Selective antibody-induced cholinergic cell and synapse loss produce sustained hippocampal and cortical hypometabolism with correlated cognitive deficits

The physiological interrelationships between cognitive impairments, neurotr ansmitter loss, amyloid processing and energy metabolism changes in AD, cho linergic dementia and Down's syndrome are largely unknown to date. This rep ort contains novel studies into the association between cognitive function and cerebral metabolism after long-term selective CNS cholinergic neuronal and synaptic loss in a rodent model. We measured local cerebral rates of gl ucose utilization (C-14-2-deoxyglucose) throughout the brains of awake rats 4.5 months after bilateral intraventricular injections of a cholinotoxic a ntibody directed against the low-affinity NGF receptor (p75 NGF) associated with cholinergic neurons (192 IgG-saporin). Permanent cholinergic synapse loss was demonstrated by [H-3]-vesamicol in vitro autoradiography defining presynaptic vesicular acetylcholine (ACh) transport sites. While other meta bolic studies have defined acute and transient glucose use changes after re latively nonspecific lesions of anatomical regions containing cholinergic n eurons, our results show sustained reductions in glucose utilization in bra in regions impacted by cholinergic synapse loss, including frontal cortical and hippocampal regions, relative to glucose use levels in control rats. I n the same animals, impaired cognitive spatial performance in a Morris wate r maze was correlated with reduced glucose use rates in the cortex and hipp ocampus at this time point, which is consistent with increased postmortem c ortical and hippocampal amyloid precursor protein (APP) levels (45, 46). Th ese results are consistent with the view of cholinergic in fluence over met abolism, APP processing, and cognition in the cortex and hippocampus. a 200 1 Academic Press.