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Abstract
Background: Alzheimer's disease (AD) plays a prominent role as the most common form of dementia. Moreover, the traditional mechanism of AD does not explain the microvascular damage observed in about 25-30 years between the onset of AD, which results in late application treatment that inhibits or delays neurodegeneration.
Objective: Our objective was to identify differentially expressed genes in human brain samples associated with vascular disruption in AD.
Methods: We analyzed 1633 post-mortem brain samples in the GEO to database and, after applying clinical and bioinformatic exclusion criteria, worked with 581 prefrontal and frontal samples.
All datasets were analyzed using GEO2R from NCBI. We identified common genes using the Venny tool, and their metabolic relevance associated with AD and the vascular system was analyzed using MetaboAnalyst tools.
Results: Our bioinformatic analysis identified PRKCB, MAP2K2, ADCY1, GNA11, GNAQ, PRKACB, KCNMB4, CALD1, and GNAS as potentially involved in AD pathogenesis. These genes are associated with signal transductions, cell death signaling, and cytoskeleton, suggesting potential modulation of cellular physiology, including endoplasmic reticulum and mitochondrial activity.
Conclusion: This study generates hypotheses regarding the roles of novel genes over critical pathways relevant to AD and its relation with vascular dysfunction. These findings suggest potential new targets for further investigation into the pathogenesis of dementia and AD
[1]
2021 Alzheimer’s disease facts and figures. Alzheimers Dement 2021; 17(3): 327-406.
[http://dx.doi.org/10.1002/alz.12328] [PMID: 33756057]
[http://dx.doi.org/10.1002/alz.12328] [PMID: 33756057]
[2]
Global action plan on the public health response to dementia 2017 - 2025. Available from: https://www.who.int/publications-detail-redirect/global-action-plan-on-the-public-health-response-to-dementia-2017---2025 [cited 2023 Jun 13].
[3]
Shin JH. Dementia epidemiology fact sheet 2022. Ann Rehabil Med 2022; 46(2): 53-9.
[http://dx.doi.org/10.5535/arm.22027] [PMID: 35508924]
[http://dx.doi.org/10.5535/arm.22027] [PMID: 35508924]
[4]
Cao Q, Tan CC, Xu W, et al. The prevalence of dementia: A systematic review and meta-analysis. J Alzheimers Dis 2020; 73(3): 1157-66.
[http://dx.doi.org/10.3233/JAD-191092] [PMID: 31884487]
[http://dx.doi.org/10.3233/JAD-191092] [PMID: 31884487]
[5]
Hugo J, Ganguli M. Dementia and cognitive impairment: Epidemiology, diagnosis, and treatment. Clin Geriatr Med 2014; 30(3): 421-42.
[http://dx.doi.org/10.1016/j.cger.2014.04.001] [PMID: 25037289]
[http://dx.doi.org/10.1016/j.cger.2014.04.001] [PMID: 25037289]
[6]
Kapasi A, DeCarli C, Schneider JA. Impact of multiple pathologies on the threshold for clinically overt dementia. Acta Neuropathol 2017; 134(2): 171-86.
[http://dx.doi.org/10.1007/s00401-017-1717-7] [PMID: 28488154]
[http://dx.doi.org/10.1007/s00401-017-1717-7] [PMID: 28488154]
[7]
Loi SM, Tsoukra P, Sun E, et al. Survival in Huntington’s disease and other young‐onset dementias. Int J Geriatr Psychiatry 2023; 38(4): e5913.
[http://dx.doi.org/10.1002/gps.5913] [PMID: 37062919]
[http://dx.doi.org/10.1002/gps.5913] [PMID: 37062919]
[8]
Chaganti SS, McCusker EA, Loy CT. What do we know about Late Onset Huntington’s Disease? J Huntingt Dis 2017; 6(2): 95-103.
[9]
Davis MY, Keene CD, Jayadev S, Bird T. The co-occurrence of Alzheimer’s disease and Huntington’s disease: A neuropathological study of 15 elderly Huntington’s disease subjects. J Huntingtons Dis 2014; 3(2): 209-17.
[http://dx.doi.org/10.3233/JHD-140111] [PMID: 25062863]
[http://dx.doi.org/10.3233/JHD-140111] [PMID: 25062863]
[10]
Ahamad S, Bhat SA. The emerging landscape of small-molecule therapeutics for the treatment of huntington’s disease. J Med Chem 2022; 65(24): 15993-6032.
