Lesions of the cholinergic nucleus basalis of Meynert elevate the ex vivo synthesis of beta amyloid precursor protein (beta-APP) in the cerebral cortex, a major projection region. We have found that this elevation is reflected by increased levels of beta-APP mRNA. The induction is rapid (occurring 60 min after placement of the lesion) and persistent (remaining for at least 45 days after lesioning). Two other subcortical lesions, which result in reductions of cortical adrenergic and serotonergic innervation, similarly induced cortical beta-APP. The beta-APP induction is reversible and does not require loss of the subcortical neurons. Infusion of lidocaine, a calcium antagonist that disrupts neurotransmitter release, into the nucleus basalis of Meynert leads to the temporary reduction of released acetylcholine in the cortex. In this model, beta-APP mRNA levels are elevated shortly after the infusion of lidocaine (90 min) but return to preinfusion levels 7 days after the lidocaine treatment. However, metabolic stresses of the brain, including chronic physostigmine, glucocorticoid, and diabetogenic treatments, fail to induce the beta-APP response. These results suggest that the induction of beta-APP is a specific response to the loss of functional innervation in the cortex. Importantly, these studies show that cortical beta-APP is induced by lesions that mimic the neurochemical deficits most frequently observed in Alzheimer disease.