Beta amyloid (Abeta) accumulation is critical to the development of Alzheimer's disease (AD), a disease that currently afflicts 4 million Americans and is predicted to affect 22 million people around the world by 2025. In particular an increase in the longer more toxic form of beta amyloid, Abeta1-42, which is proposed to trigger tau hyperphosphorylation and neural degeneration is considered a key etiological feature of AD.

Abeta1-42 is produced through the processing of amyloid precursor protein (APP). Three proteases, alpha-, beta- and gamma-secretases, are involved in APP processing. At the cell surface, APP undergoes proteolysis by alpha-secretase releasing a large, soluble ectodomain (alpha-APP; sAPP). The C-terminal fragment is retained within the cell membrane. In an alternate pathway, beta-secretase cleaves APP releasing a large secreted derivative sAPPbeta and a C-terminal fragment that can be further cleaved by gamma-secretase to form Abeta1-42 that is released into the extracellular milieu. The predominant peptide secreted is Abeta1-40 with about 10-15% being Abeta1-42.

A major event in the etiology of AD is the loss of cholinergic fibers. Consequently, current therapeutic strategies focus on the use of cholinesterase inhibitors to compensate for the loss of cholinergic innervation and the subsequent neurological deficits. Over recent years the build up of Abeta and the loss of cholinergic neurons has been shown to overlap in terms of etiology. On one hand, Abeta reduces hippocampal cholinergic release in cognitively impaired rats, binds strongly to nicotinic receptor blocking the conductance of their channel sub-units, reduces choline uptake and inhibits acetylcholine. On the other hand cholinesterase inhibitors can block Abeta accumulation. This latter point represents the focus of a recent publication by Hock and colleagues who investigate the effects of an M1 agonist, Talsaclidine on Abeta levels in the spinal fluid of AD patients. A double-blind, placebo-controlled, and randomized clinical study of 40 patients with AD was conducted. The principal finding was that Talsaclidine decreased CSF levels of Abeta 1-42 by 19%. CSF levels of Abeta 1-40 increased during treatment with placebo while they remained stable during treatment with talsaclidine. These data show that treatment with the m1 agonist talsaclidine reduced Abeta peptides, and particularly Abeta 1-42, in AD patients, suggesting it as a potential amyloid lowering therapy. This trial is supported by a number of preclinical studies and further conceptualizes the growing concept that muscarinic agonists may be useful disease modifiers in the context of AD.

Entry date Thursday, June 05, 2003

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