[http://dx.doi.org/10.1021/acs.jmedchem.2c00799] [PMID: 36490325]
[http://dx.doi.org/10.1021/acs.jmedchem.2c00799] [PMID: 36490325]
[11]
Bhat SA, Ahamad S, Dar NJ, Siddique YH, Nazir A. The emerging landscape of natural small-molecule therapeutics for huntington’s disease. Curr Neuropharmacol 2023; 21(4): 867-89.
[http://dx.doi.org/10.2174/1570159X21666230216104621] [PMID: 36797612]
[http://dx.doi.org/10.2174/1570159X21666230216104621] [PMID: 36797612]
[12]
Ahamad S, Bano N, Khan S, Hussain MK, Bhat SA. Unraveling the puzzle of therapeutic peptides: A promising frontier in huntington’s disease treatment. J Med Chem 2024; 67(2): 783-815.
[http://dx.doi.org/10.1021/acs.jmedchem.3c01131] [PMID: 38207096]
[http://dx.doi.org/10.1021/acs.jmedchem.3c01131] [PMID: 38207096]
[13]
Zhang XX, Tian Y, Wang ZT, Ma YH, Tan L, Yu JT. The epidemiology of alzheimer’s disease modifiable risk factors and prevention. J Prev Alzheimers Dis 2021; 8(3): 313-21.
[PMID: 34101789]
[PMID: 34101789]
[14]
The Economic Costs of Alzheimer’s Disease : The Economic Costs of Alzheimer’s Disease : United States Joint Economic Committee. Available from: https://www.jec.senate.gov/public/index.cfm/democrats/issue-briefs?ID=02F4CADC-954F-4E3B-8409-A4213E3C0759 [cited 2023 Sep 24].
[15]
Nandi A, Counts N, Chen S, et al. Global and regional projections of the economic burden of Alzheimer’s disease and related dementias from 2019 to 2050: A value of statistical life approach. EClinicalMed 2022; 51: 101580.
[http://dx.doi.org/10.1016/j.eclinm.2022.101580] [PMID: 35898316]
[http://dx.doi.org/10.1016/j.eclinm.2022.101580] [PMID: 35898316]
[16]
Breijyeh Z, Karaman R. Comprehensive review on alzheimer’s disease: Causes and treatment. Molecules 2020; 25(24): 5789.
[http://dx.doi.org/10.3390/molecules25245789] [PMID: 33302541]
[http://dx.doi.org/10.3390/molecules25245789] [PMID: 33302541]
[17]
Jack CR Jr, Bennett DA, Blennow K, et al. NIA‐AA Research Framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018; 14(4): 535-62.
[http://dx.doi.org/10.1016/j.jalz.2018.02.018] [PMID: 29653606]
[http://dx.doi.org/10.1016/j.jalz.2018.02.018] [PMID: 29653606]
[18]
Scheltens P, De Strooper B, Kivipelto M, et al. Alzheimer’s disease. Lancet 2021; 397(10284): 1577-90.
[http://dx.doi.org/10.1016/S0140-6736(20)32205-4] [PMID: 33667416]
[http://dx.doi.org/10.1016/S0140-6736(20)32205-4] [PMID: 33667416]
[19]
Ferrari C, Sorbi S. The complexity of Alzheimer’s disease: An evolving puzzle. Physiol Rev 2021; 101(3): 1047-81.
[http://dx.doi.org/10.1152/physrev.00015.2020] [PMID: 33475022]
[http://dx.doi.org/10.1152/physrev.00015.2020] [PMID: 33475022]
[20]
Claveau JS, Presse N, Kergoat MJ, Villalpando JM. The Lost Years: Delay between the onset of cognitive symptoms and clinical assessment at a memory clinic. Can Geriatr J 2018; 21(2): 152-6.
[http://dx.doi.org/10.5770/cgj.21.297] [PMID: 29977430]
[http://dx.doi.org/10.5770/cgj.21.297] [PMID: 29977430]
[21]
Liss JL, Seleri Assunção S, Cummings J, et al. Practical recommendations for timely, accurate diagnosis of symptomatic Alzheimer’s disease (MCI and dementia) in primary care: A review and synthesis. J Intern Med 2021; 290(2): 310-34.
[http://dx.doi.org/10.1111/joim.13244] [PMID: 33458891]
[http://dx.doi.org/10.1111/joim.13244] [PMID: 33458891]
[22]
Solis E Jr, Hascup KN, Hascup ER. Alzheimer’s Disease: The link between amyloid-β and neurovascular dysfunction. J Alzheimers Dis 2020; 76(4): 1179-98.
[http://dx.doi.org/10.3233/JAD-200473] [PMID: 32597813]
[http://dx.doi.org/10.3233/JAD-200473] [PMID: 32597813]
[23]
Zlokovic BV. Neurovascular mechanisms of Alzheimer’s neurodegeneration. Trends Neurosci 2005; 28(4): 202-8.
