M1 muscarinic agonists can modulate some of the hallmarks in Alzheimer’s disease
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M1 muscarinic receptors (M1 mAChRs) play a role in an apparent linkage of three major hallmarks of Alzheimer’s disease (AD): β-amyloid (Aβ) peptide; tau hyperphosphorylation and paired helical filaments (PHFs); and loss of cholinergic function conducive to cognitive impairments. We evaluated the M1 muscarinic agonists AF102B (Cevimeline, EVOXAC™: prescribed for Sjøgren’s syndrome), AF150(S), and AF267B on some of these hallmarks of AD. Activation of M1 mAChRs with these agonists leads, inter alia, to enhanced secretion of amyloid precursor protein (α-APP), (via α-secretase activation), to decreased Aβ (via γ-secretase inhibition), and to inhibition of Aβ- and/or oxidative stress-induced cell death. In several animal models mimicking different aspects of AD, these drugs restored cognitive impairments, and in select cases induced a decrease in brain Aβ elevation, with a high safety margin, following po administration. Notably, in mice with small hippocampi, unlike rivastigmine and nicotine, AF150(S) and AF267B restored cognitive impairments also on escape latency in a Morris water maze paradigm, in reversal learning. Studies from other labs showed that AF102B and talsaclidine (another M1 agonist) decreased cerbrospinal fluid (CSF) Aβ in AD patients following chronic treatment, being the first reported drugs with such a profile. The clinical significance of these studies remains to be elucidated, yet based on in vivo (rabbits) and in vitro studies (cell cultures), our M1 agonists can decrease brain Aβ, owing to a novel and dual complementary effect (e.g., inhibition of γ-secretase and activation of α-secretase). Remarkably, although M1 agonists can decrease CSF Aβ in AD patients, an increased AD-type pathology in Parkinson’s disease was recently been associated with chronic antimuscarinic treatment. In another aspect, these agonists decreased tau hyperphosphorylation in vitro and in vivo. Notably, nicotinic agonists or cholinesterase inhibitors increased tau hyperphosphorylation. In summary, the M1 agonists tested are effective on cognition and behavior and show unique disease-modifying properties owing to beneficial effects on major hallmarks of AD. This may place such drugs in the first line of modern AD therapies (e.g., β- or γ-secretase inhibitors, vaccines against Aβ, statins, and inhibitors of tau hyperphosphorylation).
Index EntriesM1 agonist Alzheimer’s disease β-amyloid α-APPs cell death apoptosis tau proteins animal models
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- Beach T. G., Potter P. E., Sue L. I., Fisher A., Scott S., Layne K. J., et al. (2002) Cerebral Abeta deposition induced by cortical deafferentiation is reduced by cholinergic therapy. Soc. Neurosci. Abstr. 722, 9.Google Scholar
- Buxbaum J. D., Oishi M., Chen H. I., Pinkas-Kramarski R., Jaffe E. A., Gandy S. E., and Greengard P. (1992) Cholinergic agonists and interleukin 1 regulate processing and secretion of the Alzheimer beta-A4 amyloid protein precursor. Proc. Natl. Acad. Sci. USA 89, 10,075–10,078.CrossRefGoogle Scholar
- Haring R., Pittel Z., Eizenberg O., and Fisher A. (2000) M1 muscarinic agonists protect PC12M1 cells from growth factor deprivation and beta-amyloid-induced apoptosis. World Conference on Alzheimer’s Disease, Washington, D.C., July 9–13.Google Scholar
- Hartmann T., Runz H., Grimm H., Grziwa B., Bergmann C., Simons M., et al. (2002) γ-Secretase inhibition via cholesterol depletion involves presenilin. Soc. Neurosci. Abstr. 122, 6.Google Scholar
- Hock C., Maddalena A., Heuser I., Naber D., Oertel W., von Der Krame H., et al. (2000) Treatment with the selective muscarinic agonist talsclidine decreases cerebrospinal fluid levels of total amyloid beta-peptide in patients with Alzheimer’s disease. Ann. N.Y. Acad. Sci. 920, 285–291.PubMedCrossRefGoogle Scholar
- Hung A. Y., Haass C., Nitsch R., Qiu W. Q., Citron M., Wurtman R. J., et al. (1993) Activation of protein kinase C inhibits cellular production of the amyloid beta-protein. J. Biol. Chem. 268, 22,959–22,962.Google Scholar
- Kurumatani T., Fastbom J., Bonkale W. L., Bogdanovic N., Winblad B., Ohm T. G., and Cowburn R. F. (1998) Loss of inositol 1,4,5-trisphosphate receptor sites and decreased PKC levels correlate with staging of Alzheimer’s disease neurofibrillary pathology. Brain Res. 796, 209–221.PubMedCrossRefGoogle Scholar
- Mattson M. P. (1997) Central role of oxyradicals in the mechanism of amyloid beta-peptide cytotoxicity. Alzheimer’s Dis. Rev. 2, 1–14.Google Scholar
- Perry E. K., Burn D. J., Kilford L., Lees A. J., and Perry R. H. (2002) Increased Alzheimer pathology in Parrkinson’s disease is associated with chronic antimuscarinic drug treatment. Seventh International Meeting on Parkinson Disease and Movement Disorders, Nov., Miami FL.Google Scholar
- Simons M., Schwarzler F., Lutjohann D., von Bergmann K., Beyreuther K., Dichgans J., et al. (2002) Treatment with simavastatin in normocholesterolemic patients with Alzheimer’s disease: a 26-week randomized, placebo-controlled, double-blind trial. Ann. Neurol. 52, 346–350.PubMedCrossRefGoogle Scholar
- Wolf B. A., Wertkin A. M., Jolly Y. C., Yasuda R. O., Wolfe B. B., Konrad R. J., et al. (1995) Muscarinic regulation of Alzheimer’s disease amyloid precursor protein secretion and amyloid beta-protein production in human neuronal NT2N cells. J. Biol. Chem. 270, 4916–4922.PubMedCrossRefGoogle Scholar