Animal models of Alzheimer's disease: experimental cholinergic denervation.
Several animal models of AD have been developed, based upon the consistent finding of a presynaptic cholinergic deficit in AD. Significant cell loss in the NBM, the primary cortical cholinergic afferent, has been reported in AD. Lesions of the corresponding nuclei in the rodent and primate produce a persistent cholinergic deficit, but no consistent change in other neurotransmitter systems. Significant mnestic and cerebral metabolic deficits are observed acutely after lesion, which are responsive to pharmacological reversal and recover over time. Administration of AF64A produces similar mnestic and cholinergic deficits as NBM lesion, but these effects may be less responsive to pharmacological reversal. Administration of scopolamine, a muscarinic receptor antagonist, produces transient receptor blockade, mnestic deficits and deficits in cerebral metabolism, which can be reversed with a variety of pharmacological agents. The primary dissociations between these models and the deficits in AD are the lack of pharmacological response and recovery of function in AD patients and the presence of non-cholinergic neurochemical and cytoskeletal abnormalities. Future research should focus upon the systematic production and analysis of non-cholinergic neurotransmitter and cytoskeletal abnormalities to determine the contribution of these factors to the pathology seen in AD and the production of deficit in aged animals, which may more closely approximate the deficits in AD. The analysis of factors involved in recovery of function and pharmacological response in animal models may provide insight into potential treatment approaches to AD.
Smith
G
G
Department of Biological Psychiatry, New York State Psychiatric Institute, New York 10032.
D000544:Alzheimer Disease / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002799:Cholinergic Fibers / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D003704:Dementia / Q000139:chemically induced; D004195:Disease Models, Animal; D006801:Humans; D012601:Scopolamine; D013377:Substantia Innominata / Q000503:physiopathology
D012601:Scopolamine