title: Selective antibody-induced cholinergic cell and synapse loss produce sustained hippocampal and cortical hypometabolism with correlated cognitive deficits.
abstract: The physiological interrelationships between cognitive impairments, neurotransmitter loss, amyloid processing and energy metabolism changes in AD, cholinergic dementia and Down's syndrome are largely unknown to date. This report 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 glucose utilization ((14)C-2-deoxyglucose) throughout the brains of awake rats 4.5 months after bilateral intraventricular injections of a cholinotoxic antibody directed against the low-affinity NGF receptor (p75 NGF) associated with cholinergic neurons (192 IgG-saporin). Permanent cholinergic synapse loss was demonstrated by [(3)H]-vesamicol in vitro autoradiography defining presynaptic vesicular acetylcholine (ACh) transport sites. While other metabolic studies have defined acute and transient glucose use changes after relatively nonspecific lesions of anatomical regions containing cholinergic neurons, our results show sustained reductions in glucose utilization in brain regions impacted by cholinergic synapse loss, including frontal cortical and hippocampal regions, relative to glucose use levels in control rats. In the same animals, impaired cognitive spatial performance in a Morris water maze was correlated with reduced glucose use rates in the cortex and hippocampus at this time point, which is consistent with increased postmortem cortical and hippocampal amyloid precursor protein (APP) levels (45, 46). These results are consistent with the view of cholinergic influence over metabolism, APP processing, and cognition in the cortex and hippocampus.
authors: Department of Neurology and Neuroscience, Weill Medical College at Cornell University, A502, 525 East 68th Street, New York, NY 10021, USA.
authors: S E
authors: SE
authors: Browne
authors: L
authors: L
authors: Lin
authors: A
authors: A
authors: Mattsson
authors: B
authors: B
authors: Georgievska
authors: O
authors: O
authors: Isacson
mesh_terms: D000544:Alzheimer Disease / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001345:Autoradiography; D001522:Behavior, Animal / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D018678:Cholinergic Agents / Q000008:administration & dosage; D003072:Cognition Disorders / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology*; D003847:Deoxyglucose / Q000493:pharmacokinetics; D004195:Disease Models, Animal; D005260:Female; D005947:Glucose / Q000378:metabolism; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D000922:Immunotoxins / Q000008:administration & dosage*; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D018782:Maze Learning / Q000187:drug effects; D009699:N-Glycosyl Hydrolases; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010880:Piperidines / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000037:antagonists & inhibitors; D054789:Ribosome Inactivating Proteins, Type 1; D000076985:Saporins; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D014851:Wakefulness
chemical_list: C085696:192 IgG-saporin; D000911:Antibodies, Monoclonal; D018678:Cholinergic Agents; D000922:Immunotoxins; D010880:Piperidines; D020800:Receptor, Nerve Growth Factor; D017475:Receptors, Nerve Growth Factor; D054789:Ribosome Inactivating Proteins, Type 1; C006189:vesamicol; D003847:Deoxyglucose; D009699:N-Glycosyl Hydrolases; D000076985:Saporins; D005947:Glucose