{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T23:18:06Z","timestamp":1775344686782,"version":"3.50.1"},"reference-count":132,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2021,4,10]],"date-time":"2021-04-10T00:00:00Z","timestamp":1618012800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000049","name":"National Institute on Aging","doi-asserted-by":"publisher","award":["R01AG062176"],"award-info":[{"award-number":["R01AG062176"]}],"id":[{"id":"10.13039\/100000049","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is a chronic, neurodegenerative brain disorder affecting millions of Americans that is expected to increase in incidence with the expanding aging population. Symptomatic AD patients show cognitive decline and often develop neuropsychiatric symptoms due to the accumulation of insoluble proteins that produce plaques and tangles seen in the brain at autopsy. Unexpectedly, some clinically normal individuals also show AD pathology in the brain at autopsy (asymptomatic AD, AsymAD). In this study, SWItchMiner software was used to identify key switch genes in the brain\u2019s entorhinal cortex that lead to the development of AD or disease resilience. Seventy-two switch genes were identified that are differentially expressed in AD patients compared to healthy controls. These genes are involved in inflammation, platelet activation, and phospholipase D and estrogen signaling. Peroxisome proliferator-activated receptor \u03b3 (PPARG), zinc-finger transcription factor (YY1), sterol regulatory element-binding transcription factor 2 (SREBF2), and early growth response 1 (EGR1) were identified as transcription factors that potentially regulate switch genes in AD. Comparing AD patients to AsymAD individuals revealed 51 switch genes; PPARG as a potential regulator of these genes, and platelet activation and phospholipase D as critical signaling pathways. Chemical\u2013protein interaction analysis revealed that valproic acid is a therapeutic agent that could prevent AD from progressing.<\/jats:p>","DOI":"10.3390\/ijms22083915","type":"journal-article","created":{"date-parts":[[2021,4,12]],"date-time":"2021-04-12T03:04:06Z","timestamp":1618196646000},"page":"3915","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Key Disease Mechanisms Linked to Alzheimer\u2019s Disease in the Entorhinal Cortex"],"prefix":"10.3390","volume":"22","author":[{"given":"Virginie","family":"Bottero","sequence":"first","affiliation":[{"name":"Center for Neurodegenerative Diseases and Therapeutics, Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dallen","family":"Powers","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Diseases and Therapeutics, Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ashna","family":"Yalamanchi","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Diseases and Therapeutics, Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"James P.","family":"Quinn","sequence":"additional","affiliation":[{"name":"Q Regulating Systems, LLC, Gurnee, IL 60031, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8782-3071","authenticated-orcid":false,"given":"Judith A.","family":"Potashkin","sequence":"additional","affiliation":[{"name":"Center for Neurodegenerative Diseases and Therapeutics, Discipline of Cellular and Molecular Pharmacology, The Chicago Medical School, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Mayeux, R., and Stern, Y. (2012). Epidemiology of Alzheimer disease. Cold Spring Harb. Perspect Med., 2.","DOI":"10.1101\/cshperspect.a006239"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"311","DOI":"10.3233\/JAD-2010-1221","article-title":"Alzheimer\u2019s disease and the amyloid-beta peptide","volume":"19","author":"Murphy","year":"2010","journal-title":"J. Alzheimers Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1038\/aps.2017.28","article-title":"Amyloid beta: Structure, biology and structure-based therapeutic development","volume":"38","author":"Chen","year":"2017","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.bcp.2013.12.024","article-title":"Alzheimer disease: Epidemiology, diagnostic criteria, risk factors and biomarkers","volume":"88","author":"Reitz","year":"2014","journal-title":"Biochem. Pharmacol."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Weller, J., and Budson, A. (2018). Current understanding of Alzheimer\u2019s disease diagnosis and treatment. F1000Research, 7.","DOI":"10.12688\/f1000research.14506.1"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1001\/jamaneurol.2013.5847","article-title":"Amyloid-beta and tau: The trigger and bullet in Alzheimer disease pathogenesis","volume":"71","author":"Bloom","year":"2014","journal-title":"JAMA Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s12276-019-0299-y","article-title":"Diagnosis of Alzheimer\u2019s disease utilizing amyloid and tau as fluid biomarkers","volume":"51","author":"Lee","year":"2019","journal-title":"Exp. Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"535","DOI":"10.1016\/j.jalz.2018.02.018","article-title":"Contributors, NIA-AA Research Framework: Toward a biological definition of Alzheimer\u2019s disease","volume":"14","author":"Jack","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"330","DOI":"10.2174\/156720511795745348","article-title":"Asymptomatic Alzheimer\u2019s disease: A prodrome or a state of resilience?","volume":"8","author":"Driscoll","year":"2011","journal-title":"Curr. Alzheimer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1007\/s11065-009-9118-x","article-title":"Beta-amyloid deposition and the aging brain","volume":"19","author":"Rodrigue","year":"2009","journal-title":"Neuropsychol. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.bbi.2019.05.009","article-title":"Transcriptomic analysis of probable asymptomatic and symptomatic alzheimer brains","volume":"80","author":"Patel","year":"2019","journal-title":"Brain Behav. Immun."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1751","DOI":"10.1093\/brain\/awz116","article-title":"Differentiation of mild cognitive impairment using an entorhinal cortex-based test of virtual reality navigation","volume":"142","author":"Howett","year":"2019","journal-title":"Brain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"304","DOI":"10.1038\/nn.3606","article-title":"Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer\u2019s disease","volume":"17","author":"Khan","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1515\/revneuro-2015-0019","article-title":"Entorhinal cortex: A good biomarker of mild cognitive impairment and mild Alzheimer\u2019s disease","volume":"27","author":"Zhou","year":"2016","journal-title":"Rev. Neurosci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"595282","DOI":"10.1155\/2008\/595282","article-title":"The role of the entorhinal cortex in extinction: Influences of aging","volume":"2008","author":"Bevilaqua","year":"2008","journal-title":"Neural Plast."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1152\/physiolgenomics.00208.2006","article-title":"Gene expression profiles in anatomically and functionally distinct regions of the normal aged human brain","volume":"28","author":"Liang","year":"2007","journal-title":"Physiol. Genom."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"44797","DOI":"10.1038\/srep44797","article-title":"SWIM: A computational tool to unveiling crucial nodes in complex biological networks","volume":"7","author":"Paci","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"7769","DOI":"10.1038\/s41598-018-26081-5","article-title":"Computational identification of specific genes for glioblastoma stem-like cells identity","volume":"8","author":"Fiscon","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Potashkin, J.A., Bottero, V., Santiago, J.A., and Quinn, J.P. (2019). Computational identification of key genes that may regulate gene expression reprogramming in Alzheimer\u2019s patients. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0222921"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Potashkin, J.A., Bottero, V., Santiago, J.A., and Quinn, J.P. (2020). Bioinformatic Analysis Reveals Phosphodiesterase 4D-Interacting Protein as a Key Frontal Cortex Dementia Switch Gene. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21113787"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1177\/193229680800200619","article-title":"Alzheimer\u2019s disease is type 3 diabetes-evidence reviewed","volume":"2","author":"Wands","year":"2008","journal-title":"J. Diabetes Sci. Technol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Yu, L., Li, H., Liu, W., Zhang, L., Tian, Q., Li, H., and Li, M. (2020). MiR-485-3p serves as a biomarker and therapeutic target of Alzheimer\u2019s disease via regulating neuronal cell viability and neuroinflammation by targeting AKT3. Mol. Genet. Genom. Med., e1548.","DOI":"10.1002\/mgg3.1548"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"504","DOI":"10.1007\/s12031-019-1257-9","article-title":"Combination of Insulin with a GLP1 Agonist Is Associated with Better Memory and Normal Expression of Insulin Receptor Pathway Genes in a Mouse Model of Alzheimer\u2019s Disease","volume":"67","author":"Robinson","year":"2019","journal-title":"J. Mol. Neurosci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"8814862","DOI":"10.1155\/2021\/8814862","article-title":"Downregulation of microRNA-15b-5p Targeting the Akt3-Mediated GSK-3beta\/beta-Catenin Signaling Pathway Inhibits Cell Apoptosis in Parkinson\u2019s Disease","volume":"2021","author":"Zhu","year":"2021","journal-title":"Biomed. Res. Int."