicity

Kihara

Shimohama

Sawada

et al. 2001

Journal of Biological Chemistry

396

325

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Multiple lines of evidence, from molecular and cellular to epidemiological, have implicated nicotinic transmission in the pathogenesis of Alzheimer's disease (AD). Here we show the signal transduction mechanism involved in nicotinic receptor-mediated protection against ␤-amyloid-enhanced glutamate neurotoxicity. Nicotine-induced protection was suppressed by an ␣7 nicotinic receptor antagonist (␣-bungarotoxin), a phosphatidylinositol 3-kinase (PI3K) inhibitor (LY294002 and wortmannin), and a Src inhibitor (PP2). Levels of phosphorylated Akt, an effector of PI3K, and Bcl-2 were increased by nicotine. The ␣7 nicotinic receptor was physically associated with the PI3K p85 subunit and Fyn. These findings indicate that the ␣7 nicotinic receptor transduces signals to PI3K in a cascade, which ultimately contributes to a neuroprotective effect. This might form the basis of a new treatment for AD.

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Section: Discussionmentioning

confidence: 97%

α7 Nicotinic Receptor Transduces Signals to Phosphatidylinositol 3-Kinase to Block A β-Amyloid-induced Neurotoxicity

Kihara

Shimohama

Sawada

et al. 2001

Journal of Biological Chemistry

396

325

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“…NR2B-selective antagonists are neuroprotective in a diversity of animal models of neuronal injury (O'Mahony et al, 1998;Picconi et al, 2006), and NR2A C-terminal truncated mutant mice displayed a lesser sensitivity to focal ischemia than wild-type mice (Morikawa et al, 1998). Furthermore, Ser1232 phosphorylation of NR2A subunit catalyzed by cyclin-dependent kinase 5 was found to be involved in selective neuronal death in CA1 region of hippocampus induced by transient global ischemia (Morikawa et al, 1998;Wang et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Differential Roles of NR2A- and NR2B-Containing NMDA Receptors in Activity-Dependent Brain-Derived Neurotrophic Factor Gene Regulation and Limbic Epileptogenesis

Qian

He²,

Hu³

et al. 2007

J. Neurosci.

144

103

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Fleeting activation of NMDA receptors (NMDARs) induces long-term modification of synaptic connections and refinement of neuronal circuits, which may underlie learning and memory and contribute to pathogenesis of a diversity of neurological diseases, including epilepsy. Here, we found that NR2A and NR2B subunit-containing NMDARs were coupled to distinct intracellular signaling, resulting in differential BDNF expression and extracellular signal-regulated kinase 1/2 (ERK1/2) activation. Selective activation of NR2A-containing NMDARs increased BDNF gene expression. Activation of NR2B-containing NMDARs led to ERK1/2 phosphorylation. Furthermore, selectively blocking NR2A-containing NMDARs impaired epileptogenesis and the development of mossy fiber sprouting in the kindling and pilocarpine rat models of limbic epilepsy, whereas inhibiting NR2B-containing NMDARs had no effects in epileptogenesis and mossy fiber sprouting. Interestingly, blocking either NR2A- or NR2B-containing NMDARs decreased status epilepticus-induced neuronal cell death. The specific requirement of NR2A and its downstream signaling for epileptogenesis implicates attractive new targets for the development of drugs that prevent epilepsy in patients with brain injury.