[http://dx.doi.org/10.1016/j.tins.2005.02.001] [PMID: 15808355]
[http://dx.doi.org/10.1016/j.tins.2005.02.001] [PMID: 15808355]
[24]
Scheffer S, Hermkens DMA, van der Weerd L, de Vries HE, Daemen MJAP. Vascular hypothesis of alzheimer disease. Arterioscler Thromb Vasc Biol 2021; 41(4): 1265-83.
[http://dx.doi.org/10.1161/ATVBAHA.120.311911] [PMID: 33626911]
[http://dx.doi.org/10.1161/ATVBAHA.120.311911] [PMID: 33626911]
[25]
Kisler K, Nelson AR, Montagne A, Zlokovic BV. Cerebral blood flow regulation and neurovascular dysfunction in Alzheimer disease. Nat Rev Neurosci 2017; 18(7): 419-34.
[http://dx.doi.org/10.1038/nrn.2017.48] [PMID: 28515434]
[http://dx.doi.org/10.1038/nrn.2017.48] [PMID: 28515434]
[26]
Sharma N, Singh AN. Exploring biomarkers for alzheimer’s disease. J Clin Diagn Res 2016; 10(7): KE01-6.
[PMID: 27630867]
[PMID: 27630867]
[27]
Tan MS, Cheah PL, Chin AV, Looi LM, Chang SW. A review on omics-based biomarkers discovery for Alzheimer’s disease from the bioinformatics perspectives: Statistical approach vs machine learning approach. Comput Biol Med 2021; 139: 104947.
[http://dx.doi.org/10.1016/j.compbiomed.2021.104947] [PMID: 34678481]
[http://dx.doi.org/10.1016/j.compbiomed.2021.104947] [PMID: 34678481]
[28]
Wang M, Song W, Ming C, et al. Guidelines for bioinformatics of single-cell sequencing data analysis in Alzheimer’s disease: review, recommendation, implementation and application. Mol Neurodegener 2022; 17(1): 17.
[http://dx.doi.org/10.1186/s13024-022-00517-z] [PMID: 35236372]
[http://dx.doi.org/10.1186/s13024-022-00517-z] [PMID: 35236372]
[29]
Diaz E, Barisone GA. DNA microarrays: Sample quality control, array hybridization and scanning. J Vis Exp 2011; (49): 2546.
[PMID: 21445042]
[PMID: 21445042]
[30]
Bumgarner R. DNA microarrays: Types, Applications and their future. Curr Protoc Mol Biol 2013; 22.
[31]
Chong J, Wishart DS, Xia J. Using metaboanalyst 4.0 for comprehensive and integrative metabolomics data analysis. Curr Protoc Bioinformatics 2019; 68(1): e86.
[http://dx.doi.org/10.1002/cpbi.86] [PMID: 31756036]
[http://dx.doi.org/10.1002/cpbi.86] [PMID: 31756036]
[32]
Martens M, Ammar A, Riutta A, et al. WikiPathways: Connecting communities. Nucleic Acids Res 2021; 49(D1): D613-21.
[http://dx.doi.org/10.1093/nar/gkaa1024] [PMID: 33211851]
[http://dx.doi.org/10.1093/nar/gkaa1024] [PMID: 33211851]
[33]
Pico AR, Kelder T, van Iersel MP, Hanspers K, Conklin BR, Evelo C. WikiPathways: Pathway editing for the people. PLoS Biol 2008; 6(7): e184.
[http://dx.doi.org/10.1371/journal.pbio.0060184] [PMID: 18651794]
[http://dx.doi.org/10.1371/journal.pbio.0060184] [PMID: 18651794]
[34]
Pang Z, Zhou G, Chong J, Xia J. Comprehensive meta-analysis of COVID-19 global metabolomics datasets. Metabolites 2021; 11(1): 44.
[http://dx.doi.org/10.3390/metabo11010044] [PMID: 33435351]
[http://dx.doi.org/10.3390/metabo11010044] [PMID: 33435351]
[35]
Chang CH, Lin CH, Lane HY. Machine learning and novel biomarkers for the diagnosis of alzheimer’s disease. Int J Mol Sci 2021; 22(5): 2761.
[http://dx.doi.org/10.3390/ijms22052761] [PMID: 33803217]
[http://dx.doi.org/10.3390/ijms22052761] [PMID: 33803217]
[37]
Higgins-Chen AT, Thrush KL, Levine ME. Aging biomarkers and the brain. Semin Cell Dev Biol 2021; 116: 180-93.
