Neurexin 3 transmembrane and soluble isoform expression and splicing haplotype are associated with neuron inflammasome and Alzheimer’s disease

Springer Science and Business Media LLC - Tập 11 - Trang 1-15 - 2019
Akitoyo Hishimoto1, Olga Pletnikova2, Doyle Lu Lang3, Juan C. Troncoso2, Josephine M. Egan3, Qing-Rong Liu3
1Department of Psychiatry, Kobe University Graduate School of Medicine, Kobe, Japan
2Departments of Pathology, Neuropathology Division, Johns Hopkins University School of Medicine, Baltimore, USA
3Lab of Clinical Investigation, NIA-NIH, Baltimore, USA

Tóm tắt

Synaptic damage precedes neuron death in Alzheimer’s disease (AD). Neurexins, NRXN1, NRXN2, and NRXN3, are presynaptic adhesion molecules that specify neuron synapses and regulate neurotransmitter release. Neurexins and postsynaptic neuroligins interact with amyloid beta oligomer (AβO) deposits in damaged synapses. NRXN3 gene variants have been associated with autism, addiction, and schizophrenia, however, not fully investigated in Alzheimer’s disease. In the present study, we investigated an AD association of a 3′-splicing allele of rs8019381 that produces altered expression of transmembrane or soluble NRXN3 isoforms. We carried out RT-PCR (reverse transcription polymerase chain reaction), PCR-RFLP (PCR and restriction fragment length polymorphism), Sanger sequencing, and in situ hybridization (ISH) assays for NRXN3 neuron expression and genotyping. Genetic associations were analyzed by χ2 tests, and ISH signals were analyzed by FISH v1.0 module of Indica Labs HALO software. We previously identified a functional haplotype in the 3′ region of neurexin 3 (NRXN3) gene that alters the expression ratios between NRXN3 transmembrane and soluble isoforms. In this study, we found that expression and ratio of transmembrane and soluble NRXN3 isoforms were reduced in AD postmortem brains and inversely correlated with inflammasome component NLRP3 in AD brain regions. The splicing haplotype related to the transmembrane and soluble NRXN3 expression was associated with AD samples with P = 6.3 × 10−5 (odds ratio = 2.48) and interacted with APOE genotypes. We found that the SNP rs8019381 of NRXN3 that is located adjacent to splicing site #5 (SS#5) interacts with the APOE ε4 haplotype and alters NRXN3 transmembrane or soluble isoform expression in AD postmortem cortex. Dysregulation of presynaptic NRXN3 expression and splicing might increase neuron inflammation in AD brain.

Tài liệu tham khảo

Kim SH, Tang YP, Sisodia SS. Abeta star: a light onto synaptic dysfunction? Nat Med. 2006;12(7):760–1 discussion 761. Aoto J, Martinelli DC, Malenka RC, Tabuchi K, Sudhof TC. Presynaptic neurexin-3 alternative splicing trans-synaptically controls postsynaptic AMPA receptor trafficking. Cell. 2013;154(1):75–88. Coon KD, Myers AJ, Craig DW, Webster JA, Pearson JV, Lince DH, Zismann VL, Beach TG, Leung D, Bryden L, et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease. J Clin Psychiatry. 2007;68(4):613–8. Elman JA, Oh H, Madison CM, Baker SL, Vogel JW, Marks SM, Crowley S, O'Neil JP, Jagust WJ. Neural compensation in older people with brain amyloid-beta deposition. Nat Neurosci. 2014;17(10):1316–8. Pletnikova O, Rudow GL, Hyde TM, Kleinman JE, Ali SZ, Bharadwaj R, Gangadeen S, Crain BJ, Fowler DR, Rubio AI, et al. Alzheimer lesions in the autopsied brains of people 30 to 50 years of age. Cogn Behav Neurol. 