Nicotinic acetylcholine receptor signalling: roles in Alzheimer's disease and amyloid neuroprotection

Abstract

Alzheimer's disease (AD), the major contributor to dementia in the elderly, involves accumulation in the brain of extracellular plaques containing the beta-amyloid protein (Abeta) and intracellular neurofibrillary tangles of hyperphosphorylated tau protein. AD is also characterized by a loss of neurons, particularly those expressing nicotinic acetylcholine receptors (nAChRs), thereby leading to a reduction in nAChR numbers. The Abeta(1-42) protein, which is toxic to neurons, is critical to the onset and progression of AD. The discovery of new drug therapies for AD is likely to be accelerated by an improved understanding of the mechanisms whereby Abeta causes neuronal death. We examine the evidence for a role in Abeta(1-42) toxicity of nAChRs; paradoxically, nAChRs can also protect neurons when activated by nicotinic ligands. Abeta peptides and nicotine differentially activate several intracellular signaling pathways, including the phosphatidylinositol 3-kinase/v-akt murine thymoma viral oncogene homolog pathway, the extracellular signal-regulated kinase/mitogen-activated protein kinase, and JAK-2/STAT-3 pathways. These pathways control cell death or survival and the secretion of Abeta peptides. We propose that understanding the differential activation of these pathways by nicotine and/or Abeta(1-42) may offer the prospect of new routes to therapy for AD.

Fig. 1.

Nicotinic acetylcholine receptors (nAChRs) are pentameric proteins composed of homologous nAChR subunits; they are part of the large superfamily of dicysteine loop (Cys-loop) ligand-gated ion channels, which also includes GABA-gated chloride channels, glycine-gated chloride channels, and serotonin (5-HT)-gated cation channels. The tree shows that mammals possess 16 nAChR genes, whereas an additional subunit type (α8) has been found in chicken and pufferfish. nAChRs are expressed in muscle and in the nervous system, with the most abundant brain types consisting of α7, α4β2, and α3β4. The α7 subunits form homomeric nAChRs, whereas α4β2 and α3β4 form heteromeric receptors. α4β2 heteromers can exist as two distinct stoichiometric arrangements.

Fig. 2.

Several drugs either in current use or in clinical trials for the treatment of Alzheimer's disease are active on nicotinic acetylcholine receptors. The manufacturer is shown in italics.

Fig. 3.

Aβ induces cell death through the activation of nicotinic acetylcholine receptors, as well as through other receptors. Several different signaling cascades, including the ERK/MAPK pathway and the JNK pathway, have been implicated in the actions of Aβ. Aβ also activates AKT and controls the activity of apoptotic proteins, including BAD, BAX, and BCL2. In addition to apoptosis, these pathways also often induce hyperphosphorylation of the tau microtubule protein, providing a link between Aβ-activation of nAChRs and the formation of neurofibrillary tangles. The concentration and time course of Aβ exposure can determine which of these pathways is activated. In addition, several pathways through which nicotine protects cells from Aβ toxicity have been identified, including the JAK-2/STAT-3 pathway, in which nAChR-mediated activation of Janus kinase 2 is transduced into STAT-3 activation; the PI3K/AKT pathway, which results in inhibition of apoptosis; and the ERK/MAPK pathway, which is activated by the Ras/Raf cascade and controls gene expression through c-Myc. There are also direct actions of nicotine on mitochondrial function as well as on the aggregation of Aβ.