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.3389\/fimmu.2019.01738","article-title":"Akt3-Mediated Protection Against Inflammatory Demyelinating Disease","volume":"10","author":"DuBois","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1007\/s00702-017-1796-6","article-title":"Explorative results from multistep screening for potential genetic risk loci of Alzheimer\u2019s disease in the longitudinal VITA study cohort","volume":"125","author":"Scholz","year":"2018","journal-title":"J. Neural Transm."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"67","DOI":"10.3233\/JAD-2004-6108","article-title":"The intracellular localization of amyloid beta protein precursor (AbetaPP) intracellular domain associated protein-1 (AIDA-1) is regulated by AbetaPP and alternative splicing","volume":"6","author":"Ghersi","year":"2004","journal-title":"J. Alzheimers Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"49105","DOI":"10.1074\/jbc.M405329200","article-title":"Amyloid-beta protein precursor (AbetaPP) intracellular domain-associated protein-1 proteins bind to AbetaPP and modulate its processing in an isoform-specific manner","volume":"279","author":"Ghersi","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.conb.2017.12.017","article-title":"Synapse-to-nucleus communication: From developmental disorders to Alzheimer\u2019s disease","volume":"48","author":"Marcello","year":"2018","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1093\/hmg\/ddm181","article-title":"Complexin 1 knockout mice exhibit marked deficits in social behaviours but appear to be cognitively normal","volume":"16","author":"Drew","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Yu, L., Tasaki, S., Schneider, J.A., Arfanakis, K., Duong, D.M., Wingo, A.P., Wingo, T.S., Kearns, N., Thatcher, G.R.J., and Seyfried, N.T. (2020). Cortical Proteins Associated With Cognitive Resilience in Community-Dwelling Older Persons. JAMA Psychiatry.","DOI":"10.1001\/jamapsychiatry.2020.1807"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/j.nbd.2018.02.006","article-title":"Frontotemporal dysregulation of the SNARE protein interactome is associated with faster cognitive decline in old age","volume":"114","author":"Jones","year":"2018","journal-title":"Neurobiol. Dis."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.bbrc.2020.03.041","article-title":"Growth arrest specific protein 7 inhibits tau fibrillogenesis","volume":"526","author":"Shimizu","year":"2020","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"593","DOI":"10.1093\/jb\/mvs038","article-title":"Alzheimer\u2019s disease-related protein hGas7b interferes with kinesin motility","volume":"151","author":"Hidaka","year":"2012","journal-title":"J. Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"32695","DOI":"10.1074\/jbc.M109.035998","article-title":"A novel role for hGas7b in microtubular maintenance: Possible implication in tau-associated pathology in Alzheimer disease","volume":"284","author":"Akiyama","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"103","DOI":"10.3389\/fncel.2017.00103","article-title":"Intracellular Fibroblast Growth Factor 14: Emerging Risk Factor for Brain Disorders","volume":"11","author":"Wadsworth","year":"2017","journal-title":"Front. Cell Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Sowers, M.L., Re, J.D., Wadsworth, P.A., Shavkunov, A.S., Lichti, C., Zhang, K., and Laezza, F. (2019). Sex-Specific Proteomic Changes Induced by Genetic Deletion of Fibroblast Growth Factor 14 (FGF14), a Regulator of Neuronal Ion Channels. Proteomes, 7.","DOI":"10.3390\/proteomes7010005"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.expneurol.2017.05.005","article-title":"PPARgamma agonists rescue increased phosphorylation of FGF14 at S226 in the Tg2576 mouse model of Alzheimer\u2019s disease","volume":"295","author":"Hsu","year":"2017","journal-title":"Exp. Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"903","DOI":"10.1038\/nature07456","article-title":"Neuroligins and neurexins link synaptic function to cognitive disease","volume":"455","author":"Sudhof","year":"2008","journal-title":"Nature"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"746","DOI":"10.1016\/j.neurobiolaging.2013.09.032","article-title":"Role for the neurexin-neuroligin complex in Alzheimer\u2019s disease","volume":"35","author":"Sindi","year":"2014","journal-title":"Neurobiol. Aging"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"281","DOI":"10.3389\/fncel.2020.00281","article-title":"Synaptic Organizers in Alzheimer\u2019s Disease: A Classification Based on Amyloid-beta Sensitivity","volume":"14","author":"Lee","year":"2020","journal-title":"Front Cell Neurosci."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"403","DOI":"10.3233\/JAD-122257","article-title":"Genetic study of neurexin and neuroligin genes in Alzheimer\u2019s disease","volume":"35","author":"Gayan","year":"2013","journal-title":"J. Alzheimers Dis."