RT Journal Article SR Electronic T1 Nicotinic Acetylcholine Receptor Signalling: Roles in Alzheimer's Disease and Amyloid Neuroprotection JF Pharmacological Reviews JO Pharmacol Rev FD American Society for Pharmacology and Experimental Therapeutics SP 39 OP 61 DO 10.1124/pr.108.000562 VO 61 IS 1 A1 Steven D. Buckingham A1 Andrew K. Jones A1 Laurence A. Brown A1 David B. Sattelle YR 2009 UL http://pharmrev.aspetjournals.org/content/61/1/39.abstract AB Alzheimer's disease (AD), the major contributor to dementia in the elderly, involves accumulation in the brain of extracellular plaques containing the β-amyloid protein (Aβ) 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 Aβ1–42 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 Aβ causes neuronal death. We examine the evidence for a role in Aβ1–42 toxicity of nAChRs; paradoxically, nAChRs can also protect neurons when activated by nicotinic ligands. Aβ 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 Aβ peptides. We propose that understanding the differential activation of these pathways by nicotine and/or Aβ1–42 may offer the prospect of new routes to therapy for AD.