Nicotinic Acetylcholine Receptor Signalling: Roles in Alzheimer's Disease and Amyloid Neuroprotection

Medical Research Council Functional Genomics Unit, Department of Physiology Anatomy and Genetics, University of Oxford, South Parks Road, Oxford, UK, OX1 3QX.
Pharmacological reviews (Impact Factor: 17.1). 04/2009; 61(1):39-61. DOI: 10.1124/pr.108.000562
Source: PubMed

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.

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Available from: Laurence A Brown, Jun 02, 2014
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    • "Although α7 nAChRs may interact with more than 50 different proteins to trigger multiple intracellular signals [16], [17], [31], [45]–[53], [57], our results obtained with selective inhibitors for different signaling molecules (Figure 3A–B) limit the number of possible pathways involved in the nicotine-mediated effect on IRAK-M expression to two kinases (JAK2 and PI3K) and one transcription factor (STAT3). This finding agrees with published observations [16], [31], [52] showing that these three components in the downstream signaling pathway from α7 nAChR are involved in most of the pathophysiological responses associated to this receptor subtype. "
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    ABSTRACT: Nicotine stimulation of α7 nicotinic acetylcholine receptor (α7 nAChR) powerfully inhibits pro-inflammatory cytokine production in lipopolysaccharide (LPS)-stimulated macrophages and in experimental models of endotoxemia. A signaling pathway downstream from the α7 nAChRs, which involves the collaboration of JAK2/STAT3 and NF-κB to interfere with signaling by Toll-like receptors (TLRs), has been implicated in this anti-inflammatory effect of nicotine. Here, we identifiy an alternative mechanism involving interleukin-1 receptor-associated kinase M (IRAK-M), a negative regulator of innate TLR-mediated immune responses. Our data show that nicotine up-regulates IRAK-M expression at the mRNA and protein level in human macrophages, and that this effect is secondary to α7 nAChR activation. By using selective inhibitors of different signaling molecules downstream from the receptor, we provide evidence that activation of STAT3, via either JAK2 and/or PI3K, through a single (JAK2/PI3K/STAT3) or two convergent cascades (JAK2/STAT3 and PI3K/STAT3), is necessary for nicotine-induced IRAK-M expression. Moreover, down-regulation of this expression by small interfering RNAs specific to the IRAK-M gene significantly reverses the anti-inflammatory effect of nicotine on LPS-induced TNF-α production. Interestingly, macrophages pre-exposed to nicotine exhibit higher IRAK-M levels and reduced TNF-α response to an additional LPS challenge, a behavior reminiscent of the 'endotoxin tolerant' phenotype identified in monocytes either pre-exposed to LPS or from immunocompromised septic patients. Since nicotine is a major component of tobacco smoke and increased IRAK-M expression has been considered one of the molecular determinants for the induction of the tolerant phenotype, our findings showing IRAK-M overexpression could partially explain the known influence of smoking on the onset and progression of inflammatory and infectious diseases.
    PLoS ONE 09/2014; 9(9):e108397. DOI:10.1371/journal.pone.0108397 · 3.23 Impact Factor
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    • "Receptor Signal transduction pathway References * NMDAR (NR2B subtype) Erk1/2, CamKIV [95, 176–182] mGluR5 (with PrP C ) PKC, MAPKs (Erk1/2, p38, and JNK) [79] nAchR (í µí»¼7 subtype) Erk1/2, Akt, and JAK-STAT [183] [184] Wnt receptor Wnt signalling (GSK3) [185] [186] IR/IGF PI3K-Akt [176] [187] Amylin receptor Erk1/2, PKA [177] RAGE p38 [188] Neurotrophin receptors Erk1/2, Akt [45] [189] í µí»½2AR PKA, Erk1/2, and JNK [149] [190] [191] * Including reviews with original research papers cited. "
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    ABSTRACT: Although a wide variety of genetic and nongenetic Alzheimer's disease (AD) risk factors have been identified, their role in onset and/or progression of neuronal degeneration remains elusive. Systematic analysis of AD risk factors revealed that perturbations of intraneuronal signalling pathways comprise a common mechanistic denominator in both familial and sporadic AD and that such alterations lead to increases in Aβ oligomers (Aβo) formation and phosphorylation of TAU. Conversely, Aβo and TAU impact intracellular signalling directly. This feature entails binding of Aβo to membrane receptors, whereas TAU functionally interacts with downstream transducers. Accordingly, we postulate a positive feedback mechanism in which AD risk factors or genes trigger perturbations of intraneuronal signalling leading to enhanced Aβo formation and TAU phosphorylation which in turn further derange signalling. Ultimately intraneuronal signalling becomes deregulated to the extent that neuronal function and survival cannot be sustained, whereas the resulting elevated levels of amyloidogenic Aβo and phosphorylated TAU species self-polymerizes into the AD plaques and tangles, respectively.
    BioMed Research International 08/2014; 2014:167024. DOI:10.1155/2014/167024 · 2.71 Impact Factor
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    • "The predominant clinical symptoms early associated with Alzheimer's disease (AD) include a deficiency in memory capabilities and these deficits are linked to a selective impairment of cholinergic function (Buckingham et al., 2009; Jürgensen and Ferreira, 2010). It has been reported that a significant decrease in the number of α4 nicotinic acetylcholine receptors (nAChRs) is one of the earliest events in the pathogenesis of AD (Burghaus et al., 2000) even preceding cholinergic neuronal degeneration. "
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    ABSTRACT: Contradictory results have been reported on the interaction of beta-amyloid (Aβ) with cholinergic receptors. The present paper investigates the modulatory effect of Aβ1-40 on the neurotransmitter release evoked by nicotinic (nAChRs) and muscarinic (mAChRs) receptors. Aβ1-40 inhibits both nicotinic and muscarinic-evoked [(3)H]DA overflow from rat nerve endings. Added to perfusion medium, Aβ1-40 is able to enter into synaptosomes; it exerts its inhibitory effect at extracellular sites when release is stimulated by nAChRs and intracellularly when release is evoked by mAChRs. Moreover, our data show that Aβ1-40 acts as non competitive antagonist of heteromeric α4β2* but not of α3β4* nAChRs which modulate [(3)H]NA overflow. Positive allosteric modulators of nAChRs counteract its inhibitory effect. It might be that compounds of this type could be useful to prevent, slow down the appearance or reverse the cognitive decline typical of the normal processes of brain aging.
    Frontiers in Aging Neuroscience 07/2014; 6:166. DOI:10.3389/fnagi.2014.00166 · 4.00 Impact Factor
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