Article

Nicotinic acetylcholine receptor signaling: 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: 18.55). 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.

0 Followers
 · 
117 Views
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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 · 2.84 Impact Factor
  • Source
    • "However, widespread cholinergic cell loss is still considered a major aspect of AD (Micheau and Marighetto, 2011). Another important link between AD and cholinergic signaling is through the nAChR (Buckingham et al., 2009; Jürgensen and Ferreira, 2010). It has been found that AD patients have strongly reduced levels of cortical α4β2 nAChRs (Kellar et al., 1987; Sparks et al., 1998; Perry et al., 2000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Acetylcholine (ACh) release in the medial prefrontal cortex (mPFC) is crucial for normal cognitive performance. Despite the fact that many have studied how ACh affects neuronal processing in the mPFC and thereby influences attention behavior, there is still a lot unknown about how this occurs. Here we will review the evidence that cholinergic modulation of the mPFC plays a role in attention and we will summarize the current knowledge about the role between ACh receptors (AChRs) and behavior and how ACh receptor activation changes processing in the cortical microcircuitry. Recent evidence implicates fast phasic release of ACh in cue detection and attention. This review will focus mainly on the fast ionotropic nicotinic receptors and less on the metabotropic muscarinic receptors. Finally, we will review limitations of the existing studies and address how innovative technologies might push the field forward in order to gain understanding into the relation between ACh, neuronal activity and behavior.
    Frontiers in Neural Circuits 03/2014; 8:17. DOI:10.3389/fncir.2014.00017 · 2.95 Impact Factor
Show more