2015;28(3):144–52. Iacono D, Resnick SM, O'Brien R, Zonderman AB, An Y, Pletnikova O, Rudow G, Crain B, Troncoso JC. Mild cognitive impairment and asymptomatic Alzheimer disease subjects: equivalent beta-amyloid and tau loads with divergent cognitive outcomes. J Neuropathol Exp Neurol. 2014;73(4):295–304. Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J. Synapse formation and function is modulated by the amyloid precursor protein. J Neurosci. 2006;26(27):7212–21. Viola KL, Velasco PT, Klein WL. Why Alzheimer’s is a disease of memory: the attack on synapses by a beta oligomers (ADDLs). J Nutr Health Aging. 2008;12(1):51S–7S. Ushkaryov YA, Petrenko AG, Geppert M, Sudhof TC. Neurexins: synaptic cell surface proteins related to the alpha-latrotoxin receptor and laminin. Science. 1992;257(5066):50–6. Li CY, Liu QR, Zhang PW, Li XM, Wei L, Uhl GR. OKCAM: an ontology-based, human-centered knowledgebase for cell adhesion molecules. Nucleic Acids Res. 2009;37(Database issue):D251–60. Missler M, Sudhof TC. Neurexins: three genes and 1001 products. Trends Genet. 1998;14(1):20–6. Sudhof TC. Neuroligins and neurexins link synaptic function to cognitive disease. Nature. 2008;455(7215):903–11. Missler M, Zhang W, Rohlmann A, Kattenstroth G, Hammer RE, Gottmann K, Sudhof TC. Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis. Nature. 2003;423(6943):939–48. Rudenko G. Dynamic control of synaptic adhesion and organizing molecules in synaptic plasticity. Neural Plast. 2017;2017:6526151. Sudhof TC. Synaptic neurexin complexes: a molecular code for the logic of neural circuits. Cell. 2017;171(4):745–69. Biederer T, Sudhof TC. Mints as adaptors. Direct binding to neurexins and recruitment of munc18. J Biol Chem. 2000;275(51):39803–6. Hata Y, Butz S, Sudhof TC. CASK: a novel dlg/PSD95 homolog with an N-terminal calmodulin-dependent protein kinase domain identified by interaction with neurexins. J Neurosci. 1996;16(8):2488–94. Naito Y, Tanabe Y, Lee AK, Hamel E, Takahashi H. Amyloid-beta oligomers interact with neurexin and diminish neurexin-mediated excitatory presynaptic organization. Sci Rep. 2017;7:42548. Miller CC, McLoughlin DM, Lau KF, Tennant ME, Rogelj B. The X11 proteins, Abeta production and Alzheimer’s disease. Trends Neurosci. 2006;29(5):280–5. Hishimoto A, Liu QR, Drgon T, Pletnikova O, Walther D, Zhu XG, Troncoso JC, Uhl GR. Neurexin 3 polymorphisms are associated with alcohol dependence and altered expression of specific isoforms. Hum Mol Genet. 2007;16(23):2880–91. Ushkaryov YA, Sudhof TC. Neurexin III alpha: extensive alternative splicing generates membrane-bound and soluble forms. Proc Natl Acad Sci U S A. 1993;90(14):6410–4. Anderson GR, Aoto J, Tabuchi K, Foldy C, Covy J, Yee AX, Wu D, Lee SJ, Chen L, Malenka RC, et al. beta-Neurexins control neural circuits by regulating synaptic endocannabinoid signaling. Cell. 2015;162(3):593–606. Bot N, Schweizer C, Ben Halima S, Fraering PC. Processing of the synaptic cell adhesion molecule neurexin-3beta by Alzheimer disease alpha- and gamma-secretases. J Biol Chem. 2011;286(4):2762–73. Alarcon M, Abrahams BS, Stone JL, Duvall JA, Perederiy JV, Bomar JM, Sebat J, Wigler M, Martin CL, Ledbetter DH, et al. Linkage, association, and gene-expression analyses identify CNTNAP2 as an autism-susceptibility gene. Am J Hum Genet. 2008;82(1):150–9. Arking DE, Cutler DJ, Brune CW, Teslovich TM, West K, Ikeda M, Rea A, Guy M, Lin S, Cook EH, et al. A common genetic variant in the neurexin superfamily member CNTNAP2 increases familial risk of autism. Am J Hum Genet. 