Muscarinic agonists reduce tau phosphorylation in non-neuronal cells via GSK-3beta inhibition and in neurons.
Muscarinic agonists alter the metabolism of amyloid precursor protein, leading to an increase in alpha-secretase cleavage and a decreased production of amyloidogenic peptides; suggesting that these compounds might modify the Alzheimer's disease process. A second therapeutic target in AD is the accumulation of stably phosphorylated tau into neurofibrillary tangles; an early event correlating with cognitive impairment. Glycogen synthase kinase-3 (GSK-3beta) phosphorylates tau and is inhibited via protein kinase C (PKC). As certain muscarinic receptors are linked to PKC, we examined the effect of a range of agonists on GSK-3beta phosphorylation of tau. In neurons a nonspecific muscarinic agonist, carbachol, reduced tau phosphorylation. In nonneuronal cells expressing the ml receptor a range of ml agonists reduced transiently-expressed tau phosphorylation and altered its microtubulebinding properties. These findings link the two pathological process of AD-APP metabolism and tau phosphorylation - and suggest that muscarinic and other cholinergic compounds might have disease-modifying properties.
Forlenza
O V
OV
Institute of Psychiatry, Faculty of Medicine, University of São Paulo, Brazil.
Spink
J M
JM
Dayanandan
R
R
Anderton
B H
BH
Olesen
O F
OF
Lovestone
S
S
D000109:Acetylcholine / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016564:Amyloid beta-Protein Precursor / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000187:drug effects* / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D002478:Cells, Cultured / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D005333:Fetus; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D018021:Lithium Chloride / Q000494:pharmacology; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects* / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology; D013830:Thiadiazoles / Q000494:pharmacology; D016875:tau Proteins / Q000187:drug effects* / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; C108369:LU 25-109-T; D018721:Muscarinic Agonists; D011725:Pyridines; D011976:Receptors, Muscarinic; D013777:Tetrazoles; D013830:Thiadiazoles; D016875:tau Proteins; D002217:Carbachol; C075257:xanomeline; D038341:Glycogen Synthase Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D018021:Lithium Chloride; D000109:Acetylcholine