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

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 alpha-APPs levels; iii) attenuated vicious cycles induced by A beta, and inhibited A beta- and oxidative stress-induced apoptosis; and iv) decreased tau 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 tau hyperphosphorylation. In aged microcebes, AF150(S) restored cognitive and behavioral impairments and decreased tau hyperphosphorylation, paired helical filaments and astrogliosis. In rabbits, AF267B & AF150(S) decreased CSF A beta(1-42 & 1-40), while AF102B reduced A beta(1-40). Finally AF102B decreased CSF A beta(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, A beta and tau protein hyperphosphorylation.