Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of Aβ42 in patients with Alzheimer's disease

The amyloid beta-peptides Abeta(40) and Abeta(42) are highly amyloidogenic constituents of brain beta-amyloid plaques in Alzheimer's disease (AD). Lowering their formation may be achieved by modulating the activities of proteases that cleave the amyloid precursor protein (AbetaPP), including alpha-beta, and gamma-secretases. Talsaclidine is a functionally selective muscarinic ml agonist that stimulates non-amyloidogenic alpha-secretase processing in vitro. We compared cerebrospinal fluid (CSF) levels of Abeta(40) and Abeta(42) measured by ELISA before and at the end of 4 weeks of treatment with talsaclidine. The medication was administered in a double-blind, placebo-controlled, and randomized clinical study to 40 patients with AD. Talsaclidine (n=34) decreased CSF levels of Abeta(42) by a median of 19% (p<0.001) as compared to baseline. The mean difference between CSF levels of A,8 12 before and after treatment with talsaclidine (n=34) was 46 +/- 73 (SD) pg/ml as compared to 0+/-8 (SD) pg/ml with placebo (n=6) (p<0.05). CSF levels of Abeta(40) increased during treatement with placebo (n=6) while they remained stable during treatment with talsaclidine (n=31) (1.118+/-1.710 ng/ml, and -0.170+/-0.967 ng/ml, respectively; p<0.05). These data show that treatment with the ml agonist talsaclidine reduced Aβ peptides, and particularly Aβ(42), in AD patients, suggesting it as a potential amyloid lowering therapy of AD.