A novel nicotinic mechanism underlies β-amyloid-induced neurotoxicity

Liu, Qiang; Xie, Xin; Emadi, Sharareh; Sierks, Michael R.; Wu, Jie

doi:10.1016/j.neuropharm.2015.04.025

Cited by 24 publications

(14 citation statements)

References 55 publications

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“…Several interactions between Aβ oligomers and α7n‐AchChR have been suggested, including direct binding with high affinity . Up‐regulation of α7n‐AchChR associated with the toxic effect of Aβ oligomers has been reexamined to confirm the role of these receptors in the detrimental action of Aβ peptides . Interference of Aβ oligomers has also been shown with N ‐methyl‐ d ‐aspartate (NMDA) receptors, affecting synaptic function, calcium influx, a number of downstream cascades, and postsynaptic α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) receptors .…”

Section: Aβ Oligomersmentioning

confidence: 99%

Oligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases

et al. 2016

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The term oligomeropathies defines the neurodegenerative disorders associated with protein misfolding, where small soluble aggregates (oligomers 4-200 KDa) are the cause of neuronal dysfunction and are responsible for spreading the pathology. The ability of these soluble β-sheet conformers to induce neuronal damage has been investigated in direct challenge with the monomeric and fibrillary structures, showing that only the oligomeric species affected the neurons. β amyloid oligomers were initially purified from Alzheimer brains and obtained using synthetic peptides. Together with the neuronal death, synaptic dysfunction, loss of spines, and LTP impairment were seen with the direct application of β amyloid oligomers. Similar results have been described with proteins associated with other neurodegenerative disorders. The biological activities of oligomeric forms of α synuclein have been described in Parkinson's disease and Lewy body dementia. Detrimental effects have been associated with the oligomeric forms of prion, tau, and huntingtin, the key proteins in prion diseases, frontotemporal dementia, and Huntington's disease, respectively. The molecular mechanisms of the oligomer-related toxic effects can be summarized under three headings: nonspecific perturbance of cellular and intracellular membranes, specific interaction with various cellular entities, and amyloid pore channel formation. To characterize and distinguish oligomer actions better, we compared the ability of β amyloid and α synuclein oligomers to induce cognitive impairment when applied directly into the brain in the same acute mouse model. We also investigated the role of inflammatory components. © 2016 International Parkinson and Movement Disorder Society.

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Section: Aβ Oligomersmentioning

confidence: 99%

Oligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases

et al. 2016

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“…Brain tissues and cells were lysed in RIPA lysis buffer (Sigma-Aldrich) supplemented with PMSF (Sigma-Aldrich). As has been described (18,19,21,(23)(24)(25), proteins were separated by 12% SDS polyacrylamide gel and transferred to PVDF membranes (EMS Millipore). The membranes were blocked in 5% bovine serum albumin and incubated with one of the following primary antibodies: rabbit anti-S1PR1 polyclonal antibody (1:200,10005228; Cayman Chemical), anti-phosphorylated ERK1/2 (1:1000, sc-16982; Santa Cruz Biotechnology, Paso Robles, CA, USA), anti-Bcl-2 (1:500, sc-492; Santa Cruz Biotechnology), and anti-cleaved caspase 3 (1:1000, 9661; Cell Signaling Technology, Beverly, MA, USA).…”

Section: Western Blot Analysismentioning

confidence: 99%

Neuroprotective effects of fingolimod in mouse models of Parkinson's disease

Zhao

Yang

et al. 2016

FASEB j.