[http://dx.doi.org/10.1016/j.semcdb.2021.01.003] [PMID: 33509689]
[http://dx.doi.org/10.1016/j.semcdb.2021.01.003] [PMID: 33509689]
[38]
Zhao H, Gong L, Wu S, et al. The inhibition of protein kinase C β contributes to the pathogenesis of preeclampsia by activating autophagy. EBioMedicine 2020; 56: 102813.
[http://dx.doi.org/10.1016/j.ebiom.2020.102813] [PMID: 32544612]
[http://dx.doi.org/10.1016/j.ebiom.2020.102813] [PMID: 32544612]
[39]
Zhu Z, Yang L, Zhang Y, et al. Increased expression of PRKCB mRNA in peripheral blood mononuclear cells from patients with systemic lupus erythematosus. Ann Hum Genet 2018; 82(4): 200-5.
[http://dx.doi.org/10.1111/ahg.12240] [PMID: 29297929]
[http://dx.doi.org/10.1111/ahg.12240] [PMID: 29297929]
[40]
Li N, Zhang W. Protein kinase C β inhibits autophagy and sensitizes cervical cancer Hela cells to cisplatin. Biosci Rep 2017; 37(2): BSR20160445.
[http://dx.doi.org/10.1042/BSR20160445] [PMID: 28246354]
[http://dx.doi.org/10.1042/BSR20160445] [PMID: 28246354]
[41]
Ringvold HC, Khalil RA. Protein Kinase C as regulator of vascular smooth muscle function and potential target in vascular disorders. Adv Pharmacol 2017; 78: 203-301.
[http://dx.doi.org/10.1016/bs.apha.2016.06.002] [PMID: 28212798]
[http://dx.doi.org/10.1016/bs.apha.2016.06.002] [PMID: 28212798]
[42]
Fan HC, Fernández-Hernando C, Lai JH. Protein kinase C isoforms in atherosclerosis: Pro or anti-inflammatory? Biochem Pharmacol 2014; 88(2): 139-49.
[http://dx.doi.org/10.1016/j.bcp.2014.01.006] [PMID: 24440741]
[http://dx.doi.org/10.1016/j.bcp.2014.01.006] [PMID: 24440741]
[43]
PRKCB protein kinase C beta [Homo sapiens (human)] : Gene : NCBI. Available from: https://www.ncbi.nlm.nih.gov/gene/5579#bibliography [cited 2023 Sep 5].
[44]
Zhou Z, Chen F, Zhong S, et al. Molecular identification of protein kinase C beta in Alzheimer’s disease. Aging 2020; 12(21): 21798-808.
[http://dx.doi.org/10.18632/aging.103994] [PMID: 33186918]
[http://dx.doi.org/10.18632/aging.103994] [PMID: 33186918]
[45]
Zhou Z, Bai J, Zhong S, et al. Downregulation of PIK3CB involved in alzheimer’s disease via apoptosis, axon guidance, and foxo signaling pathway. Oxid Med Cell Longev 2022; 2022: 1-15.
[http://dx.doi.org/10.1155/2022/1260161] [PMID: 35096262]
[http://dx.doi.org/10.1155/2022/1260161] [PMID: 35096262]
[46]
Antonell A, Lladó A, Sánchez-Valle R, et al. Altered blood gene expression of tumor-related genes (PRKCB, BECN1, and CDKN2A) in Alzheimer’s Disease. Mol Neurobiol 2016; 53(9): 5902-11.
[http://dx.doi.org/10.1007/s12035-015-9483-9] [PMID: 26510741]
[http://dx.doi.org/10.1007/s12035-015-9483-9] [PMID: 26510741]
[47]
Shafiq M, Jagavelu K, Iqbal H, Yadav P, Chanda D, Verma NK, et al. Inhibition of mitogen-activated protein kinase (MAPK)-Activated Protein Kinase 2 (MK2) is Protective in Pulmonary Hypertension. Hypertens Dallas Tex 1979; 77(4): 1248-59.
[48]
Schiffrin EL. Vascular remodeling in hypertension: mechanisms and treatment. Hypertens Dallas Tex 1979; 59(2): 367-74.
[49]
Lu Y, Sun X, Peng L, et al. Angiotensin II-Induced vascular remodeling and hypertension involves cathepsin L/V- MEK/ERK mediated mechanism. Int J Cardiol 2020; 298: 98-106.
