beta-Amyloid neurotoxicity is mediated by a glutamate-triggered excitotoxic cascade in rat nucleus basalis

Whereas a cardinal role for beta-amyloid protein (A beta) has been postulat ed as a major trigger of neuronal injury in Alzheimer's disease, the pathog enic mechanism by which A beta deranges nerve cells remains largely elusive . Here we report correlative in vitro and in vivo evidence that an excitoto xic cascade mediates A beta neurotoxicity in the rat magnocellular nucleus basalis (MBN). In vitro application of A beta to astrocytes elicits rapid d epolarization of astroglial membranes with a concomitant inhibition of glut amate uptake. In vivo A beta infusion by way of microdialysis in the MBN re vealed peak extracellular concentrations of excitatory amino acid neurotran smitters within 20-30 min. A beta-triggered extracellular elevation of exci tatory amino acids coincided with a significantly enhanced intracellular ac cumulation of Ca2+ in the A beta injection area, as was demonstrated by Ca- 45(2+) autoradiography. In consequence of these acute processes delayed cel l 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 t he N-methyl-d-aspartate (NMDA) receptor ligand dizocilpine maleate (MK-801) . Moreover, A beta toxicity in the MBN decreases with advancing age that ma y be associated with the age-related loss of NMDA receptor expression in ra ts. In summary, the present results indicate that A beta compromises neuron s of the rat MBN via an excitotoxic pathway including astroglial depolariza tion, extracellular glutamate accumulation, NMDA receptor activation and an intracellular Ca2+ overload leading to cell death.