Neuroprotective approaches in experimental models of β-Amyloid neurotoxicity: Relevance to Alzheimer's disease

Harkany, Tibor; Hortobágyi, Tibor; Sasvári, Mária; Kónya, Csaba; Penke, Botond; Luiten, P.G.M.; Nyakas, Csaba

doi:10.1016/s0278-5846(99)00058-5

Cited by 93 publications

(73 citation statements)

References 141 publications

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“…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). Hence, the behavioural dysfunction is probably associated with a transient acetylcholine release in the neocortex.…”

Section: Discussionmentioning

confidence: 92%

“…Dysbalance of [Ca 2+ ] i impairs the mitochondrial terminal oxidation (Lafon-Cazal et al, 1993) resulting in excessive generation of reactive oxygen species (ROS; Behl et al, 1994;Mark et al, 1997;Suo et al, 1997). It appears that Ca 2+ -and ROS-mediated toxic mechanisms following Ab (1±42) exposure exert a cumulative challenge to nerve cells in vivo (Harkany et al, 1999a;Suo et al, 1997), although the exact time-constants, interactions and sequence of the toxic cascade remain largely unclear.…”

Section: Introductionmentioning

confidence: 99%

“…To monitor cellular consequences of Ab toxicity, Ab (1±42) and Ab (25±35) were applied to cholinergic projection neurons of the rat magnocellular nucleus basalis (MBN) as a neuronal model structure that allows correlative behavioural and neuroanatomical evaluation of neuronal injury. It is to be emphasized that Ab-induced lesions of the rat MBN mimic acute neuronal injury (Harkany et al, 1999a;Stuiver et al, 1996) and thereby model initial steps of neurotoxic signalling that may turn to pathological dimensions in AD. Moreover, the age-dependent involvement of NMDA receptors in Ab toxicity and the potential therapeutic role of their neuropharmacological modulation are discussed.…”

Section: Introductionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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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“…The final concentration of DMSO was ≤0.1%, which did not affect cell viability. For each experiment, A. cordata, oleanolic acid, N G -nitro-L-arginine methyl ester (L-NAME; Sigma), (5R,10S)-(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (MK-801; RBI, Natick, MA, USA), and verapamil (Sigma) were applied 15 min prior to treatment with 10 μM Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35). They were also present in the medium during Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35) incubation.…”

Section: Induction Of Neurotoxicity In Primary Cultures Of Rat Cerebrmentioning

confidence: 99%

“…Also, α-tocopherol and anti-inflammatory agents such as indomethacin reportedly slow the progression of AD (13,14). Aβ (25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), the core toxic fragment of Aβ , produces similar neurodegenerative properties as Aβ , including oxidative damage, inflammatory responses, and memory impairment (15,16). Aralia species belong to the family Araliaceae and have long been recognized in China, Japan, and Korea as therapeutic herbs with antinociceptive, antidiabetic, antioxidant, and anti-inflammatory activities.…”

Section: Introductionmentioning

confidence: 99%

Aralia cordata Protects Against Amyloid β Protein (25–35)–Induced Neurotoxicity in Cultured Neurons and Has Antidementia Activities in Mice

et al. 2009

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Abstract. The present study investigated an ethanol extract of the aerial part of Aralia cordata Thunb. (Araliaceae) for possible neuroprotective effects on neurotoxicity induced by amyloid β (Aβ) protein (25 -35) in cultured rat cortical neurons and antidementia activity in mice. Exposure of cultured cortical neurons to 10 μM Aβ(25 -35) for 36 h induced neuronal apoptotic death. At 1 -10 μg/ml, A. cordata inhibited neuronal death, elevation of intracellular calcium ([Ca 2+ ] i ), glutamate release into the medium, and generation of reactive oxygen species (ROS) induced by in primary cultures of rat cortical neurons. Memory loss induced by intracerebroventricular injection of ICR mice with 15 nmol Aβ(25-35) was inhibited by chronic treatment with A. cordata (50 and 100 mg/kg, p.o. for 7 days) as measured by a passive avoidance test, and corresponding reductions were observed in brain cholinesterase activity and neuronal death measured histologically in the hippocampal region. Oleanolic acid isolated from A. cordata also inhibited neuronal death, elevation of [Ca 2+ ] i , glutamate release, and generation of ROS induced by Aβ(25-35) in cultured rat cortical neurons, suggesting that the neuroprotective effect of A. cordata may be, at least in part, attributable to this compound. From these results, we suggest that the antidementia effect of A. cordata is due to its neuroprotective effect against Aβ(25-35)-induced neurotoxicity and that A. cordata may have a therapeutic role in preventing the progression of Alzheimer's disease.

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Characterization of intermolecular ?-sheet peptides by mass spectrometry and hydrogen isotope exchange

Kraus

Janek

Bienert

et al. 2000

Rapid Commun. Mass Spectrom.

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Neuroprotective approaches in experimental models of β-Amyloid neurotoxicity: Relevance to Alzheimer's disease

Cited by 93 publications

References 141 publications

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

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

Aralia cordata Protects Against Amyloid β Protein (25–35)–Induced Neurotoxicity in Cultured Neurons and Has Antidementia Activities in Mice

Characterization of intermolecular ?-sheet peptides by mass spectrometry and hydrogen isotope exchange

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