Therapeutic Strategies in Alzheimer’s Disease:M1 Muscarinic Agonists

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The cholinergic hypofunction in Alzheimer’s disease(AD)appears to be linked with two other major hallmarks of this disease, β−amyloid and hyperphosphorylated tau protein.Formation of β−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 β−amyloids, aggravating further the cholinergic deficiency.This review is an attempt to explore the M1 mAChR regulation of β−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/β−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.