Altered Nup153 Expression Impairs the Function of Cultured Hippocampal Neural Stem Cells Isolated from a Mouse Model of Alzheimer’s Disease
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Impairment of adult hippocampal neurogenesis is an early event in Alzheimer’s disease (AD), playing a crucial role in cognitive dysfunction associated with this pathology. However, the mechanisms underlying defective neurogenesis in AD are still unclear. Recently, the nucleoporin Nup153 has been described as a new epigenetic determinant of adult neural stem cell (NSC) maintenance and fate. Here we investigated whether Nup153 dysfunction could affect the plasticity of NSCs in AD. Nup153 expression was strongly reduced in AD-NSCs, as well as its interaction with the transcription factor Sox2, a master regulator of NSC stemness and their neuronal differentiation. Similar Nup153 reduction was also observed in WT-NSCs treated with amyloid-β (Aβ) or stimulated with a nitric oxide donor. Accordingly, AD-NSCs treated with either a γ-secretase inhibitor or antioxidant compounds showed higher Nup153 levels suggesting that both nitrosative stress and Aβ accumulation affect Nup153 expression. Of note, restoration of Nup153 levels in AD-NSCs promoted their proliferation, as assessed by BrdU incorporation, neurosphere assay, and stemness gene expression analysis. Nup153 overexpression also recovered AD-NSC response to differentiation, increasing the expression of pro-neuronal genes, the percentage of cells positive for neuronal markers, and the acquisition of a more mature neuronal phenotype. Electrophysiological recordings revealed that neurons differentiated from Nup153-transfected AD-NSCs displayed higher Na+ current density, comparable to those deriving from WT-NSCs. Our data uncover a novel role for Nup153 in NSCs from animal model of AD and point to Nup153 as potential target to restore physiological NSC behavior and fate in neurodegenerative diseases.
KeywordsNup153 Neural stem cells Nitric oxide Adult hippocampal neurogenesis Alzheimer’s disease Personalized medicine
neural stem cells
L-NG-nitro-arginine methyl ester
mean fluorescence intensity
nuclear receptor subfamily 2 group E member 1
We thank Professor D. Puzzo, from University of Catania, who kindly provided tissues from APP knock-out mice (B6.129S7-Apptm1Dbo/J; 4 months old) that were used as negative control in Western blot experiments.
Electrophysiology: MD, VL; RT-qPCR: KG, LL, SF; ChIP: SF; NSC experiments and analysis: LL, KG, CC; confocal analysis: CC; WB and IP: CC, DDLP; conceptualization: LL, CC, CG; writing: LL, CC, CG. All authors read and approved the final manuscript.
Compliance with Ethical Standards
Mice were used in agreement with the guidelines of the European Parliament (Directive 2010/63/EU for the protection of laboratory animals) and with the guidelines of the Italian National Institute of Health and were approved by the Institutional Animal Care of Università Cattolica (approval number: 553/2016PR, Rome, Italy).
The authors declare that they have no competing interests.
- 4.Hamilton LK, Aumont A, Julien C, Vadnais A, Calon F, Fernandes KJ (2010) Widespread deficits in adult neurogenesis precede plaque and tangle formation in the 3xTg mouse model of Alzheimer’s disease. Eur J Neurosci 32(6):905–920. https://doi.org/10.1111/j.1460-9568.2010.07379.x CrossRefPubMedGoogle Scholar
- 6.Fitzsimons CP, van Bodegraven E, Schouten M, Lardenoije R, Kompotis K, Kenis G, van den Hurk M, Boks MP et al (2014) Epigenetic regulation of adult neural stem cells: implications for Alzheimer’s disease. Mol Neurodegener 9:25. https://doi.org/10.1186/1750-1326-9-25 CrossRefPubMedPubMedCentralGoogle Scholar
