Treatment with the selective muscarinic agonist talsaclidine decreases cerebrospinal fluid levels of total amyloid beta-peptide in patients with Alzheimer's disease.
Brain amyloid load in Alzheimer's disease (AD) is, at least in genetic forms, associated with overproduction of amyloid beta-peptides (A beta). Thus, lowering A beta production is a central therapeutic target in AD and may be achieved by modulating such key enzymes of amyloid precursor protein (APP) processing as beta-, gamma-, and alpha-secretase activities. Talsaclidine is a selective muscarinic M1 agonist that stimulates the nonamyloidogenic alpha-secretase pathway in model systems. Talsaclidine was administered double-blind, placebo-controlled, and randomized to 24 AD patients and cerebrospinal fluid (CSF) levels of total A beta were quantitated before and after 4 weeks of drug treatment. We observed that talsaclidine decreases CSF levels of A beta significantly over time within the treatment group (n = 20) by a median of 16% as well as compared to placebo (n = 4) by a median of 27%. We conclude that treatment with selective M1 agonists may reduce A beta production and may thus be further evaluated as a potential amyloid-lowering therapy of AD.
Hock
C
C
Department of Psychiatry Research, University of Zürich, Lenggstrasse 31, CH-8029 Zürich 8, Switzerland. chock@bli.unizh.ch
Maddalena
A
A
Heuser
I
I
Naber
D
D
Oertel
W
W
von der Kammer
H
H
Wienrich
M
M
Raschig
A
A
Deng
M
M
Growdon
J H
JH
Nitsch
R M
RM
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000134:cerebrospinal fluid* / Q000188:drug therapy*; D016229:Amyloid beta-Peptides / Q000134:cerebrospinal fluid*; D004311:Double-Blind Method; D006801:Humans; D018721:Muscarinic Agonists / Q000627:therapeutic use*; D010919:Placebos; D011812:Quinuclidines / Q000627:therapeutic use*
D016229:Amyloid beta-Peptides; D018721:Muscarinic Agonists; D010919:Placebos; D011812:Quinuclidines; C079885:talsaclidine fumarate