Why Cholinergic Agents Help Alzheimer's Patients

Abstract

Alzheimer's disease is a neurodegenerative disease that impairs cognition and ultimately results in death. Cholinergic agents are used to improve symptoms associated with the disease, and one mechanism may be the replacement of lost cholinergic input. Gu et al . provide a possible molecular mechanism for the benefits of cholinergic therapies by showing that the β-amyloid peptide (Aβ), which is a major constituent of senile plaques, stimulates intracellular signaling pathways in cortical neurons and that this can be blocked by the presence of agonists of the M1 muscarinic acetylcholine receptors (mAChRs). Cortical slices exposed to either the aggregated form of Aβ 25-35 or the full-length Aβ 1-42 or nonaggregated Aβ peptides exhibited increased phosphorylation of protein kinase C (PKC) and calcium-calmodulin-dependent kinase II (CaMKII), which was taken as a measure of activation of these enzymes. Treatment of the slices with N -methyl-D-aspartate (NMDA) and non-NMDA glutamate receptor antagonists and antagonists of the voltage-dependent calcium channels blocked stimulation of PKC and CaMKII by Aβ peptides, as did chelation of calcium with EGTA and inhibition of action potentials by application of the sodium channel blocker tetrodotoxin. Thus, synaptic transmission appeared to be required for Aβ to stimulate intracellular signaling. Indeed, Aβ stimulated the frequency of action potentials and decreased the interval between excitatory postsynaptic currents (EPSCs). Application of a mAChR agonist or a γ-aminobutyric acid A (GABA A ) receptor agonist inhibited phosphorylation of PKC and CaMKII in response to Aβ peptides, suggesting that mAChR may stimulate inhibitory neuronal signals mediated by GABA. As expected, application of the mAChR agonist increased the frequency of inhibitory synaptic transmission in the slices and decreased the interval between inhibitory postsynaptic currents (IPSCs). Thus, increased inhibitory synaptic transmission stimulated by mAChR agonists may compensate for the increased excitatory transmission triggered by excess Aβ peptide produced during Alzheimer's disease. Z. Gu, P. Zhong, Z. Yan, Activation of muscarinic receptors inhibits β-amyloid peptide-induced signaling in cortical slices. J. Biol. Chem. 278 , 17546-17556 (2003). [Abstract] [Full Text]