[http://dx.doi.org/10.1016/j.ijcard.2019.09.070] [PMID: 31668507]
[http://dx.doi.org/10.1016/j.ijcard.2019.09.070] [PMID: 31668507]
[50]
PubChem. MAP2K2 : mitogen-activated protein kinase kinase 2 (human). Available from: https://pubchem.ncbi.nlm.nih.gov/gene/MAP2K2/human [cited 2023 Sep 5].
[51]
Yoon G, Rosenberg J, Blaser S, Rauen KA. Neurological complications of cardio‐facio‐cutaneous syndrome. Dev Med Child Neurol 2007; 49(12): 894-9.
[http://dx.doi.org/10.1111/j.1469-8749.2007.00894.x] [PMID: 18039235]
[http://dx.doi.org/10.1111/j.1469-8749.2007.00894.x] [PMID: 18039235]
[52]
Buljan M, Ciuffa R, van Drogen A, et al. Kinase interaction network expands functional and disease roles of human kinases. Mol Cell 2020; 79(3): 504-520.e9.
[http://dx.doi.org/10.1016/j.molcel.2020.07.001] [PMID: 32707033]
[http://dx.doi.org/10.1016/j.molcel.2020.07.001] [PMID: 32707033]
[53]
Pei JJ, Braak H, An WL, et al. Up-regulation of mitogen-activated protein kinases ERK1/2 and MEK1/2 is associated with the progression of neurofibrillary degeneration in Alzheimer’s disease. Brain Res Mol Brain Res 2002; 109(1-2): 45-55.
[http://dx.doi.org/10.1016/S0169-328X(02)00488-6] [PMID: 12531514]
[http://dx.doi.org/10.1016/S0169-328X(02)00488-6] [PMID: 12531514]
[54]
Ferrer I, Blanco R, Carmona M, et al. Phosphorylated map kinase (ERK1, ERK2) expression is associated with early tau deposition in neurones and glial cells, but not with increased nuclear DNA vulnerability and cell death, in Alzheimer disease, Pick’s disease, progressive supranuclear palsy and corticobasal degeneration. Brain Pathol 2001; 11(2): 144-58.
[http://dx.doi.org/10.1111/j.1750-3639.2001.tb00387.x] [PMID: 11303790]
[http://dx.doi.org/10.1111/j.1750-3639.2001.tb00387.x] [PMID: 11303790]
[55]
Khezri MR, Yousefi K, Esmaeili A, Ghasemnejad-Berenji M. The Role of ERK1/2 pathway in the pathophysiology of alzheimer’s disease: An overview and update on new developments. Cell Mol Neurobiol 2023; 43(1): 177-91.
[http://dx.doi.org/10.1007/s10571-022-01191-x] [PMID: 35038057]
[http://dx.doi.org/10.1007/s10571-022-01191-x] [PMID: 35038057]
[56]
PubChem. DCY1 : adenylate cyclase 1 (human). Available from: https://pubchem.ncbi.nlm.nih.gov/gene/ADCY1/human [cited 2023 Sep 5].
[57]
Chen J, Ding Q, An L, Wang H. Ca2+-stimulated adenylyl cyclases as therapeutic targets for psychiatric and neurodevelopmental disorders. Front Pharmacol 2022; 13: 949384.
[http://dx.doi.org/10.3389/fphar.2022.949384] [PMID: 36188604]
[http://dx.doi.org/10.3389/fphar.2022.949384] [PMID: 36188604]
[58]
Sundararajan T, Manzardo AM, Butler MG. Functional analysis of schizophrenia genes using GeneAnalytics program and integrated databases. Gene 2018; 641: 25-34.
[http://dx.doi.org/10.1016/j.gene.2017.10.035] [PMID: 29032150]
[http://dx.doi.org/10.1016/j.gene.2017.10.035] [PMID: 29032150]
[59]
Zhang M, Wang H. Ca2+-stimulated ADCY1 and ADCY8 regulate distinct aspects of synaptic and cognitive flexibility. Front Cell Neurosci 2023; 17: 1215255.
[http://dx.doi.org/10.3389/fncel.2023.1215255] [PMID: 37465213]
[http://dx.doi.org/10.3389/fncel.2023.1215255] [PMID: 37465213]
[60]
Sethna F, Feng W, Ding Q, Robison AJ, Feng Y, Wang H. Enhanced expression of ADCY1 underlies aberrant neuronal signalling and behaviour in a syndromic autism model. Nat Commun 2017; 8(1): 14359.
[http://dx.doi.org/10.1038/ncomms14359] [PMID: 28218269]
[http://dx.doi.org/10.1038/ncomms14359] [PMID: 28218269]
[61]
Wang H, Ferguson GD, Pineda VV, Cundiff PE, Storm DR. Overexpression of type-1 adenylyl cyclase in mouse forebrain enhances recognition memory and LTP. Nat Neurosci 2004; 7(6): 635-42.