},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Saura, C.A., Servian-Morilla, E., and Scholl, F.G. (2011). Presenilin\/gamma-secretase regulates neurexin processing at synapses. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0019430"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"870","DOI":"10.2174\/1567205014666170317113606","article-title":"Impact of Cytokines and Chemokines on Alzheimer\u2019s Disease Neuropathological Hallmarks","volume":"14","author":"Domingues","year":"2017","journal-title":"Curr. Alzheimer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.2174\/1567205014666170203141717","article-title":"Neuroinflammation and Alzheimer\u2019s Disease: Implications for Microglial Activation","volume":"14","author":"Regen","year":"2017","journal-title":"Curr. Alzheimer Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1172\/JCI77487","article-title":"Prostaglandin signaling suppresses beneficial microglial function in Alzheimer\u2019s disease models","volume":"125","author":"Johansson","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"427","DOI":"10.3389\/fnmol.2017.00427","article-title":"Involvement of Astrocytes in Alzheimer\u2019s Disease from a Neuroinflammatory and Oxidative Stress Perspective","volume":"10","year":"2017","journal-title":"Front. Mol. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"365","DOI":"10.1172\/JCI66771","article-title":"CXCR3 promotes plaque formation and behavioral deficits in an Alzheimer\u2019s disease model","volume":"125","author":"Krauthausen","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1136\/bmj.38814.696493.AE","article-title":"Cerebral emboli as a potential cause of Alzheimer\u2019s disease and vascular dementia: Case-control study","volume":"332","author":"Purandare","year":"2006","journal-title":"BMJ"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.jalz.2014.01.003","article-title":"Risk factors for incident dementia after stroke and transient ischemic attack","volume":"11","author":"Yang","year":"2015","journal-title":"Alzheimers Dement."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.3906\/sag-1212-5","article-title":"The increase of mean platelet volume in patients with Alzheimer disease","volume":"44","author":"Koc","year":"2014","journal-title":"Turk. J. Med. Sci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"433","DOI":"10.3109\/09537104.2013.831064","article-title":"Mean platelet volume and platelet distribution width in vascular dementia and Alzheimer\u2019s disease","volume":"25","author":"Liang","year":"2014","journal-title":"Platelets"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.jpsychires.2013.01.014","article-title":"Decreased mean platelet volume and platelet distribution width are associated with mild cognitive impairment and Alzheimer\u2019s disease","volume":"47","author":"Wang","year":"2013","journal-title":"J. Psychiatr. Res."},{"key":"ref_54","first-page":"843","article-title":"Platelet-generated amyloid beta peptides in Alzheimer\u2019s disease and glaucoma","volume":"34","author":"Inyushin","year":"2019","journal-title":"Histol. Histopathol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"102","DOI":"10.5498\/wjp.v2.i6.102","article-title":"Platelets and Alzheimer\u2019s disease: Potential of APP as a biomarker","volume":"2","author":"Evin","year":"2012","journal-title":"World J. Psychiatry"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1001\/archneur.1997.00550140019007","article-title":"Altered amyloid protein processing in platelets of patients with Alzheimer disease","volume":"54","author":"Rosenberg","year":"1997","journal-title":"Arch Neurol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1907","DOI":"10.1212\/WNL.54.10.1907","article-title":"Platelet APP isoform ratios correlate with declining cognition in AD","volume":"54","author":"Baskin","year":"2000","journal-title":"Neurology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1033","DOI":"10.1124\/pr.114.009217","article-title":"Phospholipase D signaling pathways and phosphatidic acid as therapeutic targets in cancer","volume":"66","author":"Bruntz","year":"2014","journal-title":"Pharmacol. Rev."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1016\/j.tips.2015.01.001","article-title":"The phospholipase D superfamily as therapeutic targets","volume":"36","author":"Frohman","year":"2015","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1038\/nature12825","article-title":"Rare coding variants in the phospholipase D3 gene confer risk for Alzheimer\u2019s disease","volume":"505","author":"Cruchaga","year":"2014","journal-title":"Nature"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1016\/j.bbalip.2010.04.004","article-title":"Phospholipase D in brain function and Alzheimer\u2019s disease","volume":"1801","author":"Oliveira","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_62","first-page":"89","article-title":"Elevated phospholipase D isoform 1 in Alzheimer\u2019s disease patients\u2019 hippocampus: Relevance to synaptic dysfunction and memory deficits","volume":"4","author":"Krishnan","year":"2018","journal-title":"Alzheimers Dement."