Abstract
Overproduction of the peptide amyloid Ξ² (AΞ²) is thought to be a critical pathogenic event in Alzheimer's disease (AD), leading to the formation of senile (amyloid) plaques, which in turn lead to neurofibrillary tangles, neuronal and synaptic loss, and dementia. Mendelian inheritance of AD, which occurs in a very small proportion of cases, is caused by mutations in the genes for Ξ²βamyloid precursor protein (Ξ²βAPP), presenilin 1 or presenilin 2; the mutations are thought to be pathogenic because they result in increased AΞ² production. The majority of AD is not inherited in a Mendelian fashion, and is therefore termed sporadic. The cause or causes of this common form of AD is unknown, although it is assumed that overproduction of AΞ² is also the critical event. Recent animal experiments suggest that AΞ² overproduction in aging and sporadic AD may be the result of cortical cholinergic deafferentation, which occurs as part of normal human aging. Decreasing AΞ² production may therefore slow or halt the progression of AD, and cholinergic agents may be particularly suitable for this role. In vitro work has indicated that cholinergic muscarinic M1 receptor agonists may reduce the cellular production of AΞ². In vivo experiments have shown that both muscarinic agonists and acetylcholinesterase inhibitors lower central nervous system (CNS) AΞ² concentrations. These results suggest that cholinergic agents may be particularly well suited to a preventative role in AD therapy by limiting the initial accumulation of AΞ². Drug Dev. Res. 56:242β247, 2002. Β© 2002 WileyβLiss, Inc.