Generic placeholder image

Current Alzheimer Research

Editor-in-Chief

ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

Research Article

A Comprehensive Investigation of Molecular Signatures and Pathways Linking Alzheimer’s Disease and Epilepsy via Bioinformatic Approaches

Author(s): Jiao Wu, Shu Zhu, Chenyang Zhao and Xiaoxue Xu*

Volume 19, Issue 2, 2022

Published on: 08 March, 2022

Page: [146 - 160] Pages: 15

DOI: 10.2174/1567205019666220202120638

Price: $65

Open Access Journals Promotions 2
Abstract

Background: Epileptic activity frequently occurs in patients with Alzheimer’s disease (AD), which may accelerate AD progression; however, the relationship between AD and epilepsy remains unclear.

Objective: We aimed to investigate the molecular pathways and genes linking AD and epilepsy using bioinformatics approaches.

Methods: Gene expression profiles of AD (GSE1297) and epilepsy (GSE28674) were derived from the Gene Expression Omnibus (GEO) database. The top 50% expression variants were subjected to weighted gene co-expression network analysis (WGCNA) to identify key modules associated with these diseases. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses for the key modules were performed, and the intersected terms of functional enrichment and common genes within the key modules were selected. The overlapping genes were subjected to analyses of protein-protein interaction (PPI) network, transcription factor (TF)-mRNA network, microRNA (miRNA)-mRNA network, and drug prediction.

Results: We identified 229 and 1187 genes in the AD-associated purple and epilepsy-associated blue modules, respectively. Six shared functional terms between the two modules included “calcium ion binding” and “calcium signaling pathway.” According to 17 common genes discovered, 130 TFmRNA pairs and 56 miRNA-mRNA pairs were established. The topological analyses of the constructed regulatory networks suggested that TF - FOXC1 and miRNA - hsa-mir-335-5p might be vital co-regulators of gene expression in AD and epilepsy. In addition, CXCR4 was identified as a hub gene, becoming the putative target for 20 drugs.

Conclusion: Our study provided novel insights into the molecular connection between AD and epilepsy, which might be beneficial for exploring shared mechanisms and designing disease-modifying therapies.

Keywords: Alzheimer’s disease, epilepsy, calcium, miRNA, transcription factor, network.