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"18342","DOI":"10.1038\/s41598-019-54974-6","article-title":"Suppressing aberrant phospholipase D1 signaling in 3xTg Alzheimer\u2019s disease mouse model promotes synaptic resilience","volume":"9","author":"Bourne","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"16419","DOI":"10.1523\/JNEUROSCI.3317-10.2010","article-title":"Phospholipase d2 ablation ameliorates Alzheimer\u2019s disease-linked synaptic dysfunction and cognitive deficits","volume":"30","author":"Oliveira","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1172\/JCI59903","article-title":"Demonstrated brain insulin resistance in Alzheimer\u2019s disease patients is associated with IGF-1 resistance, IRS-1 dysregulation, and cognitive decline","volume":"122","author":"Talbot","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.neuropharm.2018.01.044","article-title":"Brain insulin signalling, glucose metabolism and females\u2019 reproductive aging: A dangerous triad in Alzheimer\u2019s disease","volume":"136","author":"Duarte","year":"2018","journal-title":"Neuropharmacology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s40265-016-0674-0","article-title":"Insulin Resistance and Neurodegeneration: Progress Towards the Development of New Therapeutics for Alzheimer\u2019s Disease","volume":"77","year":"2017","journal-title":"Drugs"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"857","DOI":"10.3233\/JAD-180735","article-title":"Metabolic Syndrome, Brain Insulin Resistance, and Alzheimer\u2019s Disease: Thioredoxin Interacting Protein (TXNIP) and Inflammasome as Core Amplifiers","volume":"66","author":"Nasoohi","year":"2018","journal-title":"J. Alzheimers Dis."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1148\/radiology.173.2.2798872","article-title":"Esophageal motility: Assessment with synchronous video tape fluoroscopy and manometry","volume":"173","author":"Ott","year":"1989","journal-title":"Radiology"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1038\/nm.2332","article-title":"Brain PPAR-gamma promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones","volume":"17","author":"Lu","year":"2011","journal-title":"Nat. Med."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1177\/1533317509348208","article-title":"Obesity and Alzheimer\u2019s disease: A link between body weight and cognitive function in old age","volume":"24","author":"Naderali","year":"2009","journal-title":"Am. J. Alzheimers Dis. Other Demen."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1007\/s12603-016-0794-y","article-title":"Gene- Gene Interaction between PPARG and APOE Gene on Late-Onset Alzheimer\u2019s Disease: A Case- Control Study in Chinese Han Population","volume":"21","author":"Wang","year":"2017","journal-title":"J. Nutr. Health Aging"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1097\/WAD.0000000000000217","article-title":"The PPARG Pro12Ala Polymorphism and 20-year Cognitive Decline: Race and Sex Heterogeneity","volume":"32","author":"West","year":"2018","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.neulet.2008.06.029","article-title":"Lack of genetic association between PPARG gene polymorphisms and Finnish late-onset Alzheimer\u2019s disease","volume":"441","author":"Helisalmi","year":"2008","journal-title":"Neurosci. Lett."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.4103\/1673-5374.251193","article-title":"Transcriptional dysregulation in neurodegenerative diseases: Who tipped the balance of Yin Yang 1 in the brain?","volume":"14","author":"Chen","year":"2019","journal-title":"Neural Regen. Res."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1696","DOI":"10.1111\/j.1471-4159.2006.03692.x","article-title":"The transcription factor Yin Yang 1 is an activator of BACE1 expression","volume":"96","author":"Nowak","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_77","doi-asserted-by":"crossref","unstructured":"Chen, Z.S., Li, L., Peng, S., Chen, F.M., Zhang, Q., An, Y., Lin, X., Li, W., Koon, A.C., and Chan, T.F. (2018). Planar cell polarity gene Fuz triggers apoptosis in neurodegenerative disease models. EMBO Rep., 19.","DOI":"10.15252\/embr.201745409"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1111\/j.1474-9726.2011.00708.x","article-title":"The -980C\/G polymorphism in APH-1A promoter confers risk of Alzheimer\u2019s disease","volume":"10","author":"Qin","year":"2011","journal-title":"Aging Cell"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1016\/j.cmet.2012.09.002","article-title":"Expanding roles for SREBP in metabolism","volume":"16","author":"Shao","year":"2012","journal-title":"Cell Metab."