Beta-amyloid-induced cholinergic denervation correlates with enhanced nitric oxide synthase activity in rat cerebral cortex: Reversal by NMDA receptor blockade: Reversal by NMDA receptor blockade

Ample experimental evidence indicates that acute beta-amyloid infusion into the nucleus basalis of rats elicits abrupt degeneration of the magnocellular cholinergic neurons projecting to the cerebral cortex, In fact, involvement of a permanent Ca2+ overload, partially via N-methyl-D-aspartate (NMDA) receptors, was proposed as a pivotal mechanism in beta-amyloid-induced neurodegeneration, A definite measure of NMDA receptor-mediated processes and subsequent Ca2+ entry is the induction of Ca2+/calmodulin-activated neuronal nitric oxide synthase (nNOS) in nerve cells, In the present account we therefore assessed activation of nNOS in correlation with cholinergic decline after beta-amyloid((1-42)) or beta-amyloid((25-35)) infusion into the rat nucleus basalis, The results demonstrate the beta-amyloid conformation-dependent enhancement of cortical nitric oxide synthase (NOS) activity, Furthermore, chronic application of the polyamine site NMDA receptor blocker ifenprodil effectively attenuated beta-amyloid neurotoxicity, We propose that nNOS activation reflects the degree of beta-amyloid-induced excitotoxic injury in a proportional manner. Moreover, Ca2+-mediated processes via NMDA receptors, or direct binding of beta-amyloid to this receptor may be a critical step in the neurotoxic mechanisms in vivo. (C) 1998 Elsevier Science Inc.