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“…Although insuf®cient to account for recently suggested peptidic ligand-like characteristics of Ab (Lambert et al, 1998), such a notion is favoured by the selective displacement of MK-801 binding from regulatory sites of the NMDA receptor by Ab (Cowburn et al, 1994(Cowburn et al, , 1997 and the exceptional ef®cacy of NMDA receptor antagonists in ameliorating Ab toxicity in vivo (Morimoto et al, 1998;O'Mahony et al, 1998;Harkany et al, 1999b). Supportive to the proposed role of NMDA receptors in Ab (1±42) toxicity (Cowburn et al, 1997;Mattson et al, 1993;Harkany et al, 1999a), the spontaneous behavioural activation of Ab (1±42) -dialysed animals may well be a measure of glutamate-mediated excitation of cholinergic projection neurons, as its time delay correlates with that of a persistent Ca 2+ overload following NMDA receptor stimulation in vitro (Randall & Thayer, 1992).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, loss of cholinergic basal forebrain neurons was demonstrated after local intraparenchymal application of Ab fragments (Giovannelli et al, 1995;Harkany et al, 1995bHarkany et al, , 1998, whilst the presence of local Ca 2+ -binding proteins, and pharmacological blockade of N-Methyl-D-Aspartate (NMDA) receptors were unveiled as factors that may rescue cholinergic neurons from Ab toxicity (Harkany et al, 1995a;O'Mahony et al, 1998;1999b).…”

Section: Introductionmentioning

confidence: 99%

β‐Amyloid neurotoxicity is mediated by a glutamate‐triggered excitotoxic cascade in rat nucleus basalis

Harkany

Ábrahám

Timmerman

et al. 2000

Eur J of Neuroscience

261

151

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β-Amyloid neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis Harkany, T.; Ábrahám, I.; Timmerman, W.; Laskay, G.; Tóth, B.; Sasvári, M.; Kónya, C.; Sebens, J.B.; Korf, Jakob; Nyakas, C. Link to publication in University of Groningen/UMCG research database Citation for published version (APA): Harkany, T., Ábrahám, I., Timmerman, W., Laskay, G., Tóth, B., Sasvári, M., ... Luiten, P. G. M. (2000). β-Amyloid neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis. European Journal of Neuroscience, 12, 2735-2745. CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum. SummaryWhereas a cardinal role for b-amyloid protein (Ab) has been postulated as a major trigger of neuronal injury in Alzheimer's disease, the pathogenic mechanism by which Ab deranges nerve cells remains largely elusive. Here we report correlative in vitro and in vivo evidence that an excitotoxic cascade mediates Ab neurotoxicity in the rat magnocellular nucleus basalis (MBN). In vitro application of Ab to astrocytes elicits rapid depolarization of astroglial membranes with a concomitant inhibition of glutamate uptake. In vivo Ab infusion by way of microdialysis in the MBN revealed peak extracellular concentrations of excitatory amino acid neurotransmitters within 20±30 min. Ab-triggered extracellular elevation of excitatory amino acids coincided with a signi®cantly enhanced intracellular accumulation of Ca 2+ in the Ab injection area, as was demonstrated by 45 Ca 2+ autoradiography. In consequence of these acute processes delayed cell death in the MBN and persistent loss of cholinergic ®bre projections to the neocortex appear as early as 3 days following the Ab-induced toxic insult. Such a sequence of Ab toxicity was effectively antagonized by the N-methyl-D-aspartate (NMDA) receptor ligand dizocilpine maleate (MK-801). Moreover, Ab toxicity in the MBN decreases with advancing age that may be associated with the age-related loss of NMDA receptor expression in rats. In summary, the present results indicate that Ab compromises neurons of the rat MBN via an excitotoxic pathway including astroglial depolarization, extracellular glutamate accumulation, NMDA receptor activation and an intracellular Ca 2+ overload leading to cell death.

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β-Amyloid-Induced Cholinergic Denervation Correlates with Enhanced Nitric Oxide Synthase Activity in Rat Cerebral Cortex: Reversal by NMDA Receptor Blockade

Cited by 44 publications

References 25 publications

α7 Nicotinic Receptor Transduces Signals to Phosphatidylinositol 3-Kinase to Block A β-Amyloid-induced Neurotoxicity

α7 Nicotinic Receptor Transduces Signals to Phosphatidylinositol 3-Kinase to Block A β-Amyloid-induced Neurotoxicity

Differential Roles of NR2A- and NR2B-Containing NMDA Receptors in Activity-Dependent Brain-Derived Neurotrophic Factor Gene Regulation and Limbic Epileptogenesis

β‐Amyloid neurotoxicity is mediated by a glutamate‐triggered excitotoxic cascade in rat nucleus basalis

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