[1]
Stanciu GD, Rusu RN, Bild V, Filipiuc LE, Tamba BI, Ababei DC. Systemic actions of SGLT2 inhibition on chronic mTOR activation as a shared pathogenic mechanism between Alzheimer’s disease and diabetes. Biomedicines 2021; 9(5): 576.
[http://dx.doi.org/10.3390/biomedicines9050576] [PMID: 34069618]
[2]
Joe E, Ringman JM. Cognitive symptoms of Alzheimer’s disease: Clinical management and prevention. BMJ 2019; 367: l6217.
[http://dx.doi.org/10.1136/bmj.l6217] [PMID: 31810978]
[3]
Bateman RJ, Xiong C, Benzinger TL, et al. Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 2012; 367(9): 795-804.
[http://dx.doi.org/10.1056/NEJMoa1202753] [PMID: 22784036]
[4]
Mohseni-Moghaddam P, Roghani M, Khaleghzadeh-Ahangar H, Sadr SS, Sala C. A literature overview on epilepsy and inflammasome activation. Brain Res Bull 2021; 172: 229-35.
[http://dx.doi.org/10.1016/j.brainresbull.2021.05.001] [PMID: 33964347]
[5]
Thijs RD, Surges R, O’Brien TJ, Sander JW. Epilepsy in adults. Lancet 2019; 393(10172): 689-701.
[http://dx.doi.org/10.1016/S0140-6736(18)32596-0] [PMID: 30686584]
[6]
Dejakaisaya H, Kwan P, Jones NC. Astrocyte and glutamate involvement in the pathogenesis of epilepsy in Alzheimer’s disease. Epilepsia 2021; 62(7): 1485-93.
[http://dx.doi.org/10.1111/epi.16918] [PMID: 33971019]
[7]
Bell B, Lin JJ, Seidenberg M, Hermann B. The neurobiology of cognitive disorders in temporal lobe epilepsy. Nat Rev Neurol 2011; 7(3): 154-64.
[http://dx.doi.org/10.1038/nrneurol.2011.3] [PMID: 21304484]
[8]
Busche MA, Eichhoff G, Adelsberger H, et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer’s disease. Science 2008; 321(5896): 1686-9.
[http://dx.doi.org/10.1126/science.1162844] [PMID: 18802001]
[9]
Palop JJ, Chin J, Roberson ED, et al. Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of Alzheimer’s disease. Neuron 2007; 55(5): 697-711.
[http://dx.doi.org/10.1016/j.neuron.2007.07.025] [PMID: 17785178]
[10]
Leissring MA, Farris W, Chang AY, et al. Enhanced proteolysis of beta-amyloid in APP transgenic mice prevents plaque formation, secondary pathology, and premature death. Neuron 2003; 40(6): 1087-93.
[http://dx.doi.org/10.1016/S0896-6273(03)00787-6] [PMID: 14687544]
[11]
Born HA. Seizures in Alzheimer’s disease. Neuroscience 2015; 286: 251-63.
[http://dx.doi.org/10.1016/j.neuroscience.2014.11.051] [PMID: 25484360]
[12]
Tombini M, Assenza G, Ricci L, et al. Temporal lobe epilepsy and alzheimer’s disease: from preclinical to clinical evidence of a strong association. J Alzheimers Dis Rep 2021; 5(1): 243-61.
[http://dx.doi.org/10.3233/ADR-200286] [PMID: 34113782]
[13]
Henshall DC, Hamer HM, Pasterkamp RJ, et al. MicroRNAs in epilepsy: Pathophysiology and clinical utility. Lancet Neurol 2016; 15(13): 1368-76.
[http://dx.doi.org/10.1016/S1474-4422(16)30246-0] [PMID: 27839653]
[14]
Navarrete-Modesto V, Orozco-Suárez S, Alonso-Vanegas M, Feria-Romero IA, Rocha L. REST/NRSF transcription factor is overexpressed in hippocampus of patients with drug-resistant mesial temporal lobe epilepsy. Epilepsy Behav 2019; 94: 118-23.
[http://dx.doi.org/10.1016/j.yebeh.2019.02.012] [PMID: 30903955]
[15]
Osama A, Zhang J, Yao J, Yao X, Fang J. Nrf2: A dark horse in Alzheimer’s disease treatment. Ageing Res Rev 2020; 64: 101206.