2008;82(1):160–4. Kim HG, Kishikawa S, Higgins AW, Seong IS, Donovan DJ, Shen Y, Lally E, Weiss LA, Najm J, Kutsche K, et al. Disruption of neurexin 1 associated with autism spectrum disorder. Am J Hum Genet. 2008;82(1):199–207. Bierut LJ, Madden PA, Breslau N, Johnson EO, Hatsukami D, Pomerleau OF, Swan GE, Rutter J, Bertelsen S, Fox L, et al. Novel genes identified in a high-density genome wide association study for nicotine dependence. Hum Mol Genet. 2007;16(1):24–35. Lachman HM, Fann CS, Bartzis M, Evgrafov OV, Rosenthal RN, Nunes EV, Miner C, Santana M, Gaffney J, Riddick A, et al. Genomewide suggestive linkage of opioid dependence to chromosome 14q. Hum Mol Genet. 2007;16(11):1327–34. Kirov G, Gumus D, Chen W, Norton N, Georgieva L, Sari M, O'Donovan MC, Erdogan F, Owen MJ, Ropers HH, et al. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum Mol Genet. 2008;17(3):458–65. Rujescu D, Ingason A, Cichon S, Pietilainen OP, Barnes MR, Toulopoulou T, Picchioni M, Vassos E, Ettinger U, Bramon E, et al. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum Mol Genet. 2009;18(5):988–96. Aoto J, Foldy C, Ilcus SM, Tabuchi K, Sudhof TC. Distinct circuit-dependent functions of presynaptic neurexin-3 at GABAergic and glutamatergic synapses. Nat Neurosci. 2015;18(7):997–1007. Zheng JJ, Li WX, Liu JQ, Guo YC, Wang Q, Li GH, Dai SX, Huang JF. Low expression of aging-related NRXN3 is associated with Alzheimer disease: a systematic review and meta-analysis. Medicine (Baltimore). 2018;97(28):e11343. Braak H, Braak E. Neuropathological staging of Alzheimer-related changes. Acta Neuropathol. 1991;82(4):239–59. Bobinski M, de Leon MJ, Wegiel J, Desanti S, Convit A, Saint Louis LA, Rusinek H, Wisniewski HM. The histological validation of post mortem magnetic resonance imaging-determined hippocampal volume in Alzheimer’s disease. Neuroscience. 2000;95(3):721–5. Troncoso JC, Cataldo AM, Nixon RA, Barnett JL, Lee MK, Checler F, Fowler DR, Smialek JE, Crain B, Martin LJ, et al. Neuropathology of preclinical and clinical late-onset Alzheimer’s disease. Ann Neurol. 1998;43(5):673–6. Edenberg HJ, Bierut LJ, Boyce P, Cao M, Cawley S, Chiles R, Doheny KF, Hansen M, Hinrichs T, Jones K, et al. Description of the data from the Collaborative Study on the Genetics of Alcoholism (COGA) and single-nucleotide polymorphism genotyping for Genetic Analysis Workshop 14. BMC Genet. 2005;6(Suppl 1):S2. Liu QR, Drgon T, Johnson C, Walther D, Hess J, Uhl GR. Addiction molecular genetics: 639,401 SNP whole genome association identifies many “cell adhesion” genes. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(8):918–25. Wenham PR, Price WH, Blandell G. Apolipoprotein E genotyping by one-stage PCR. Lancet. 1991;337(8750):1158–9. Doyle ME, Fiori JL, Gonzalez Mariscal I, Liu QR, Goodstein E, Yang H, Shin YK, Santa-Cruz Calvo S, Indig FE, Egan JM. Insulin is transcribed and translated in mammalian taste bud cells. Endocrinology. 2018;159(9):3331–9. Dupont WD, Plummer WD Jr. Power and sample size calculations for studies involving linear regression. Control Clin Trials. 1998;19(6):589–601. Heneka MT, Kummer MP, Stutz A, Delekate A, Schwartz S, Vieira-Saecker A, Griep A, Axt D, Remus A, Tzeng TC, et al. NLRP3 is activated in Alzheimer’s disease and contributes to pathology in APP/PS1 mice. Nature. 2013;493(7434):674–8. O'Rourke NA, Weiler NC, Micheva KD, Smith SJ. Deep molecular diversity of mammalian synapses: why it matters and how to measure it. Nat Rev Neurosci. 