Therapeutic strategies in Alzheimer's disease: M1 muscarinic agonists.
The cholinergic hypofunction in Alzheimer's disease (AD) appears to be linked with two other major hallmarks of this disease, beta-amyloid and hyperphosphorylated tau protein. Formation of beta-amyloids might impair the coupling of M1 muscarinic acetylcholine receptors (mAChR) with G-proteins. This can lead to decreased signal transduction, a decrease of trophic and non-amyloidogenic amyloid precursor protein (APPs) and generation of more beta-amyloids, aggravating further the cholinergic deficiency. This review is an attempt to explore the M1 mAChR regulation of beta-amyloid metabolism, tau hyperphosphorylation and cognitive functions. The therapeutic potential of M1-selective muscarinic agonists including AF102B, AF150(S), AF267B (the AF series) is evaluated and compared, when possible, with several FDA-approved acetylcholinesterase inhibitors. These M1 agonists can elevate APPs, decrease tau protein phosphorylation/hyperphosphorylation in vitro and in vivo and restore cognitive impairments in several animal models for AD. Except for the M1 agonists, no other compounds were reported yet with combined effects; e.g., amelioration of cognition dysfunction and beneficial modulation of APPs/beta-amyloid together with tau hyperphosphorylation/phosphorylation. This property of M1 agonists to alter different aspects associated with AD pathogenesis could represent the most remarkable clinical value of such drugs.
Fisher
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Israel Institute for Biological Research, Ness-Ziona. fisher_a@netvision.net.il
D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000502:physiology; D000818:Animals; D017209:Apoptosis; D002219:Carbamates / Q000627:therapeutic use; D016565:Cheirogaleidae; D004195:Disease Models, Animal; D006801:Humans; D018721:Muscarinic Agonists / Q000627:therapeutic use*; D018696:Neuroprotective Agents / Q000627:therapeutic use; D048448:Phenylcarbamates; D010880:Piperidines / Q000627:therapeutic use; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism*; D000068836:Rivastigmine; D015398:Signal Transduction; D013844:Thiazoles / Q000627:therapeutic use; D016875:tau Proteins / Q000378:metabolism
C111926:1-methylpiperidine-4-spiro-(2'-methylthiazoline); D016229:Amyloid beta-Peptides; D002219:Carbamates; D018721:Muscarinic Agonists; D018696:Neuroprotective Agents; D048448:Phenylcarbamates; D010880:Piperidines; D043643:Receptor, Muscarinic M1; D011976:Receptors, Muscarinic; D013844:Thiazoles; D016875:tau Proteins; D000068836:Rivastigmine