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"180.e181","DOI":"10.1016\/j.neurobiolaging.2018.01.018","article-title":"Alterations in cholesterol metabolism-related genes in sporadic Alzheimer\u2019s disease","volume":"66","author":"Picard","year":"2018","journal-title":"Neurobiol. Aging"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1111\/bpa.12691","article-title":"The sterol regulatory element-binding protein 2 is dysregulated by tau alterations in Alzheimer disease","volume":"29","author":"Wang","year":"2019","journal-title":"Brain Pathol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"3460","DOI":"10.1093\/hmg\/ddt201","article-title":"APP\/PS1 mice overexpressing SREBP-2 exhibit combined Abeta accumulation and tau pathology underlying Alzheimer\u2019s disease","volume":"22","author":"Fernandez","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1129","DOI":"10.1080\/15548627.2018.1438807","article-title":"Cholesterol impairs autophagy-mediated clearance of amyloid beta while promoting its secretion","volume":"14","author":"Bartolessis","year":"2018","journal-title":"Autophagy"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"35","DOI":"10.3389\/fnbeh.2017.00035","article-title":"The Role of Early Growth Response 1 (EGR1) in Brain Plasticity and Neuropsychiatric Disorders","volume":"11","author":"Duclot","year":"2017","journal-title":"Front. Behav. Neurosci."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"153","DOI":"10.3389\/fnagi.2018.00153","article-title":"Integrative Analysis of Hippocampus Gene Expression Profiles Identifies Network Alterations in Aging and Alzheimer\u2019s Disease","volume":"10","author":"Lanke","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1111\/bpa.12688","article-title":"Early growth response-1 regulates acetylcholinesterase and its relation with the course of Alzheimer\u2019s disease","volume":"29","author":"Hu","year":"2019","journal-title":"Brain Pathol."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"908","DOI":"10.1093\/brain\/awv383","article-title":"MicroRNA-132 and early growth response-1 in nucleus basalis of Meynert during the course of Alzheimer\u2019s disease","volume":"139","author":"Zhu","year":"2016","journal-title":"Brain"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"2721","DOI":"10.12659\/MSM.905064","article-title":"Genome-Wide Profiling of miRNA and mRNA Expression in Alzheimer\u2019s Disease","volume":"23","author":"Chang","year":"2017","journal-title":"Med. Sci. Monit"},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"e3014","DOI":"10.1002\/jgm.3014","article-title":"MicroRNA expression data analysis to identify key miRNAs associated with Alzheimer\u2019s disease","volume":"20","author":"Chen","year":"2018","journal-title":"J. Gene Med."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1007\/s12031-018-1223-y","article-title":"Amyloid Beta 1-42 Alters the Expression of miRNAs in Cortical Neurons","volume":"67","author":"Dursun","year":"2019","journal-title":"J. Mol. Neurosci."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"24314","DOI":"10.18632\/oncotarget.15149","article-title":"MiR-124-3p attenuates hyperphosphorylation of Tau protein-induced apoptosis via caveolin-1-PI3K\/Akt\/GSK3beta pathway in N2a\/APP695swe cells","volume":"8","author":"Kang","year":"2017","journal-title":"Oncotarget"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"571","DOI":"10.3233\/JAD-181053","article-title":"Role of Post-Transcriptional Control of Calpain by miR-124-3p in the Development of Alzheimer\u2019s Disease","volume":"67","author":"Zhou","year":"2019","journal-title":"J. Alzheimers Dis."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"503","DOI":"10.1016\/j.ymthe.2019.11.017","article-title":"Increased Microglial Exosomal miR-124-3p Alleviates Neurodegeneration and Improves Cognitive Outcome after rmTBI","volume":"28","author":"Ge","year":"2020","journal-title":"Mol. Ther."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"8826","DOI":"10.1007\/s12035-018-1032-x","article-title":"MicroRNA Expression Levels Are Altered in the Cerebrospinal Fluid of Patients with Young-Onset Alzheimer\u2019s Disease","volume":"55","author":"McKeever","year":"2018","journal-title":"Mol. Neurobiol."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"110954","DOI":"10.1016\/j.exger.2020.110954","article-title":"miR-16-5p is upregulated by amyloid beta deposition in Alzheimer\u2019s disease models and induces neuronal cell apoptosis through direct targeting and suppression of BCL-2","volume":"136","author":"Kim","year":"2020","journal-title":"Exp. Gerontol."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"846","DOI":"10.3389\/fgene.2019.00846","article-title":"Candidate Genes and MiRNAs Linked to the Inverse Relationship Between Cancer and Alzheimer\u2019s Disease: Insights From Data Mining and Enrichment Analysis","volume":"10","author":"Battaglia","year":"2019","journal-title":"Front. Genet."