2012;13(6):365–79. Spires-Jones TL, Hyman BT. The intersection of amyloid beta and tau at synapses in Alzheimer’s disease. Neuron. 2014;82(4):756–71. Kay KR, Smith C, Wright AK, Serrano-Pozo A, Pooler AM, Koffie R, Bastin ME, Bak TH, Abrahams S, Kopeikina KJ, et al. Studying synapses in human brain with array tomography and electron microscopy. Nat Protoc. 2013;8(7):1366–80. Richter MC, Ludewig S, Winschel A, Abel T, Bold C, Salzburger LR, Klein S, Han K, Weyer SW, Fritz AK, et al. Distinct in vivo roles of secreted APP ectodomain variants APPsalpha and APPsbeta in regulation of spine density, synaptic plasticity, and cognition. EMBO J. 2018;37(11). https://doi.org/10.15252/embj.201798335. Lane-Donovan C, Herz J. ApoE, ApoE receptors, and the synapse in Alzheimer’s disease. Trends Endocrinol Metab. 2017;28(4):273–84. Salazar SV, Cox TO, Lee S, Brody AH, Chyung AS, Haas LT, Strittmatter SM. Alzheimer’s disease risk factor Pyk2 mediates amyloid-beta-induced synaptic dysfunction and loss. J Neurosci. 2019;39(4):758–72. Chiocco MJ, Zhu X, Walther D, Pletnikova O, Troncoso JC, Uhl GR, Liu QR. Fine mapping of calcineurin (PPP3CA) gene reveals novel alternative splicing patterns, association of 5′UTR trinucleotide repeat with addiction vulnerability, and differential isoform expression in Alzheimer’s disease. Subst Use Misuse. 2010;45(11):1809–26. Cruchaga C, Kauwe JS, Mayo K, Spiegel N, Bertelsen S, Nowotny P, Shah AR, Abraham R, Hollingworth P, Harold D, et al. SNPs associated with cerebrospinal fluid phospho-tau levels influence rate of decline in Alzheimer’s disease. PLoS Genet. 2010;6(9):e1001101. Stallings NR, O'Neal MA, Hu J, Kavalali ET, Bezprozvanny I, Malter JS. Pin1 mediates Abeta42-induced dendritic spine loss. Sci Signal. 2018;11(522). https://doi.org/10.1126/scisignal.aap8734. Levy M, Thaiss CA, Elinav E. Taming the inflammasome. Nat Med. 2015;21(3):213–5. Supnet C, Bezprozvanny I. Neuronal calcium signaling, mitochondrial dysfunction, and Alzheimer’s disease. J Alzheimers Dis. 2010;20(Suppl 2):S487–98. Wu HY, Hudry E, Hashimoto T, Kuchibhotla K, Rozkalne A, Fan Z, Spires-Jones T, Xie H, Arbel-Ornath M, Grosskreutz CL, et al. Amyloid beta induces the morphological neurodegenerative triad of spine loss, dendritic simplification, and neuritic dystrophies through calcineurin activation. J Neurosci. 2010;30(7):2636–49. Holtzman DM, Morris JC, Goate AM. Alzheimer’s disease: the challenge of the second century. Sci Transl Med. 2011;3(77):77sr71. Li H, Wetten S, Li L, St Jean PL, Upmanyu R, Surh L, Hosford D, Barnes MR, Briley JD, Borrie M, et al. Candidate single-nucleotide polymorphisms from a genomewide association study of Alzheimer disease. Arch Neurol. 2008;65(1):45–53. Reiman EM, Webster JA, Myers AJ, Hardy J, Dunckley T, Zismann VL, Joshipura KD, Pearson JV, Hu-Lince D, Huentelman MJ, et al. GAB2 alleles modify Alzheimer’s risk in APOE epsilon4 carriers. Neuron. 2007;54(5):713–20. Bertram L, McQueen MB, Mullin K, Blacker D, Tanzi RE. Systematic meta-analyses of Alzheimer disease genetic association studies: the AlzGene database. Nat Genet. 2007;39(1):17–23. Chung WS, Verghese PB, Chakraborty C, Joung J, Hyman BT, Ulrich JD, Holtzman DM, Barres BA. Novel allele-dependent role for APOE in controlling the rate of synapse pruning by astrocytes. Proc Natl Acad Sci U S A. 2016;113(36):10186–91. Octave JN. The amyloid peptide precursor in Alzheimer’s disease. Acta Neurol Belg. 1995;95(4):197–209. Kero M, Paetau A, Polvikoski T, Tanskanen M, Sulkava R, Jansson L, Myllykangas L, Tienari PJ. Amyloid precursor protein (APP) A673T mutation in the elderly Finnish population. Neurobiol Aging. 