Janus Kinase 2, an Early Target of α7 Nicotinic Acetylcholine Receptor-mediated Neuroprotection against Aβ-(1–42) Amyloid

Abstract

The molecular mechanisms of ␣7 nicotinic acetylcholine receptor (nAChR)-mediated neuroprotection remain unclear. In this study we provide evidence that nicotine stimulation of ␣7 nAChR transduces signals to phosphatidylinositol 3-kinase and Akt via Janus kinase 2 (JAK2) in a cascade, which results in neuroprotection. Exposure to ␤-amyloid results in the activation of the apoptotic enzyme caspase-3 and cleavage of the DNA-repairing enzyme poly-(ADP-ribose) polymerase. This cascade is inhibited by nicotine through JAK2 activation, and these effects are blocked by preincubation with the JAK2-specific inhibitor AG-490. We also found that pretreatment of cells with angiotensin II blocks the nicotine-induced activation of JAK2 via the AT 2 receptor and completely prevents ␣7 nAChR-mediated neuroprotective effects further suggesting a pivotal role for JAK2. These findings identify novel mechanisms of receptor interactions relevant to neuronal viability and suggest novel therapeutic strategies to optimize neuroprotection.The cholinergic deficit in Alzheimer's disease (AD) 1 has been clearly established and is the basis for the current symptomatic strategy. There is an early and significant depletion of high affinity nicotinic receptors in the brains of Alzheimer's patients (1), and a number of studies have shown cognitive improvement in rodent and primates including humans following administration of ligands targeting nicotinic acetylcholine receptor (nAChR) (2). In addition to their known symptomatic effects, neuronal nicotinic ligands have shown neuroprotective activity in vitro (3) and in vivo (4) suggesting an additional potential for disease modification.The ␣7 nAChR forms functional homomeric ligand-gated ion channels that promote rapidly desensitizing Ca 2ϩ influx, is widely expressed throughout the mammalian brain, and has been implicated in sensory gating, cognition, and neuroprotection (5). In addition, nicotine-induced neuroprotection against ␤-amyloid-induced toxicity is suppressed by ␣-bungarotoxin (␣-Bgt), and the selective ␣7 nAChR agonist, anabasine-derived 3-(4)-dimethylaminocinnamylidine, exerts cytoprotective effects (6, 7). Furthermore, a recent study (8), has reported that the levels of phosphorylated Akt, an effector of phosphatidylinositol 3-kinase (PI-3-K), are increased by nicotine and that the nicotine-induced cytoprotective effects are suppressed by the PI-3-K inhibitors (LY294002 and wortmannin). These findings suggest that the ␣7 nAChR transduces signals to PI-3-K in a cascade, which ultimately contributes to a neuroprotective effect against A␤-(1-42).In comparison to the findings above, another study (9) has shown that whereas nicotine activates the PI-3-K neuroprotective cascade, A␤-(1-42) chronically activates the mitogen-activated protein kinase (MAPK) cascade via the hippocampal ␣7 nAChR. The investigators suggest that this chronic activation of the MAPK pathway by A␤-(1-42) eventually leads to the down-regulation of MAPK which then sets up a positive feedback for A␤ accumulation and de...

Alpha7 nicotinic acetylcholine receptor: A link between inflammation and neurodegeneration

“…In the neuronal cell line PC12, nicotine competes with Aβ42 for the binding to alpha7nAChR (in a "dominant" way), and prevents the Aβ42-induction of caspase 3 and apoptosis. The latter seems to be the result of nicotinic activation of the JAK2-PI3K-Akt signalling pathway, rather than blockade of Aβ42 binding to the alpha7nAChR (Shaw et al, 2002). This effect appears to be mediated by alpha7nAChR because the protection is blocked by alpha-bungarotoxin and is mimicked by the alpha7nAChR-agonist TC-1698 (Marrero et al, 2004;Shaw et al, 2002Shaw et al, , 2003.…”

“…The latter seems to be the result of nicotinic activation of the JAK2-PI3K-Akt signalling pathway, rather than blockade of Aβ42 binding to the alpha7nAChR (Shaw et al, 2002). This effect appears to be mediated by alpha7nAChR because the protection is blocked by alpha-bungarotoxin and is mimicked by the alpha7nAChR-agonist TC-1698 (Marrero et al, 2004;Shaw et al, 2002Shaw et al, , 2003. Treatment with nicotine for ten days in the APPsw mice model (transgenic mice overproducing mutant amyloid β protein precursor, βAPP) reduced insoluble amyloid Aβ1-40 and Aβ1-42 peptides by 80% in the brain cortex of 9 month-old mice (Hellstrom-Lindahl et al, 2004a).…”

“…Alpha7nAChR-agonists trigger activation of tyrosine kinase Janus 2 (JAK2) and phosphorylation of Akt via activation of phosphatidylinositol-3-kinase (PI3K) (Kihara et al, 2001;Shaw et al, 2002) (Fig. 4).…”

Roles of Nicotinic Receptors in Acetylcholinesterase Inhibitor-Induced Neuroprotection and Nicotinic Receptor Up-Regulation

“…31,52) Activation of Akt in turn increases the expression level of Bcl-2 transcript. We observed that treatment with donepezil and galantamine, but not tacrine, also increases the phosphorylation level of Akt and the expression level of Bcl-2 transcript.…”

“…31,52) With the involvement of nAChR in acetylcholinesterase inhibitor-induced neuroprotection, we examined the involvement of this pathway in acetylcholinesterase inhibitor-induced neuroprotection. Treatment with PP2, AG490, LY294002 and wortmannin, inhibitors of Fyn, JAK2 and PI3K, respectively, significantly inhibited neuroprotection by donepezil and galantamine, but not tacrine, which is in good accordance with the results of MLA treatment described above.…”