Activation of muscarinic receptors inhibits β-amyloid peptide-induced signaling in cortical slices

Deposition of fibrillar aggregates of the β-amyloid peptide (Aβ) is a key pathologic feature during the early stage of Alzheimer's disease. The initial neuronal responses to Aβ in cortical circuits and the regulation of Aβ-induced signaling remain unclear. In this study, we found that exposure of cortical slices to Aβ_1-42 or Aβ_25-35 induced a marked increase in the activation of protein kinase C (PKC) and Ca²⁺/calmodulin-dependent kinase II (CaMKII), two enzymes critically involved in a variety of cellular functions. Activation of M1 muscarinic receptors, but not nicotinic receptors, significantly inhibited the Aβ activation of PKC and CaMKII. Increasing inhibitory transmission mimicked the M1 effect on Aβ, whereas blocking GABA_A receptors eliminated the M1 action. Moreover, electrophysiological evidence shows that application of Aβ to cortical slices induced action potential firing and enhanced excitatory postsynaptic currents, whereas muscarinic agonists potently increased inhibitory postsynaptic currents. These results suggest that Aβ activates PKC and CaMKII through enhancing excitatory activity in glutamatergic synaptic networks. Activation of M1 receptors inhibits Aβ signaling by enhancing the counteracting GABA_ergic inhibitory transmission. Thus the muscarinic reversal of the Aβ-induced biochemical and physiological changes provides a potential mechanism for the treatment of Alzheimer's disease with cholinergic enhancers.