},{"key":"ref_97","first-page":"43","article-title":"A review of bipolar disorder in adults","volume":"3","author":"Hilty","year":"2006","journal-title":"Psychiatry"},{"key":"ref_98","first-page":"75","article-title":"Inflammation and Neurodegeneration in Patients with Early-Stageand Chronic Bipolar Disorder","volume":"30","author":"Karabulut","year":"2019","journal-title":"Turk. Psikiyatri Derg."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"1214","DOI":"10.1021\/acschemneuro.8b00629","article-title":"cis pT231-Tau Drives Neurodegeneration in Bipolar Disorder","volume":"10","author":"Naserkhaki","year":"2019","journal-title":"ACS Chem. Neurosci."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/mp.2016.96","article-title":"Lithium suppression of tau induces brain iron accumulation and neurodegeneration","volume":"22","author":"Lei","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.pscychresns.2010.12.015","article-title":"Hippocampal and amygdalar volume changes in elderly patients with Alzheimer\u2019s disease and schizophrenia","volume":"192","author":"Prestia","year":"2011","journal-title":"Psychiatry Res."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1176\/appi.ajp.160.5.867","article-title":"Amyloid beta pathology in Alzheimer\u2019s disease and schizophrenia","volume":"160","author":"Religa","year":"2003","journal-title":"Am. J. Psychiatry"},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2","DOI":"10.4161\/pri.21767","article-title":"Dysregulation of neural calcium signaling in Alzheimer disease, bipolar disorder and schizophrenia","volume":"7","author":"Berridge","year":"2013","journal-title":"Prion"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1007\/s11481-012-9417-5","article-title":"Wnt signaling: Role in Alzheimer disease and schizophrenia","volume":"7","author":"Inestrosa","year":"2012","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_105","first-page":"CD012197","article-title":"Pharmacological interventions for apathy in Alzheimer\u2019s disease","volume":"5","author":"Ruthirakuhan","year":"2018","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/j.jagp.2016.11.014","article-title":"History of Bipolar Disorder and the Risk of Dementia: A Systematic Review and Meta-Analysis","volume":"25","author":"Diniz","year":"2017","journal-title":"Am. J. Geriatr. Psychiatry"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"10678","DOI":"10.1074\/jbc.M109.057836","article-title":"Histone deacetylase inhibitor valproic acid inhibits cancer cell proliferation via down-regulation of the alzheimer amyloid precursor protein","volume":"285","author":"Venkataramani","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.biopha.2018.06.080","article-title":"Valproic acid attenuates Abeta25-35-induced neurotoxicity in PC12 cells through suppression of mitochondria-mediated apoptotic pathway","volume":"106","author":"Zhao","year":"2018","journal-title":"Biomed. Pharmacother."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1007\/s12035-014-8751-4","article-title":"Valproic acid alleviates memory deficits and attenuates amyloid-beta deposition in transgenic mouse model of Alzheimer\u2019s disease","volume":"51","author":"Xuan","year":"2015","journal-title":"Mol. Neurobiol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.4103\/1673-5374.308103","article-title":"Combined treatment with valproic acid and estrogen has neuroprotective effects in ovariectomized mice with Alzheimer\u2019s disease","volume":"16","author":"Li","year":"2021","journal-title":"Neural Regen. Res."},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1212\/WNL.0b013e318230a16c","article-title":"Chronic divalproex sodium use and brain atrophy in Alzheimer disease","volume":"77","author":"Fleisher","year":"2011","journal-title":"Neurology"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1159\/000493390","article-title":"Rheumatoid Arthritis: A Brief Overview of the Treatment","volume":"27","author":"Bullock","year":"2018","journal-title":"Med. Princ. Pract."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"1111","DOI":"10.1007\/s40263-016-0374-z","article-title":"Treatment for Rheumatoid Arthritis and Risk of Alzheimer\u2019s Disease: A Nested Case-Control Analysis","volume":"30","author":"Chou","year":"2016","journal-title":"CNS Drugs"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"853","DOI":"10.3233\/JAD-160488","article-title":"Inflammation, Antiinflammatory Agents, and Alzheimer\u2019s Disease: The Last 22 Years","volume":"54","author":"McGeer","year":"2016","journal-title":"J. Alzheimers Dis."