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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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Physical exercise above a certain load has been suggested as being a cause of oxidative stress. We have tested whether training with moderate (MT), strenuous (ST), or over (OT) load can cause alterations in the activities of antioxidant enzymes, lipid peroxidation, protein oxidation, DNA damage, or activity of 8-oxoG-DNA glycosylase (OGG1) in rat liver. The levels of corticosterone decreased in all exercising groups but the differences were not significant. Adrenocorticotrophin hormone (ACTH) levels decreased, not significantly, in MT and OT compared to C. Activity levels of antioxidant enzymes did not change significantly in the liver. The levels of reactive carbonyl derivative (RCD) content decreased in the liver of exercising animals, and the differences reached significance between control and moderately trained groups. The changes in the levels of lipid peroxidation (LIPOX) were not significant, but were lower in the exercised groups. The 8-hydroxydeoxyguanosine (8-OHdG) levels increased in the OT group, and the activity of OGG1 measured from crude cell extracts tended to increase in MT and ST. The findings of this study imply that overtraining induces oxidative damage to nuclear DNA, but not to liver lipids and proteins.

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