Rationale for the development of cholinesterase inhibitors as anti-Alzheimer agents

Alzheimer's disease (AD) is characterized by progressive dementia caused by the loss of the presynaptic markers of the cholinergic system in the brain areas related to memory and learning and brain deposits of amyloid beta peptide (Abeta) and neurofibrillary tangles (NFT). A small fraction of early onset familial AD (FAD) is caused by mutations in genes, such as the beta-amyloid precursor protein (APP) and presenilins that increase the load of Abeta in the brain. These studies together with findings that Abeta is neurotoxic in vitro, provide evidence that some aggregates of this peptide are the key to the pathogenesis of AD. The yield of Abeta and the processing and turnover of APP are regulated by a number of pathways including apolipoprotein E, cholesterol and cholinergic agonists. Early studies showed that muscarinic agonists increased APP processing within the Abeta sequence (sAPPalpha). More recently, we have presented evidence showing that some, but not all, anticholinesterases reduce secretion of sAPPalpha as well as Abeta into the media suggesting that cholinergic agonists modulate Abeta levels by multiple mechanisms. Herein we review the recent advances in understanding the function of cholinesterase (ChE) in the brain and the use of ChE-inhibitors in AD. We propose and support the position that the influence of cholinergic stimulation on amyloid formation is critical in light of the early targeting of the cholinergic basal forebrain in AD and the possibility that maintenance of this cholinergic tone might slow amyloid deposition. In this context, the dual action of certain cholinesterase inhibitors on their ability to increase acetylcholine levels and decrease amyloid burden assumes significance as it may identify a single drug to both arrest the progression of the disease as well as treat its symptoms. A new generation of acetyl- and butyryl cholinesterase inhibitors is being studied and tested in human clinical trials for AD. We critically discuss recent trends in AD research, from molecular and genetic to clinical areas, as it relates to the effects of cholinergic agents and their secondary effects on Abeta. Finally, we examine different neurobiological mechanisms that provide the basis of new targets for AD drug development.