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1007\/s12272-010-1006-7","article-title":"Inflammation and Alzheimer\u2019s disease","volume":"33","author":"Lee","year":"2010","journal-title":"Arch Pharm. Res."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"6682","DOI":"10.1523\/JNEUROSCI.0054-18.2018","article-title":"Aspirin Induces Lysosomal Biogenesis and Attenuates Amyloid Plaque Pathology in a Mouse Model of Alzheimer\u2019s Disease via PPARalpha","volume":"38","author":"Chandra","year":"2018","journal-title":"J. Neurosci."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"385","DOI":"10.3233\/JAD-141506","article-title":"Anti-inflammatory drugs and risk of Alzheimer\u2019s disease: An updated systematic review and meta-analysis","volume":"44","author":"Wang","year":"2015","journal-title":"J. Alzheimers Dis."},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/nrn2212","article-title":"Retinoic acid in the development, regeneration and maintenance of the nervous system","volume":"8","author":"Maden","year":"2007","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1586\/14737175.2015.1008456","article-title":"Retinoic acid as a therapeutic option in Alzheimer\u2019s disease: A focus on cholinergic restoration","volume":"15","author":"Szutowicz","year":"2015","journal-title":"Expert Rev. Neurother."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1016\/j.taap.2018.07.015","article-title":"Risk of Alzheimer\u2019s disease with metal concentrations in whole blood and urine: A case-control study using propensity score matching","volume":"356","author":"Yang","year":"2018","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1097\/WAD.0b013e3181d71bc7","article-title":"The arsenic exposure hypothesis for Alzheimer disease","volume":"24","author":"Gong","year":"2010","journal-title":"Alzheimer Dis. Assoc. Disord."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1021\/acs.chemrestox.7b00215","article-title":"Chronic Arsenic Exposure Increases Abeta(1-42) Production and Receptor for Advanced Glycation End Products Expression in Rat Brain","volume":"31","author":"Nino","year":"2018","journal-title":"Chem. Res. Toxicol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"W234","DOI":"10.1093\/nar\/gkz240","article-title":"NetworkAnalyst 3.0: A visual analytics platform for comprehensive gene expression profiling and meta-analysis","volume":"47","author":"Zhou","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto encyclopedia of genes and genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"2502","DOI":"10.1038\/nprot.2013.150","article-title":"Target analysis by integration of transcriptome and ChIP-seq data with BETA","volume":"8","author":"Wang","year":"2013","journal-title":"Nat. Protoc."},{"key":"ref_126","first-page":"D87","article-title":"JASPAR 2020: Update of the open-access database of transcription factor binding profiles","volume":"48","author":"Fornes","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"2438","DOI":"10.1093\/bioinformatics\/btq466","article-title":"ChEA: Transcription factor regulation inferred from integrating genome-wide ChIP-X experiments","volume":"26","author":"Lachmann","year":"2010","journal-title":"Bioinformatics"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"D239","DOI":"10.1093\/nar\/gkv1258","article-title":"miRTarBase 2016: Updates to the experimentally validated miRNA-target interactions database","volume":"44","author":"Chou","year":"2016","journal-title":"Nucleic Acids Res."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"D296","DOI":"10.1093\/nar\/gkx1067","article-title":"miRTarBase update 2018: A resource for experimentally validated microRNA-target interactions","volume":"46","author":"Chou","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"D239","DOI":"10.1093\/nar\/gkx1141","article-title":"DIANA-TarBase v8: A decade-long collection of experimentally supported miRNA-gene interactions","volume":"46","author":"Karagkouni","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_131","first-page":"D845","article-title":"The DisGeNET knowledge platform for disease genomics: 2019 update","volume":"48","author":"Pinero","year":"2020","journal-title":"Nucleic Acids Res."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1289\/ehp.6028","article-title":"The Comparative Toxicogenomics Database (CTD)","volume":"111","author":"Mattingly","year":"2003","journal-title":"Environ. Health Perspect."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/3915\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:26:43Z","timestamp":1760362003000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/8\/3915"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,10]]},"references-count":132,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2021,4]]}},"alternative-id":["ijms22083915"],"URL":"https:\/\/doi.org\/10.3390\/ijms22083915","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,10]]}}}