[http://dx.doi.org/10.1016/j.arr.2020.101206] [PMID: 33144124]
[16]
Takousis P, Sadlon A, Schulz J, et al. Differential expression of microRNAs in Alzheimer’s disease brain, blood, and cerebrospinal fluid. Alzheimers Dement 2019; 15(11): 1468-77.
[http://dx.doi.org/10.1016/j.jalz.2019.06.4952] [PMID: 31495604]
[17]
Liu T, Li X, Cui Y, et al. Bioinformatics analysis identifies potential ferroptosis key genes in the pathogenesis of intracerebral hemorrhage. Front Neurosci 2021; 15: 661663.
[http://dx.doi.org/10.3389/fnins.2021.661663] [PMID: 34163322]
[18]
Fornes O, Castro-Mondragon JA, Khan A, et al. JASPAR 2020: update of the open-access database of transcription factor binding profiles. Nucleic Acids Res 2020; 48(D1): D87-92.
[PMID: 31701148]
[19]
Rahman MR, Islam T, Turanli B, et al. Network-based approach to identify molecular signatures and therapeutic agents in Alzheimer’s disease. Comput Biol Chem 2019; 78: 431-9.
[http://dx.doi.org/10.1016/j.compbiolchem.2018.12.011] [PMID: 30606694]
[20]
Xia J, Gill EE, Hancock RE. NetworkAnalyst for statistical, visual and network-based meta-analysis of gene expression data. Nat Protoc 2015; 10(6): 823-44.
[http://dx.doi.org/10.1038/nprot.2015.052] [PMID: 25950236]
[21]
Griffiths-Jones S, Grocock RJ, van Dongen S, Bateman A, Enright AJ. miRBase: microRNA sequences, targets and gene nomenclature. Nucleic Acids Res 2006; 34(Database issue): D140-4.
[http://dx.doi.org/10.1093/nar/gkj112] [PMID: 16381832]
[22]
Hsu SD, Lin FM, Wu WY, et al. miRTarBase: a database curates experimentally validated microRNA-target interactions. Nucleic Acids Res 2011; 39(Database issue): D163-9.
[http://dx.doi.org/10.1093/nar/gkq1107] [PMID: 21071411]
[23]
Zeng Y, Li N, Zheng Z, et al. Screening of hub genes associated with pulmonary arterial hypertension by integrated bioinformatic analysis. BioMed Res Int 2021; 2021: 6626094.
[http://dx.doi.org/10.1155/2021/6626094] [PMID: 33816621]
[24]
Wagner AH, Coffman AC, Ainscough BJ, et al. DGIdb 2.0: Mining clinically relevant drug-gene interactions. Nucleic Acids Res 2016; 44(D1): D1036-44.
[http://dx.doi.org/10.1093/nar/gkv1165] [PMID: 26531824]
[25]
Lyou HJ, Seo KD, Lee JE, Pak HY, Lee JH. Association of Alzheimer’s disease with the risk of developing epilepsy: A 10-year nationwide cohort study. Dement Neurocognitive Disord 2018; 17(4): 156-62.
[http://dx.doi.org/10.12779/dnd.2018.17.4.156] [PMID: 30906405]
[26]
Palop JJ, Mucke L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nat Rev Neurosci 2016; 17(12): 777-92.
[http://dx.doi.org/10.1038/nrn.2016.141] [PMID: 27829687]
[27]
Stefanidou M, Beiser AS, Himali JJ, et al. Bi-directional association between epilepsy and dementia: The Framingham heart study. Neurology 2020; 95(24): e3241-7.
[http://dx.doi.org/10.1212/WNL.0000000000011077] [PMID: 33097599]
[28]
von Rüden EL, Zellinger C, Gedon J, et al. Regulation of Alzheimer’s disease-associated proteins during epileptogenesis. Neuroscience 2020; 424: 102-20.
[http://dx.doi.org/10.1016/j.neuroscience.2019.08.037] [PMID: 31705965]
[29]
Powell G, Ziso B, Larner AJ. The overlap between epilepsy and Alzheimer’s disease and the consequences for treatment. Expert Rev Neurother 2019; 19(7): 653-61.
[http://dx.doi.org/10.1080/14737175.2019.1629289] [PMID: 31238746]
[30]
