β-Amyloid-Induced Cholinergic Denervation Correlates with Enhanced Nitric Oxide Synthase Activity in Rat Cerebral Cortex: Reversal by NMDA Receptor Blockade

Abstract

Ample experimental evidence indicates that acute β-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 Ca 2+ overload, partially via N -methyl- d-aspartate (NMDA) receptors, was proposed as a pivotal mechanism in β-amyloid-induced neurodegeneration. A definite measure of NMDA receptor-mediated processes and subsequent Ca 2+ entry is the induction of Ca 2+/calmodulin-activated neuronal nitric oxide synthase ( n NOS) in nerve cells. In the present account we therefore assessed activation of n NOS in correlation with cholinergic decline after β-amyloid (1–42) or β-amyloid (25–35) infusion into the rat nucleus basalis. The results demonstrate the β-amyloid conformation-dependent enhancement of cortical nitric oxide synthase (NOS) activity. Furthermore, chronic application of the polyamine site NMDA receptor blocker ifenprodil effectively attenuated β-amyloid neurotoxicity. We propose that n NOS activation reflects the degree of β-amyloid-induced excitotoxic injury in a proportional manner. Moreover, Ca 2+-mediated processes via NMDA receptors, or direct binding of β-amyloid to this receptor may be a critical step in the neurotoxic mechanisms in vivo.