Impact of muscarinic agonists for successful therapy of Alzheimer's disease

Abstract

The M1 muscarinic agonists AF102B, AF150(S) & AF267B - i) restored cognitive impairments in several animal models for AD with an excellent safety margin; ii) elevated α-APPs levels; iii) attenuated vicious cycles induced by Aβ, and inhibited Aβ- and oxidative stress-induced apoptosis; and iv) decreased τ hyperphosphorylation. AF150(S) and AF267B were more effectve than rivastigmine and nicotine in restoring memory impairments in mice with small hippocampi. In apolipoprotein E-knockout mice, AF150(S) restored cognitive impairments and cholinergic hypofunction and decreased τ hyperphosphorylation. In aged microcebes, AF150(S) restored cognitive and behavioral impairments and decreased τ hyperphosphorylation, paired helical filaments and astrogliosis. In rabbits, AF267B & AF150(S) decreased CSF Aβ(1-42 & 1-40), while AF102B reduced Aβ(1-40). Finally AF102B decreased CSF Aβ(total) in AD patients. Taken together, M1 agonists may represent a unique therapy in AD due to their beneficial effects on three major hallmarks of AD - cholinergic hypofunction, Aβ and τ protein hyperphosphorylation.