Jiang L, Dong H, Cao H, Ji X, Luan S, Liu J. Exosomes in pathogenesis, diagnosis, and treatment of Alzheimer’s Disease. Med Sci Monit 2019; 25: 3329-35.
[http://dx.doi.org/10.12659/MSM.914027] [PMID: 31056537]
[31]
Bennett RE, Robbins AB, Hu M, et al. Tau induces blood vessel abnormalities and angiogenesis-related gene expression in P301L transgenic mice and human Alzheimer’s disease. Proc Natl Acad Sci USA 2018; 115(6): E1289-98.
[http://dx.doi.org/10.1073/pnas.1710329115] [PMID: 29358399]
[32]
Vingtdeux V, Hamdane M, Loyens A, et al. Alkalizing drugs induce accumulation of amyloid precursor protein by-products in luminal vesicles of multivesicular bodies. J Biol Chem 2007; 282(25): 18197-205.
[http://dx.doi.org/10.1074/jbc.M609475200] [PMID: 17468104]
[33]
Rosas-Hernandez H, Cuevas E, Raymick JB, et al. Characterization of serum exosomes from a transgenic mouse model of Alzheimer’s Disease. Curr Alzheimer Res 2019; 16(5): 388-95.
[http://dx.doi.org/10.2174/1567205016666190321155422] [PMID: 30907317]
[34]
Gao G, Zhao S, Xia X, et al. Glutaminase C regulates microglial activation and pro-inflammatory exosome release: Relevance to the pathogenesis of Alzheimer’s Disease. Front Cell Neurosci 2019; 13: 264.
[http://dx.doi.org/10.3389/fncel.2019.00264] [PMID: 31316350]
[35]
Soares Martins T, Trindade D, Vaz M, et al. Diagnostic and therapeutic potential of exosomes in Alzheimer’s disease. J Neurochem 2021; 156(2): 162-81.
[http://dx.doi.org/10.1111/jnc.15112] [PMID: 32618370]
[36]
Soliman HM, Ghonaim GA, Gharib SM, et al. Exosomes in Alzheimer’s disease: From being pathological players to potential diagnostics and therapeutics. Int J Mol Sci 2021; 22(19): 10794.
[http://dx.doi.org/10.3390/ijms221910794] [PMID: 34639135]
[37]
Lv X, Guo F, Xu X, et al. Abnormal alterations in the Ca2+/CaV1.2/calmodulin/caMKII signaling pathway in a tremor rat model and in cultured hippocampal neurons exposed to Mg2+-free solution. Mol Med Rep 2015; 12(5): 6663-71.
[http://dx.doi.org/10.3892/mmr.2015.4227] [PMID: 26299765]
[38]
Min D, Guo F, Zhu S, et al. The alterations of Ca2+/calmodulin/CaMKII/CaV1.2 signaling in experimental models of Alzheimer’s disease and vascular dementia. Neurosci Lett 2013; 538: 60-5.
[http://dx.doi.org/10.1016/j.neulet.2013.02.001] [PMID: 23403102]
[39]
Tong BC, Wu AJ, Li M, Cheung KH. Calcium signaling in Alzheimer’s disease & therapies. Biochim Biophys Acta Mol Cell Res 2018; 1865(11 Pt B): 1745-60.
[http://dx.doi.org/10.1016/j.bbamcr.2018.07.018] [PMID: 30059692]
[40]
Uberti D, Cenini G, Bonini SA, et al. Increased CD44 gene expression in lymphocytes derived from Alzheimer disease patients. Neurodegener Dis 2010; 7(1-3): 143-7.
[http://dx.doi.org/10.1159/000289225] [PMID: 20197694]
[41]
Tse K, Hammond D, Simpson D, et al. The impact of postsynaptic density 95 blocking peptide (Tat-NR2B9c) and an iNOS inhibitor (1400W) on proteomic profile of the hippocampus in C57BL/6J mouse model of kainate-induced epileptogenesis. J Neurosci Res 2019; 97(11): 1378-92.
[http://dx.doi.org/10.1002/jnr.24441] [PMID: 31090233]
[42]
Mercado-Gómez OF, Córdova-Dávalos L, García-Betanzo D, et al. Overexpression of inflammatory-related and nitric oxide synthase genes in olfactory bulbs from frontal lobe epilepsy patients. Epilepsy Res 2018; 148: 37-43.
