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

Abstract

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.

Amyloid beta peptide directly inhibits PKC activation

“…It is thus of great interest to elucidate the physiological role of Ah under normal conditions. At present, the physiological role of Ah is not clear, but suggestions include a neurotrophic action at a low concentration (Chauhan et al, 1991), enhancement of N-methyl-D-aspartate (NMDA) receptormediated current (Furukawa and Mattson, 1998;Harkany et al, 2000) and long-term potentiation (Ishida et al, 1997), enhancement of AMPA receptor-mediated current (Blanchard et al, 1997), formation of calcium channels (Bhatia et al, 2000), and effects on intracellular calcium homeostasis (Bhatia et al, 2000;Mattson et al, 1993). Most of these suggestions need to be confirmed, and it is not clear whether the suggested actions of Ah can be mediated by physiological concentrations of Ah.…”

Calpain inhibition prevents amyloid-β-induced neurodegeneration and associated behavioral dysfunction in rats

“…3) (Gaykema et al, 1992). Cholinergic neurons and fibers were visualized with the cholinergic marker choline-acetyl transferase (ChAT, EC3.2.1.6) (Harkany et al, 2000). The fiber density was measured in the superficial sublayer of the layer V as described earlier (Horváth et al, 2000).…”

“…A number of studies suggest that Ab-induced toxicity in AD is caused by excessive glutamate stimulation, over activation of the NMDA receptor, and subsequent calcium accumulation in the postsynaptic neuron (Harkany et al, 2000;Molnár et al, 2004;Mattson et al, 2000). Recently, the pathology of Ab has been correlated to oligomeric forms of the peptide (for review see Walsh and Selkoe, 2007), and studies indicate an involvement of the NMDA receptor also in oligomer toxicity (Shankar et al, 2007).…”

Emerging Therapeutic Strategies for Treating Alzheimer’s Disease in Primary Care

“…Several studies [3][4][5][6] have shown the benefits of early diagnosis and treatment, according to Dr. Small. Early, accurate diagnosis and treatment maintained patients at a higher level of functioning, leading to fewer doctor and hospital visits compared with patients who were not treated early.…”

“…3 Reduced caregiver burden 3,4 and delay in nursing home placement 5 can also result from early treatment of Alzheimer's disease, as can reduced use of other psychotropic drugs. 6 …”