- 9.Nanni S, Re A, Ripoli C, Gowran A, Nigro P, D'Amario D, Amodeo A, Crea F et al (2016) The nuclear pore protein Nup153 associates with chromatin and regulates cardiac gene expression in dystrophic mdx hearts. Cardiovasc Res 112(2):555–567. https://doi.org/10.1093/cvr/cvw204 CrossRefPubMedGoogle Scholar
- 10.Re A, Colussi C, Nanni S, Aiello A, Bacci L, Grassi C, Pontecorvi A, Farsetti A (2018) Nucleoporin 153 regulates estrogen-dependent nuclear translocation of endothelial nitric oxide synthase and estrogen receptor beta in prostate cancer. Oncotarget 9(46):27985–27997. https://doi.org/10.18632/oncotarget.25462 CrossRefPubMedPubMedCentralGoogle Scholar
- 14.Zhang J, Snyder SH (1995) Nitric oxide in the nervous system. Annu Rev Pharmacol Toxicol 35:213–233. https://doi.org/10.1146/annurev.pa.35.040195.001241 CrossRefPubMedGoogle Scholar
- 15.Podda MV, Marcocci ME, Oggiano L, D'Ascenzo M, Tolu E, Palamara AT, Azzena GB, Grassi C (2004) Nitric oxide increases the spontaneous firing rate of rat medial vestibular nucleus neurons in vitro via a cyclic GMP-mediated PKG-independent mechanism. Eur J Neurosci 20(8):2124–2132. https://doi.org/10.1111/j.1460-9568.2004.03674.x CrossRefPubMedGoogle Scholar
- 21.Colussi C, Mozzetta C, Gurtner A, Illi B, Rosati J, Straino S, Ragone G, Pescatori M et al (2008) HDAC2 blockade by nitric oxide and histone deacetylase inhibitors reveals a common target in Duchenne muscular dystrophy treatment. Proc Natl Acad Sci U S A 105(49):19183–19187. https://doi.org/10.1073/pnas.0805514105 CrossRefPubMedPubMedCentralGoogle Scholar
- 24.Kodiha M, Tran D, Qian C, Morogan A, Presley JF, Brown CM, Stochaj U (2008) Oxidative stress mislocalizes and retains transport factor importin-alpha and nucleoporins Nup153 and Nup88 in nuclei where they generate high molecular mass complexes. Biochim Biophys Acta 1783(3):405–418. https://doi.org/10.1016/j.bbamcr.2007.10.022 CrossRefPubMedGoogle Scholar
- 25.Mastrodonato A, Barbati SA, Leone L, Colussi C, Gironi K, Rinaudo M, Piacentini R, Denny CA et al (2018) Olfactory memory is enhanced in mice exposed to extremely low-frequency electromagnetic fields via Wnt/beta-catenin dependent modulation of subventricular zone neurogenesis. Sci Rep 8(1):262. https://doi.org/10.1038/s41598-017-18676-1 CrossRefPubMedPubMedCentralGoogle Scholar
- 26.Puzzo D, Piacentini R, Fa M, Gulisano W, Li Puma DD, Staniszewski A, Zhang H, Tropea MR et al (2017) LTP and memory impairment caused by extracellular Abeta and Tau oligomers is APP-dependent. Elife 6. https://doi.org/10.7554/eLife.26991
- 28.Nanni S, Benvenuti V, Grasselli A, Priolo C, Aiello A, Mattiussi S, Colussi C, Lirangi V et al (2009) Endothelial NOS, estrogen receptor beta, and HIFs cooperate in the activation of a prognostic transcriptional pattern in aggressive human prostate cancer. J Clin Invest 119(5):1093–1108. https://doi.org/10.1172/JCI35079 CrossRefPubMedPubMedCentralGoogle Scholar
- 29.Re A, Aiello A, Nanni S, Grasselli A, Benvenuti V, Pantisano V, Strigari L, Colussi C et al (2011) Silencing of GSTP1, a prostate cancer prognostic gene, by the estrogen receptor-beta and endothelial nitric oxide synthase complex. Mol Endocrinol 25(12):2003–2016. https://doi.org/10.1210/me.2011-1024 CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Spinelli M, Fusco S, Mainardi M, Scala F, Natale F, Lapenta R, Mattera A, Rinaudo M et al (2017) Brain insulin resistance impairs hippocampal synaptic plasticity and memory by increasing GluA1 palmitoylation through FoxO3a. Nat Commun 8(1):2009. https://doi.org/10.1038/s41467-017-02221-9 CrossRefPubMedPubMedCentralGoogle Scholar
