Chronic elevation of amyloid precursor protein expression in the neocortex and hippocampus of rats with selective cholinergic lesions

Overexpression or aberrant processing of the β-amyloid precursor protein (APP) and loss of cortical cholinergic function represent two hallmark pathological features of Alzheimer's disease, although it is still unclear whether these alterations take place independently or in an inter- related manner. In the present study, the possible relationships between altered APP expression and cholinergic hypofunction in the neocortex and hippocampus were addressed histologically following selective and complete (90-95%) removal of the basal forebrain cholinergic neurons by the 192 IgG- saporin immunotoxin, at a dose (5.0 μg, intraventricularly) producing profound and permanent cognitive deficits. Computer-aided densitometric analyses revealed, at 6 months post-lesion, a virtually complete loss of terminal cholinergic innervation in various neocortical and hippocampal regions (up to 80%), which correlated highly with the marked (up to 71%) increases in APP expression measured in the same territories. The present results indicate that the integrity of ascending basal forebrain cholinergic inputs to the neocortex and hippocampus may be required for the maintenance of physiological levels of APP expression in the same regions, thus providing a novel rationale for interventions aimed at restoring or enhancing cortical cholinergic neurotransmission.