Journal of Molecular Neuroscience

, Volume 20, Issue 3, pp 349–356

M1 muscarinic agonists can modulate some of the hallmarks in Alzheimer’s disease

Implications in future therapy


    • Israel Institute for Biological Research
  • Zipora Pittel
    • Israel Institute for Biological Research
  • Rachel Haring
    • Israel Institute for Biological Research
  • Nira Bar-Ner
    • Israel Institute for Biological Research
  • Michal Kliger-Spatz
    • Israel Institute for Biological Research
  • Niva Natan
    • Israel Institute for Biological Research
  • Inbal Egozi
    • Israel Institute for Biological Research
  • Hagar Sonego
    • Israel Institute for Biological Research
  • Itzhak Marcovitch
    • Israel Institute for Biological Research
  • Rachel Brandeis
    • Israel Institute for Biological Research
Alzheimer’s Therapeutics: Cognitive Enhancement

DOI: 10.1385/JMN:20:3:349

Cite this article as:
Fisher, A., Pittel, Z., Haring, R. et al. J Mol Neurosci (2003) 20: 349. doi:10.1385/JMN:20:3:349


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 Entries

M1 agonistAlzheimer’s diseaseβ-amyloidα-APPscell deathapoptosistau proteinsanimal models
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© Humana Press Inc 2003