2013;34(5):1518 e1511–1513. Terry RD. Cell death or synaptic loss in Alzheimer disease. J Neuropathol Exp Neurol. 2000;59(12):1118–9. Azevedo FA, Carvalho LR, Grinberg LT, Farfel JM, Ferretti RE, Leite RE, Jacob Filho W, Lent R, Herculano-Houzel S. Equal numbers of neuronal and nonneuronal cells make the human brain an isometrically scaled-up primate brain. J Comp Neurol. 2009;513(5):532–41. Brito-Moreira J, Lourenco MV, Oliveira MM, Ribeiro FC, Ledo JH, Diniz LP, Vital JFS, Magdesian MH, Melo HM, Barros-Aragao F, et al. Interaction of amyloid-beta (Abeta) oligomers with neurexin 2alpha and neuroligin 1 mediates synapse damage and memory loss in mice. J Biol Chem. 2017;292(18):7327–37. Quinn DP, Kolar A, Wigerius M, Gomm-Kolisko RN, Atwi H, Fawcett JP, Krueger SR. Pan-neurexin perturbation results in compromised synapse stability and a reduction in readily releasable synaptic vesicle pool size. Sci Rep. 2017;7:42920. Wang H. Endocannabinoid mediates excitatory synaptic function of beta-neurexins. Commentary: beta-neurexins control neural circuits by regulating synaptic endocannabinoid signaling. Front Neurosci. 2016;10:203. Schenk U, Verderio C, Benfenati F, Matteoli M. Regulated delivery of AMPA receptor subunits to the presynaptic membrane. EMBO J. 2003;22(3):558–68. Han X, He Y, Bi GH, Zhang HY, Song R, Liu QR, Egan JM, Gardner EL, Li J, Xi ZX. CB1 receptor activation on VgluT2-expressing glutamatergic neurons underlies delta(9)-tetrahydrocannabinol (delta(9)-THC)-induced aversive effects in mice. Sci Rep. 2017;7(1):12315. Liu QR, Canseco-Alba A, Zhang HY, Tagliaferro P, Chung M, Dennis E, Sanabria B, Schanz N, Escosteguy-Neto JC, Ishiguro H, et al. Cannabinoid type 2 receptors in dopamine neurons inhibits psychomotor behaviors, alters anxiety, depression and alcohol preference. Sci Rep. 2017;7(1):17410. Brusco A, Tagliaferro P, Saez T, Onaivi ES. Postsynaptic localization of CB2 cannabinoid receptors in the rat hippocampus. Synapse. 2008;62(12):944–9. Bilkei-Gorzo A, Albayram O, Draffehn A, Michel K, Piyanova A, Oppenheimer H, Dvir-Ginzberg M, Racz I, Ulas T, Imbeault S, et al. A chronic low dose of delta(9)-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat Med. 2017;23(6):782–7. Sarne Y, Toledano R, Rachmany L, Sasson E, Doron R. Reversal of age-related cognitive impairments in mice by an extremely low dose of tetrahydrocannabinol. Neurobiol Aging. 2018;61:177–86. Brinkmalm G, Sjodin S, Simonsen AH, Hasselbalch SG, Zetterberg H, Brinkmalm A, Blennow K. A parallel reaction monitoring mass spectrometric method for analysis of potential CSF biomarkers for Alzheimer’s disease. Proteomics Clin Appl. 2018;12(1). https://doi.org/10.1002/prca.201700131. Duits FH, Brinkmalm G, Teunissen CE, Brinkmalm A, Scheltens P, Van der Flier WM, Zetterberg H, Blennow K. Synaptic proteins in CSF as potential novel biomarkers for prognosis in prodromal Alzheimer’s disease. Alzheimers Res Ther. 2018;10(1):5. Sterky FH, Trotter JH, Lee SJ, Recktenwald CV, Du X, Zhou B, Zhou P, Schwenk J, Fakler B, Sudhof TC. Carbonic anhydrase-related protein CA10 is an evolutionarily conserved pan-neurexin ligand. Proc Natl Acad Sci U S A. 2017;114(7):E1253–62. Khalsa DS. Stress, meditation, and Alzheimer’s disease prevention: where the evidence stands. J Alzheimers Dis. 2015;48(1):1–12.