[http://dx.doi.org/10.1038/nn1248] [PMID: 15133516]
[http://dx.doi.org/10.1038/nn1248] [PMID: 15133516]
[62]
Guo R, Liu T, Shasaltaneh MD, Wang X, Imani S, Wen Q. Targeting adenylate cyclase family: New concept of targeted cancer therapy. Front Oncol 2022; 12: 829212.
[http://dx.doi.org/10.3389/fonc.2022.829212] [PMID: 35832555]
[http://dx.doi.org/10.3389/fonc.2022.829212] [PMID: 35832555]
[63]
Zou T, Liu J, She L, et al. A perspective profile of ADCY1 in cAMP signaling with drug-resistance in lung cancer. J Cancer 2019; 10(27): 6848-57.
[http://dx.doi.org/10.7150/jca.36614] [PMID: 31839819]
[http://dx.doi.org/10.7150/jca.36614] [PMID: 31839819]
[64]
PubChem. GNA11 : G protein subunit alpha 11 (human). Available from: https://pubchem.ncbi.nlm.nih.gov/gene/GNA11/human [cited 2023 Sep 5].
[65]
Silva-Rodríguez P, Fernández-Díaz D, Bande M, Pardo M, Loidi L, Blanco-Teijeiro MJ. GNAQ and GNA11 Genes: A Comprehensive Review on Oncogenesis, Prognosis and Therapeutic Opportunities in Uveal Melanoma. Cancers 2022; 14(13): 3066.
[http://dx.doi.org/10.3390/cancers14133066] [PMID: 35804836]
[http://dx.doi.org/10.3390/cancers14133066] [PMID: 35804836]
[66]
Shirley MD, Tang H, Gallione CJ, et al. Sturge-Weber syndrome and port-wine stains caused by somatic mutation in GNAQ. N Engl J Med 2013; 368(21): 1971-9.
[http://dx.doi.org/10.1056/NEJMoa1213507] [PMID: 23656586]
[http://dx.doi.org/10.1056/NEJMoa1213507] [PMID: 23656586]
[67]
Moore AR, Ceraudo E, Sher JJ, et al. Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma. Nat Genet 2016; 48(6): 675-80.
[http://dx.doi.org/10.1038/ng.3549] [PMID: 27089179]
[http://dx.doi.org/10.1038/ng.3549] [PMID: 27089179]
[68]
Jia N, Li G, Huang P, et al. Protective role and related mechanism of Gnaq in neural cells damaged by oxidative stress. Acta Biochim Biophys Sin 2017; 49(5): 428-34.
[http://dx.doi.org/10.1093/abbs/gmx024] [PMID: 28369206]
[http://dx.doi.org/10.1093/abbs/gmx024] [PMID: 28369206]
[69]
Sun X, Li GP, Huang P, et al. Gnaq Protects PC12 cells from oxidative damage by activation of Nrf2 and inhibition of NF-kB. Neuromolecular Med 2020; 22(3): 401-10.
[http://dx.doi.org/10.1007/s12017-020-08598-z] [PMID: 32253686]
[http://dx.doi.org/10.1007/s12017-020-08598-z] [PMID: 32253686]
[70]
GNAQ G protein subunit alpha q [Homo sapiens (human)] : Gene : NCBI. Available from: https://www.ncbi.nlm.nih.gov/gene/2776#summary [cited 2023 Sep 6].
[71]
GNAS GNAS complex locus [Homo sapiens (human)] : Gene : NCBI. Available from: https://www.ncbi.nlm.nih.gov/gene/2778#summary [cited 2023 Sep 6].
[72]
Vitvitsky VM, Garg SK, Keep RF, Albin RL, Banerjee R. Na+ and K+ ion imbalances in Alzheimer’s disease. Biochim Biophys Acta Mol Basis Dis 2012; 1822(11): 1671-81.
[http://dx.doi.org/10.1016/j.bbadis.2012.07.004] [PMID: 22820549]
[http://dx.doi.org/10.1016/j.bbadis.2012.07.004] [PMID: 22820549]
[73]
Barh D, García-Solano M, Tiwari S, et al. BARHL1 is downregulated in alzheimer’s disease and may regulate cognitive functions through ESR1 and multiple pathways. Genes 2017; 8(10): 245.
[http://dx.doi.org/10.3390/genes8100245] [PMID: 28956815]
[http://dx.doi.org/10.3390/genes8100245] [PMID: 28956815]
[74]
Chowriappa P, Dua P, Walter J. An exploratory analysis of conservation of co-expressed genes across alzheimer’s disease progression. J Comput Sci Syst Biol 2013; 6(4): 221-7.
