| Autor: |
Harkany, T, Abraham, I, Timmerman, W, Laskay, G, Toth, B, Sasvari, M, Konya, C, Sebens, JB, Korf, J, Nyakas, C, Zarandi, M, Soos, K, Penke, B, Luiten, PGM |
| Přispěvatelé: |
Groningen Research Institute of Pharmacy, Medicinal Chemistry |
| Jazyk: |
angličtina |
| Rok vydání: |
2000 |
| Předmět: |
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| Zdroj: |
European Journal of Neuroscience, 12(8), 2735-2745. Blackwell Publishing |
| ISSN: |
0953-816X |
| Popis: |
Whereas a cardinal role for beta-amyloid protein (A beta) has been postulated as a major trigger of neuronal injury in Alzheimer's disease, the pathogenic mechanism by which A beta deranges nerve cells remains largely elusive. Here we report correlative in vitro and in vivo evidence that an excitotoxic cascade mediates A beta neurotoxicity in the rat magnocellular nucleus basalis (MBN). In vitro application of A beta to astrocytes elicits rapid depolarization of astroglial membranes with a concomitant inhibition of glutamate uptake. In vivo A beta infusion by way of microdialysis in the MBN revealed peak extracellular concentrations of excitatory amino acid neurotransmitters within 20-30 min. A beta-triggered extracellular elevation of excitatory amino acids coincided with a significantly enhanced intracellular accumulation of Ca2+ in the A beta injection area, as was demonstrated by Ca-45(2+) autoradiography. In consequence of these acute processes delayed cell death in the MBN and persistent loss of cholinergic fibre projections to the neocortex appear as early as 3 days following the A beta-induced toxic insult. Such a sequence of A beta toxicity was effectively antagonized by the N-methyl-d-aspartate (NMDA) receptor ligand dizocilpine maleate (MK-801). Moreover, A beta 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 A beta compromises neurons of the rat MBN via an excitotoxic pathway including astroglial depolarization, extracellular glutamate accumulation, NMDA receptor activation and an intracellular Ca2+ overload leading to cell death. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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