Multilevel Approaches to AChE-Induced Impairments in Learning and Memory

Alzheimer’s disease (AD) is a late-onset neurodegenerative disease characterized by progressive deterioration of cholinergic functions including learning, short-term memory, problem solving and abstract thinking. The only FDA-approved drugs for AD are potent cholinesterase inhibitors. It is well recognized, however, that cholinesterase inhibitors do not slow progress of the disease state. Our work is based on the premise that AChE plays an active role in the etiology of AD through non-catalytic neuritogenic activities of the polypeptide, and that the failure of pharmacological inhibitors of AChE to provide lasting relief is due, in part, to their activation of feedback mechanisms promoting overexpression of the protein. To study this issue, we have developed gain- and loss-of-function models of AChE gene expression.