[http://dx.doi.org/10.4172/jcsb.1000119]
[http://dx.doi.org/10.4172/jcsb.1000119]
[75]
Taguchi K, Yamagata HD, Zhong W, et al. Identification of hippocampus‐related candidate genes for Alzheimer’s disease. Ann Neurol 2005; 57(4): 585-8.
[http://dx.doi.org/10.1002/ana.20433] [PMID: 15786443]
[http://dx.doi.org/10.1002/ana.20433] [PMID: 15786443]
[76]
KEGG PATHWAY. Gap junction : Reference pathway. Available from: https://www.kegg.jp/pathway/map04540 [cited 2023 Sep 6].
[77]
PRKACB protein kinase cAMP-activated catalytic subunit beta [Homo sapiens (human)] : Gene : NCBI. Available from: https://www.ncbi.nlm.nih.gov/gene/5567#summary [cited 2023 Sep 5].
[78]
Yoon C, Korade Z, Carter BD. Protein kinase A-induced phosphorylation of the p65 subunit of nuclear factor-kappaB promotes Schwann cell differentiation into a myelinating phenotype. J Neurosci 2008; 28(14): 3738-46.
[http://dx.doi.org/10.1523/JNEUROSCI.4439-07.2008] [PMID: 18385332]
[http://dx.doi.org/10.1523/JNEUROSCI.4439-07.2008] [PMID: 18385332]
[79]
Espiard S, Knape MJ, Bathon K, Assié G, Rizk-Rabin M, Faillot S, et al. Activating PRKACB somatic mutation in cortisol-producing adenomas. JCI Insight 2018; 3(8): e98296.
[http://dx.doi.org/10.1172/jci.insight.98296]
[http://dx.doi.org/10.1172/jci.insight.98296]
[80]
Palencia-Campos A, Aoto PC, Machal EMF, et al. Germline and mosaic variants in PRKACA and PRKACB cause a multiple congenital malformation syndrome. Am J Hum Genet 2020; 107(5): 977-88.
[http://dx.doi.org/10.1016/j.ajhg.2020.09.005] [PMID: 33058759]
[http://dx.doi.org/10.1016/j.ajhg.2020.09.005] [PMID: 33058759]
[81]
PRKACB variants in skeletal disease or adrenocortical hyperplasia: effects on protein kinase A : PubMed. Available from: https://pubmed.ncbi.nlm.nih.gov/33055300/ [cited 2023 Sep 5].
[82]
Dwivedi Y, Rizavi HS, Shukla PK, et al. Protein kinase a in postmortem brain of depressed suicide victims: altered expression of specific regulatory and catalytic subunits. Biol Psychiatry 2004; 55(3): 234-43.
[http://dx.doi.org/10.1016/j.biopsych.2003.11.003] [PMID: 14744463]
[http://dx.doi.org/10.1016/j.biopsych.2003.11.003] [PMID: 14744463]
[83]
Wang L, Liu J, Wang Q, et al. MicroRNA-200a-3p mediates neuroprotection in alzheimer-related deficits and attenuates amyloid-beta overproduction and tau hyperphosphorylation via Coregulating BACE1 and PRKACB. Front Pharmacol 2019; 10: 806.
[http://dx.doi.org/10.3389/fphar.2019.00806] [PMID: 31379578]
[http://dx.doi.org/10.3389/fphar.2019.00806] [PMID: 31379578]
[84]
Li H, Liu Q, Zhang Q, et al. miR-200a-3p Regulates PRKACB and participates in aluminium-induced tau phosphorylation in PC12 cells. Neurotox Res 2022; 40(6): 1963-78.
[http://dx.doi.org/10.1007/s12640-022-00609-0] [PMID: 36459375]
[http://dx.doi.org/10.1007/s12640-022-00609-0] [PMID: 36459375]
[85]
Iwanicki T, Balcerzyk A, Kazek B, et al. Family-based cohort association study of PRKCB1, CBLN1 and KCNMB4 gene polymorphisms and autism in polish population. J Autism Dev Disord 2022; 52(10): 4213-8.
[http://dx.doi.org/10.1007/s10803-021-05291-3] [PMID: 34562210]
[http://dx.doi.org/10.1007/s10803-021-05291-3] [PMID: 34562210]
[86]
Whitmire LE, Ling L, Bugay V, et al. Downregulation of KCNMB4 expression and changes in BK channel subtype in hippocampal granule neurons following seizure activity. PLoS One 2017; 12(11): e0188064.