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Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons with limited treatment options. Emerging evidence shows that FTY720 protects against neural injury via modulation of the sphingosine-1-phosphate 1 receptor (S1PR1). However, it remains unclear whether FTY720 could influence neurodegeneration in PD. Therefore, the present study was designed to determine the impact of fingolimod (FTY720), a sphingosine-1-phosphate receptor (S1PR) agonist, on 2 mouse models of PD. We found that FTY720 significantly reduced the deficit of motor function, diminished the loss of tyrosine hydroxylase-positive neurons in the substantia nigra, and attenuated the decrease of striatal dopamine and metabolite levels in mice receiving 6-hydroxydopamine (6-OHDA) or rotenone to simulate PD. An S1PR1-selective antagonist, W146, blocked the neuroprotective effects of FTY720. Of note, FTY720 retained the phosphorylation of ERK, together with a decreased expression of cleaved caspase-3 in mice treated with 6-OHDA or rotenone. In vitro studies revealed that FTY720 also attenuated 6-OHDA- or rotenone-induced toxicity in SH-SY5Y cells. These findings suggest the potential of S1PR modulation as a treatment for PD.-Zhao, P., Yang, X., Yang, L., Li, M., Wood, K., Liu, Q., Zhu, X. Neuroprotective effects of fingolimod in mouse models of Parkinson's disease.

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“…First, the acute inhibition of α7β2 nAChRs by Aβ 1–42 may directly lead to basal forebrain cholinergic signaling impairments in the hippocampus and subsequent learning and memory deficits [29]. Second, the Aβ 1–42 -sensitive α7β2 nAChRs may mediate chronic upregulation of α7-containing nAChRs because acute inhibition of α7 nAChRs triggers receptor upregulation [37–39]. In primary hippocampal neuronal cultures, we found that chronic treatment of neurons with Aβ 1–42 (100 nM, fibrils or oligomers) upregulated α7 nAChR surface expression and function, which can be abolished by α7 nAChR antagonists and was absent in cultures prepared from α7 nAChR KO [38].…”

Section: Significance Of the Heteromeric α7β2 Nachrmentioning

confidence: 99%

“…This upregulation by Aβ 1–42 required a higher concentration (i.e., 100 nM) than we found was necessary to block the heteromeric α7β2 receptors, suggesting that the receptors responsible for this upregulation were homomeric α7 nAChRs [38]. Moreover, using human neuroblastoma (SH-SY5Y) cells differentiated by the addition of 10 μM retinoic acid to each dish, and incubating at 37 °C for 4 days to have cholinergic characteristics, we tested the effects of large Aβ 1–42 aggregates (100 nM) on α7 nAChR function and cell toxicity, and found that chronic exposure of Aβ 1–42 aggregates upregulated α7 nAChR function, and consequently resulted in cellular toxicity, which was prevented by pharmacological block of α7 (but not α4β2) nAChRs [39]. These results suggest that α7 nAChRs (likely homomeric) play an important role in Aβ 1–42 -induced mediation of neuronal excitability as well as cellular toxicity.…”

Section: Significance Of the Heteromeric α7β2 Nachrmentioning

confidence: 99%

Heteromeric α7β2 Nicotinic Acetylcholine Receptors in the Brain

Liu

Tang

et al. 2016

Trends in Pharmacological Sciences

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The α7 nicotinic acetylcholine receptor (α7 nAChR) is highly expressed in the brain, where it maintains various neuronal functions including (but not limited to) learning and memory. In addition, the protein expression levels of α7 nAChRs are altered in various brain disorders. The classic rule governing α7 nAChR assembly in the mammalian brain was that it was assembled from five α7 subunits to form a homomeric receptor pentamer. However, emerging evidence demonstrates the presence of heteromeric α7 nAChRs in heterologously expressed systems and naturally in brain neurons, where α7 subunits are co-assembled with β2 subunits to form a novel type of α7β2 nAChR. Interestingly, the α7β2 nAChR exhibits distinctive function and pharmacology from traditional homomeric α7 nAChRs. We review recent advances in probing the distribution, function, pharmacology, pathophysiology, and stoichiometry of the heteromeric α7β2 nAChR, which have provided new insights into the understanding of a novel target of cholinergic signaling.

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A novel nicotinic mechanism underlies β-amyloid-induced neurotoxicity

Cited by 24 publications

References 55 publications

Oligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases

Oligomeropathies and pathogenesis of Alzheimer and Parkinson's diseases

Neuroprotective effects of fingolimod in mouse models of Parkinson's disease

Heteromeric α7β2 Nicotinic Acetylcholine Receptors in the Brain

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