[http://dx.doi.org/10.1016/j.eplepsyres.2018.09.012] [PMID: 30366204]
[43]
Hariharan A, Jing Y, Collie ND, Zhang H, Liu P. Altered neurovascular coupling and brain arginine metabolism in endothelial nitric oxide synthase deficient mice. Nitric Oxide 2019; 87: 60-72.
[http://dx.doi.org/10.1016/j.niox.2019.03.006] [PMID: 30877024]
[44]
Li C, Wu X, Liu S, Zhao Y, Zhu J, Liu K. Roles of neuropeptide Y in neurodegenerative and neuroimmune diseases. Front Neurosci 2019; 13: 869.
[http://dx.doi.org/10.3389/fnins.2019.00869] [PMID: 31481869]
[45]
Xu X, Guo F, He Q, et al. Altered expression of neuropeptide Y, Y1 and Y2 receptors, but not Y5 receptor, within hippocampus and temporal lobe cortex of tremor rats. Neuropeptides 2014; 48(2): 97-105.
[http://dx.doi.org/10.1016/j.npep.2013.12.003] [PMID: 24444822]
[46]
Xu X, Guo F, Cai X, et al. Aberrant changes of somatostatin and neuropeptide Y in brain of a genetic rat model for epilepsy: tremor rat. Acta Neurobiol Exp (Warsz) 2016; 76(3): 165-75.
[http://dx.doi.org/10.21307/ane-2017-016] [PMID: 27685769]
[47]
Kim SY, Jang SS, Kim H, et al. Genetic diagnosis of infantile-onset epilepsy in the clinic: Application of whole-exome sequencing following epilepsy gene panel testing. Clin Genet 2021; 99(3): 418-24.
[http://dx.doi.org/10.1111/cge.13903] [PMID: 33349918]
[48]
Andrade-Talavera Y, Arroyo-García LE, Chen G, Johansson J, Fisahn A. Modulation of Kv3.1/Kv3.2 promotes gamma oscillations by rescuing Aβ-induced desynchronization of fast-spiking interneuron firing in an AD mouse model in vitro. J Physiol 2020; 598(17): 3711-25.
[http://dx.doi.org/10.1113/JP279718] [PMID: 32638407]
[49]
Gilding LN, Somervaille TCP. The diverse consequences of FOXC1 deregulation in cancer. Cancers (Basel) 2019; 11(2): E184.
[http://dx.doi.org/10.3390/cancers11020184] [PMID: 30764547]
[50]
Aldinger KA, Lehmann OJ, Hudgins L, et al. FOXC1 is required for normal cerebellar development and is a major contributor to chromosome 6p25.3 Dandy-Walker malformation. Nat Genet 2009; 41(9): 1037-42.
[http://dx.doi.org/10.1038/ng.422] [PMID: 19668217]
[51]
Shrestha S, Offer SM. Epigenetic regulations of GABAergic neurotransmission: Relevance for neurological disorders and epigenetic therapy. Med Epigenet 2016; 4(1): 1-19.
[http://dx.doi.org/10.1159/000444713]
[52]
Jun GR, Chung J, Mez J, et al. Transethnic genome-wide scan identifies novel Alzheimer’s disease loci. Alzheimers Dement 2017; 13(7): 727-38.
[http://dx.doi.org/10.1016/j.jalz.2016.12.012] [PMID: 28183528]
[53]
Fiala M, Avagyan H, Merino JJ, et al. Chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy. Pathophysiology 2013; 20(1): 59-69.
[http://dx.doi.org/10.1016/j.pathophys.2012.02.003] [PMID: 22444245]
[54]
Hou ST. The regulatory and enzymatic functions of CRMPs in neuritogenesis, synaptic plasticity, and gene transcription. Neurochem Int 2020; 139: 104795.
[http://dx.doi.org/10.1016/j.neuint.2020.104795] [PMID: 32652266]
[55]
Tian Y, Chang JC, Fan EY, Flajolet M, Greengard P. Adaptor complex AP2/PICALM, through interaction with LC3, targets Alzheimer’s APP-CTF for terminal degradation via autophagy. Proc Natl Acad Sci USA 2013; 110(42): 17071-6.
[http://dx.doi.org/10.1073/pnas.1315110110] [PMID: 24067654]
[56]