[http://dx.doi.org/10.1371/journal.pone.0188064] [PMID: 29145442]
[http://dx.doi.org/10.1371/journal.pone.0188064] [PMID: 29145442]
[87]
Wang B, Bugay V, Ling L, Chuang HH, Jaffe DB, Brenner R. Knockout of the BK β 4 -subunit promotes a functional coupling of BK channels and ryanodine receptors that mediate a fAHP-induced increase in excitability. J Neurophysiol 2016; 116(2): 456-65.
[http://dx.doi.org/10.1152/jn.00857.2015] [PMID: 27146987]
[http://dx.doi.org/10.1152/jn.00857.2015] [PMID: 27146987]
[88]
Petrik D, Wang B, Brenner R. Modulation by the BK accessory β4 subunit of phosphorylation-dependent changes in excitability of dentate gyrus granule neurons. Eur J Neurosci 2011; 34(5): 695-704.
[http://dx.doi.org/10.1111/j.1460-9568.2011.07799.x] [PMID: 21848922]
[http://dx.doi.org/10.1111/j.1460-9568.2011.07799.x] [PMID: 21848922]
[89]
Ancatén-González C, Segura I, Alvarado-Sánchez R, Chávez AE, Latorre R. Ca2+- and Voltage-Activated K+ (BK) Channels in the Nervous System: One Gene, a Myriad of Physiological Functions. Int J Mol Sci 2023; 24(4): 3407.
[http://dx.doi.org/10.3390/ijms24043407] [PMID: 36834817]
[http://dx.doi.org/10.3390/ijms24043407] [PMID: 36834817]
[90]
Liu Y, Xie S, Zhu K, Guan X, Guo L, Lu R. CALD1 is a prognostic biomarker and correlated with immune infiltrates in gastric cancers. Heliyon 2021; 7(6): e07257.
[http://dx.doi.org/10.1016/j.heliyon.2021.e07257] [PMID: 34189308]
[http://dx.doi.org/10.1016/j.heliyon.2021.e07257] [PMID: 34189308]
[91]
Zheng PP, Sieuwerts AM, Luider TM, van der Weiden M, Sillevis-Smitt PAE, Kros JM. Differential expression of splicing variants of the human caldesmon gene (CALD1) in glioma neovascularization versus normal brain microvasculature. Am J Pathol 2004; 164(6): 2217-28.
[http://dx.doi.org/10.1016/S0002-9440(10)63778-9] [PMID: 15161654]
[http://dx.doi.org/10.1016/S0002-9440(10)63778-9] [PMID: 15161654]
[92]
Li C, Yang F, Wang R, et al. CALD1 promotes the expression of PD-L1 in bladder cancer via the JAK/STAT signaling pathway. Ann Transl Med 2021; 9(18): 1441.
[http://dx.doi.org/10.21037/atm-21-4192] [PMID: 34733993]
[http://dx.doi.org/10.21037/atm-21-4192] [PMID: 34733993]
[93]
Su Q, Dai B, Zhang H, Zhang S. Discovering gene signature shared by prostate cancer and neurodegenerative diseases based on the bioinformatics approach. Comput Math Methods Med 2022; 2022: 1-8.
[http://dx.doi.org/10.1155/2022/8430485] [PMID: 35799671]
[http://dx.doi.org/10.1155/2022/8430485] [PMID: 35799671]
[94]
Pereira AC, Gray JD, Kogan JF, et al. Age and Alzheimer’s disease gene expression profiles reversed by the glutamate modulator riluzole. Mol Psychiatry 2017; 22(2): 296-305.
[http://dx.doi.org/10.1038/mp.2016.33] [PMID: 27021815]
[http://dx.doi.org/10.1038/mp.2016.33] [PMID: 27021815]
[95]
Li QS, De Muynck L. Differentially expressed genes in Alzheimer’s disease highlighting the roles of microglia genes including OLR1 and astrocyte gene CDK2AP1. Brain Behav Immun Health 2021; 13: 100227.
[http://dx.doi.org/10.1016/j.bbih.2021.100227]
[http://dx.doi.org/10.1016/j.bbih.2021.100227]
[96]
Kumari A, Rahaman A, Zeng XA, et al. Temporal cortex microarray analysis revealed impaired ribosomal biogenesis and hyperactivity of the glutamatergic system: an early signature of asymptomatic alzheimer’s disease. Front Neurosci 2022; 16: 966877.
[http://dx.doi.org/10.3389/fnins.2022.966877] [PMID: 35958988]
[http://dx.doi.org/10.3389/fnins.2022.966877] [PMID: 35958988]