Treatment with the selective muscarinic m1 agonist talsaclidine decreases cerebrospinal fluid levels of A beta 42 in patients with Alzheimer's disease.
The amyloid beta-peptides A beta 40 and A beta 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 (A beta PP), including alpha- beta-, and gamma-secretases. Talsaclidine is a functionally selective muscarinic m1 agonist that stimulates non-amyloidogenic alpha-secretase processing in vitro. We compared cerebrospinal fluid (CSF) levels of A beta 40 and A beta 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 A beta 42 by a median of 19% (p < 0.001) as compared to baseline. The mean difference between CSF levels of A beta 42 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 A beta 40 increased during treatment 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 m1 agonist talsaclidine reduced A beta peptides, and particularly A beta 42, in AD patients, suggesting it as a potential amyloid lowering therapy of AD.
Hock
Christoph
C
Division of Psychiatry Research, University of Zürich, Lenggstrasse 31, CH-8029 Zürich, Switzerland. chock@bli.unizh.ch
Maddalena
Alessia
A
Raschig
Andreas
A
Müller-Spahn
Franz
F
Eschweiler
Gerhard
G
Hager
Klaus
K
Heuser
Isabella
I
Hampel
Harald
H
Müller-Thomsen
Thomas
T
Oertel
Wolfgang
W
Wienrich
Marion
M
Signorell
Andri
A
Gonzalez-Agosti
Charo
C
Nitsch
Roger M
RM
D000368:Aged; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018721:Muscarinic Agonists / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000134:cerebrospinal fluid*; D010919:Placebos; D011812:Quinuclidines / Q000627:therapeutic use*; D043643:Receptor, Muscarinic M1 / Q000819:agonists*
D016229:Amyloid beta-Peptides; D018721:Muscarinic Agonists; D010446:Peptide Fragments; D010919:Placebos; D011812:Quinuclidines; D043643:Receptor, Muscarinic M1; C079885:talsaclidine fumarate