- 31.Aceto G, Re A, Mattera A, Leone L, Colussi C, Rinaudo M, Scala F, Gironi K et al (2018) GSK3beta modulates timing-dependent long-term depression through direct phosphorylation of Kv4.2 channels. Cereb Cortex. https://doi.org/10.1093/cercor/bhy042
- 32.Biella G, Di Febo F, Goffredo D, Moiana A, Taglietti V, Conti L, Cattaneo E, Toselli M (2007) Differentiating embryonic stem-derived neural stem cells show a maturation-dependent pattern of voltage-gated sodium current expression and graded action potentials. Neuroscience 149(1):38–52. https://doi.org/10.1016/j.neuroscience.2007.07.021 CrossRefPubMedGoogle Scholar
- 33.Haughey NJ, Liu D, Nath A, Borchard AC, Mattson MP (2002) Disruption of neurogenesis in the subventricular zone of adult mice, and in human cortical neuronal precursor cells in culture, by amyloid beta-peptide: implications for the pathogenesis of Alzheimer’s disease. NeuroMolecular Med 1(2):125–135. https://doi.org/10.1385/NMM:1:2:125 CrossRefPubMedGoogle Scholar
- 34.Lugert S, Basak O, Knuckles P, Haussler U, Fabel K, Gotz M, Haas CA, Kempermann G et al (2010) Quiescent and active hippocampal neural stem cells with distinct morphologies respond selectively to physiological and pathological stimuli and aging. Cell Stem Cell 6(5):445–456. https://doi.org/10.1016/j.stem.2010.03.017 CrossRefPubMedGoogle Scholar
- 41.Molokanova E, Akhtar MW, Sanz-Blasco S, Tu S, Pina-Crespo JC, McKercher SR, Lipton SA (2014) Differential effects of synaptic and extrasynaptic NMDA receptors on Abeta-induced nitric oxide production in cerebrocortical neurons. J Neurosci 34(14):5023–5028. https://doi.org/10.1523/JNEUROSCI.2907-13.2014 CrossRefPubMedPubMedCentralGoogle Scholar
- 42.Tajes M, Eraso-Pichot A, Rubio-Moscardo F, Guivernau B, Ramos-Fernandez E, Bosch-Morato M, Guix FX, Clarimon J et al (2014) Methylglyoxal produced by amyloid-beta peptide-induced nitrotyrosination of triosephosphate isomerase triggers neuronal death in Alzheimer’s disease. J Alzheimers Dis 41(1):273–288. https://doi.org/10.3233/JAD-131685 CrossRefPubMedGoogle Scholar
- 43.Dias C, Lourenco CF, Ferreiro E, Barbosa RM, Laranjinha J, Ledo A (2016) Age-dependent changes in the glutamate-nitric oxide pathway in the hippocampus of the triple transgenic model of Alzheimer’s disease: implications for neurometabolic regulation. Neurobiol Aging 46:84–95. https://doi.org/10.1016/j.neurobiolaging.2016.06.012 CrossRefPubMedGoogle Scholar
- 44.Lourenco CF, Ledo A, Barbosa RM, Laranjinha J (2017) Neurovascular uncoupling in the triple transgenic model of Alzheimer’s disease: impaired cerebral blood flow response to neuronal-derived nitric oxide signaling. Exp Neurol 291:36–43. https://doi.org/10.1016/j.expneurol.2017.01.013 CrossRefPubMedGoogle Scholar
- 45.Shariatpanahi M, Khodagholi F, Ashabi G, Aghazadeh Khasraghi A, Azimi L, Abdollahi M, Ghahremani MH, Ostad SN et al (2015) Ameliorating of memory impairment and apoptosis in amyloid beta-injected rats via inhibition of nitric oxide synthase: possible participation of autophagy. Iran J Pharm Res 14(3):811–824PubMedPubMedCentralGoogle Scholar
- 46.Diaz A, Rojas K, Espinosa B, Chavez R, Zenteno E, Limon D, Guevara J (2014) Aminoguanidine treatment ameliorates inflammatory responses and memory impairment induced by amyloid-beta 25-35 injection in rats. Neuropeptides 48(3):153–159. https://doi.org/10.1016/j.npep.2014.03.002 CrossRefPubMedGoogle Scholar
- 49.Ferreira NR, Ledo A, Laranjinha J, Gerhardt GA, Barbosa RM (2018) Simultaneous measurements of ascorbate and glutamate in vivo in the rat brain using carbon fiber nanocomposite sensors and microbiosensor arrays. Bioelectrochemistry 121:142–150. https://doi.org/10.1016/j.bioelechem.2018.01.009 CrossRefPubMedGoogle Scholar