The selective muscarinic M1 agonist AF102B decreases levels of total Abeta in cerebrospinal fluid of patients with Alzheimer's disease.
beta-Amyloid (Abeta) deposits in diffuse and compact senile plaques in the brain are one of the defining histopathological features of Alzheimer's disease (AD). Preventing Abeta deposition is a goal of drug therapy for AD, because excessive amounts of Abeta may be toxic to neurons. In preclinical studies, activation of the muscarinic M1 receptor subtype inhibited Abeta secretion from cultured cells. To determine whether a similar sequence occurs in human beings, we administered the selective M1 agonist AF102B to 19 AD patients and measured total Abeta (Abeta(total)) levels in cerebrospinal fluid (CSF) before and during treatment. Abeta(total) levels in CSF decreased in 14 patients by 22%, increased in 3 patients, and were unchanged in 2 patients; the overall decrease in the group as a whole was statistically significant. To test the specificity of the M1 effect, we also measured the relative changes in Abeta(total) levels in CSF during treatments in separate sets of AD patients with the acetylcholinesterase inhibitor physostigmine or the anti-inflammatory drug hydroxychloroquine. CSF Abeta(total) levels did not change significantly in the 9 AD patients in the physostigmine protocol or in the 10 AD patients in the hydroxychloroquine study. These data provide evidence that the activation of M1 receptors reduces Abeta levels in the CSF of AD patients. If this effect also occurs in brain, M1 agonists may have long-term therapeutic benefits by lowering amyloid in AD.
Nitsch
R M
RM
Division of Psychiatry Research, University of Zurich, Switzerland.
Deng
M
M
Tennis
M
M
Schoenfeld
D
D
Growdon
J H
JH
D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D005260:Female; D006801:Humans; D008297:Male; D011812:Quinuclidines / Q000627:therapeutic use*; D013876:Thiophenes
D016229:Amyloid beta-Peptides; D011812:Quinuclidines; D013876:Thiophenes; C059240:cevimeline