Lösing P, Niturad CE, Harrer M, et al. SRF modulates seizure occurrence, activity induced gene transcription and hippocampal circuit reorganization in the mouse pilocarpine epilepsy model. Mol Brain 2017; 10(1): 30.
[http://dx.doi.org/10.1186/s13041-017-0310-2] [PMID: 28716058]
[57]
Bell RD, Deane R, Chow N, et al. SRF and myocardin regulate LRP-mediated amyloid-beta clearance in brain vascular cells. Nat Cell Biol 2009; 11(2): 143-53.
[http://dx.doi.org/10.1038/ncb1819] [PMID: 19098903]
[58]
Zhang M, Bian Z. Alzheimer’s Disease and microRNA-132: A widespread pathological factor and potential therapeutic target. Front Neurosci 2021; 15: 687973.
[http://dx.doi.org/10.3389/fnins.2021.687973] [PMID: 34108863]
[59]
Wang J, Zhao J. MicroRNA Dysregulation in epilepsy: From pathogenetic involvement to diagnostic biomarker and therapeutic agent development. Front Mol Neurosci 2021; 14: 650372.
[http://dx.doi.org/10.3389/fnmol.2021.650372] [PMID: 33776649]
[60]
Wang D, Fei Z, Luo S, Wang H. MiR-335-5p inhibits β-Amyloid (Aβ) accumulation to attenuate cognitive deficits through targeting c-jun-N-terminal kinase 3 in Alzheimer’s Disease. Curr Neurovasc Res 2020; 17(1): 93-101.
[http://dx.doi.org/10.2174/1567202617666200128141938] [PMID: 32003672]
[61]
De Luna N, Turon-Sans J, Cortes-Vicente E, et al. Downregulation of miR-335-5P in amyotrophic lateral sclerosis can contribute to neuronal mitochondrial dysfunction and apoptosis. Sci Rep 2020; 10(1): 4308.
[http://dx.doi.org/10.1038/s41598-020-61246-1] [PMID: 32152380]
[62]
Capitano F, Camon J, Licursi V, et al. MicroRNA-335-5p modulates spatial memory and hippocampal synaptic plasticity. Neurobiol Learn Mem 2017; 139: 63-8.
[http://dx.doi.org/10.1016/j.nlm.2016.12.019] [PMID: 28039088]
[63]
Li H, Wang R. A focus on CXCR4 in Alzheimer’s disease. Brain Circ 2017; 3(4): 199-203.
[http://dx.doi.org/10.4103/bc.bc_13_17] [PMID: 30276325]
[64]
Calì C, Bezzi P. CXCR4-mediated glutamate exocytosis from astrocytes. J Neuroimmunol 2010; 224(1-2): 13-21.
[http://dx.doi.org/10.1016/j.jneuroim.2010.05.004] [PMID: 20580441]
[65]
Yan Y, Su J, Zhang Z. The CXCL12/CXCR4/ACKR3 response axis in chronic neurodegenerative disorders of the central nervous System: Therapeutic target and biomarker. Cell Mol Neurobiol 2021.
[http://dx.doi.org/10.1007/s10571-021-01115-1]
[66]
Zhou Z, Liu T, Sun X, Mu X, Zhu G, Xiao T, et al. CXCR4 antagonist AMD3100 reverses the neurogenesis promoted by enriched environment and suppresses long-term seizure activity in adult rats of temporal lobe epilepsy. Behav Brain Res 2017; 322(Pt A): 83-91.
[http://dx.doi.org/10.1016/j.bbr.2017.01.014]
[67]
Shin JW, Lee JK, Lee JE, et al. Combined effects of hematopoietic progenitor cell mobilization from bone marrow by granulocyte colony stimulating factor and AMD3100 and chemotaxis into the brain using stromal cell-derived factor-1α in an Alzheimer’s disease mouse model. Stem Cells 2011; 29(7): 1075-89.
[http://dx.doi.org/10.1002/stem.659] [PMID: 21608078]
[68]
Walke GR, Rapole S, Kulkarni PP. Cisplatin inhibits the formation of a reactive intermediate during copper-catalyzed oxidation of amyloid β peptide. Inorg Chem 2014; 53(19): 10003-5.
[http://dx.doi.org/10.1021/ic5007764] [PMID: 25237806]

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy