{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:40:10Z","timestamp":1787067610700,"version":"build-2736575974"},"reference-count":75,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,4]],"date-time":"2022-01-04T00:00:00Z","timestamp":1641254400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is the most common form of dementia globally; however, the aetiology of AD remains elusive hindering the development of effective therapeutics. MicroRNAs (miRNAs) are regulators of gene expression and have been of growing interest in recent studies in many pathologies including AD not only for their use as biomarkers but also for their implications in the therapeutic field. In this study, miRNA and protein profiles were obtained from brain tissues of different stage (Braak III-IV and Braak V-VI) of AD patients and compared to matched controls. The aim of the study was to identify in the late stage of AD, the key dysregulated pathways that may contribute to pathogenesis and then to evaluate whether any of these pathways could be detected in the early phase of AD, opening new opportunity for early treatment that could stop or delay the pathology. Six common pathways were found regulated by miRNAs and proteins in the late stage of AD, with one of them (Rap1 signalling) activated since the early phase. MiRNAs and proteins were also compared to explore an inverse trend of expression which could lead to the identification of new therapeutic targets. These results suggest that specific miRNA changes could represent molecular fingerprint of neurodegenerative processes and potential therapeutic targets for early intervention.<\/jats:p>","DOI":"10.3390\/cells11010163","type":"journal-article","created":{"date-parts":[[2022,1,5]],"date-time":"2022-01-05T20:42:16Z","timestamp":1641415336000},"page":"163","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Co-Expression Analysis of microRNAs and Proteins in Brain of Alzheimer\u2019s Disease Patients"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2511-5501","authenticated-orcid":false,"given":"Callum N.","family":"Watson","sequence":"first","affiliation":[{"name":"Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ghazala","family":"Begum","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Ashman","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniella","family":"Thorn","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7697-2453","authenticated-orcid":false,"given":"Kamal M.","family":"Yakoub","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK"},{"name":"Surgical Reconstruction and Microbiology Research Centre, National Institute for Health Research, Queen Elizabeth Hospital, Birmingham B15 2TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moustafa Al","family":"Hariri","sequence":"additional","affiliation":[{"name":"Department of Emergency Medicine, American University of Beirut Medical Center, Beirut 1107 2020, Lebanon"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5254-848X","authenticated-orcid":false,"given":"Ali","family":"Nehme","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8587-3614","authenticated-orcid":false,"given":"Stefania","family":"Mondello","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, 98165 Messina, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5008-6944","authenticated-orcid":false,"given":"Firas","family":"Kobeissy","sequence":"additional","affiliation":[{"name":"Program for Neurotrauma, Neuroproteomics & Biomarkers Research, Departments of Emergency Medicine, Psychiatry, Neuroscience and Chemistry, University of Florida, Gainesville, FL 32611, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Belli","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK"},{"name":"Surgical Reconstruction and Microbiology Research Centre, National Institute for Health Research, Queen Elizabeth Hospital, Birmingham B15 2TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9430-4723","authenticated-orcid":false,"given":"Valentina","family":"Di Pietro","sequence":"additional","affiliation":[{"name":"Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK"},{"name":"Surgical Reconstruction and Microbiology Research Centre, National Institute for Health Research, Queen Elizabeth Hospital, Birmingham B15 2TH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,4]]},"reference":[{"key":"ref_1","unstructured":"(2021, April 18). Dementia. Available online: https:\/\/www.who.int\/news-room\/fact-sheets\/detail\/dementia."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/S1474-4422(18)30403-4","article-title":"Global, Regional, and National Burden of Alzheimer\u2019s Disease and Other Dementias, 1990\u20132016: A Systematic Analysis for the Global Burden of Disease Study 2016","volume":"18","author":"Nichols","year":"2019","journal-title":"Lancet Neurol."},{"key":"ref_3","unstructured":"(2021, April 18). Worldwide Dementia Cases to Triple by 2050. Available online: https:\/\/www.alzheimersresearchuk.org\/worldwide-dementia-cases-to-triple-by-2050."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.neuron.2009.06.026","article-title":"The Role of Apolipoprotein E in Alzheimer\u2019s disease","volume":"63","author":"Kim","year":"2009","journal-title":"Neuron"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1177\/0891988710383571","article-title":"Review Article: Genetics of Alzheimer Disease","volume":"23","author":"Bekris","year":"2010","journal-title":"J. Geriatr. Psychiatry Neurol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1111\/ene.13439","article-title":"Alzheimer\u2019s Disease","volume":"25","author":"Lane","year":"2017","journal-title":"Eur. J. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.jalz.2011.03.005","article-title":"The Diagnosis of Dementia due to Alzheimer\u2019s Disease: Recommendations from the National Institute on Aging-Alzheimer\u2019s Association Workgroups on Diagnostic Guidelines for Alzheimer\u2019s Disease","volume":"7","author":"McKhann","year":"2011","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/BF00308809","article-title":"Neuropathological Stageing of Alzheimer-Related Changes","volume":"82","author":"Braak","year":"1991","journal-title":"Acta Neuropathol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1001\/jama.2021.11558","article-title":"Recently Approved Alzheimer Drug Raises Questions That Might Never Be Answered","volume":"326","author":"Rubin","year":"2021","journal-title":"JAMA"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"962","DOI":"10.1016\/j.jconrel.2013.09.015","article-title":"Progress in MicroRNA Delivery","volume":"172","author":"Zhang","year":"2013","journal-title":"J. Control. Release"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/mt.2012.180","article-title":"Systemically Injected Exosomes Targeted to EGFR Deliver Antitumor MicroRNA to Breast Cancer Cells","volume":"21","author":"Ohno","year":"2013","journal-title":"Mol. Ther."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"690","DOI":"10.1016\/j.jconrel.2013.09.027","article-title":"Enhanced Hepatic Delivery of SiRNA and MicroRNA Using Oleic Acid Based Lipid Nanoparticle Formulations","volume":"172","author":"Wang","year":"2013","journal-title":"J. Control. Release"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"2294","DOI":"10.1093\/nar\/gkl183","article-title":"Improved Targeting of MiRNA with Antisense Oligonucleotides","volume":"34","author":"Davis","year":"2006","journal-title":"Nucleic Acids Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1089\/hgtb.2017.036","article-title":"Improving MiRNA Delivery by Optimizing MiRNA Expression Cassettes in Diverse Virus Vectors","volume":"28","author":"Liu","year":"2017","journal-title":"Hum. Gene Ther. Methods"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1901081","DOI":"10.1002\/adma.201901081","article-title":"Cancer-Targeting Nanoparticles for Combinatorial Nucleic Acid Delivery","volume":"32","author":"Vaughan","year":"2019","journal-title":"Adv. Mater."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1038\/nrd1632","article-title":"Recent Advances with Liposomes as Pharmaceutical Carriers","volume":"4","author":"Torchilin","year":"2005","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1277","DOI":"10.1021\/mp900033j","article-title":"Engineered Nanoscaled Polyplex Gene Delivery Systems","volume":"6","author":"Fernandez","year":"2009","journal-title":"Mol. Pharm."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"15524","DOI":"10.1073\/pnas.242606799","article-title":"Nonlinear Partial Differential Equations and Applications: Frequent Deletions and Down-Regulation of Micro- RNA Genes MiR15 and MiR16 at 13q14 in Chronic Lymphocytic Leukemia","volume":"99","author":"Calin","year":"2002","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1016\/j.neurobiolaging.2010.04.034","article-title":"MicroRNA-16 Targets Amyloid Precursor Protein to Potentially Modulate Alzheimer\u2019s-Associated Pathogenesis in SAMP8 Mice","volume":"33","author":"Liu","year":"2012","journal-title":"Neurobiol. Aging."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"37","DOI":"10.3389\/fncel.2014.00037","article-title":"A Lentiviral Sponge for MiR-101 Regulates RanBP9 Expression and Amyloid Precursor Protein Metabolism in Hippocampal Neurons","volume":"8","author":"Barbato","year":"2014","journal-title":"Front. Cell. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.molcel.2007.07.015","article-title":"The MicroRNA MiR-124 Promotes Neuronal Differentiation by Triggering Brain-Specific Alternative Pre-MRNA Splicing","volume":"27","author":"Makeyev","year":"2007","journal-title":"Mol. Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6415","DOI":"10.1073\/pnas.0710263105","article-title":"Loss of MicroRNA Cluster MiR-29a\/B-1 in Sporadic Alzheimer\u2019s Disease Correlates with Increased BACE1\/ -Secretase Expression","volume":"105","author":"Hebert","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3081","DOI":"10.3892\/mmr.2015.3728","article-title":"MicroRNA-29c Targets \u03b2-Site Amyloid Precursor Protein-Cleaving Enzyme 1 and Has a Neuroprotective Role in Vitro and in Vivo","volume":"12","author":"Yang","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"14919","DOI":"10.1523\/JNEUROSCI.1165-14.2014","article-title":"Synaptic and Cognitive Improvements by Inhibition of 2-AG Metabolism Are through Upregulation of MicroRNA-188-3p in a Mouse Model of Alzheimer\u2019s Disease","volume":"34","author":"Zhang","year":"2014","journal-title":"J. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5184","DOI":"10.1074\/jbc.M113.518241","article-title":"MicroRNA-339-5p Down-Regulates Protein Expression of \u03b2-Site Amyloid Precursor Protein-Cleaving Enzyme 1 (BACE1) in Human Primary Brain Cultures and Is Reduced in Brain Tissue Specimens of Alzheimer Disease Subjects","volume":"289","author":"Long","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"3989","DOI":"10.1523\/JNEUROSCI.1997-12.2013","article-title":"MicroRNA-195 Protects against Dementia Induced by Chronic Brain Hypoperfusion via Its Anti-Amyloidogenic Effect in Rats","volume":"33","author":"Ai","year":"2013","journal-title":"J. Neurosci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"436","DOI":"10.1111\/jnc.13507","article-title":"MiR-186 Is Decreased in Aged Brain and Suppresses BACE1 Expression","volume":"137","author":"Kim","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1016\/j.toxlet.2011.11.032","article-title":"The MiR-124 Regulates the Expression of BACE1\/\u03b2-Secretase Correlated with Cell Death in Alzheimer\u2019s Disease","volume":"209","author":"Fang","year":"2012","journal-title":"Toxicol. Lett."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"6721","DOI":"10.1093\/hmg\/ddv377","article-title":"MiR-132\/212 Deficiency Impairs Tau Metabolism and Promotes Pathological Aggregationin Vivo","volume":"24","author":"Smith","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"759","DOI":"10.1177\/0300985813502820","article-title":"MicroRNAs","volume":"51","author":"Bhaskaran","year":"2013","journal-title":"Vet. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"160","DOI":"10.3389\/fnmol.2020.00160","article-title":"MicroRNAs in Alzheimer\u2019s Disease: Function and potential application as diagnostics biomarkers","volume":"13","author":"Wei","year":"2020","journal-title":"Font. Mol. Neuorsci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1186\/s13195-021-00862-z","article-title":"Prediction of differentially expressed microRNAs in blood as potential biomarkers for Alzheimer\u2019s disease by meta-analysis and adaptive boosting ensemble learning","volume":"13","author":"Yuen","year":"2021","journal-title":"Alzheimers Res. Ther."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"8191","DOI":"10.1007\/s12035-016-0316-2","article-title":"A Customized Quantitative PCR MicroRNA Panel Provides a Technically Robust Context for Studying Neurodegenerative Disease Biomarkers and Indicates a High Correlation between Cerebrospinal Fluid and Choroid Plexus MicroRNA Expression","volume":"54","author":"Wang","year":"2016","journal-title":"Mol. Neurobiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"399","DOI":"10.3389\/fncel.2019.00399","article-title":"Upregulated Expression of MicroRNA-204-5p Leads to the Death of Dopaminergic Cells by Targeting DYRK1A-Mediated Apoptotic Signaling Cascade","volume":"13","author":"Chiu","year":"2019","journal-title":"Front. Cell. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.ceb.2005.02.009","article-title":"Linking Rap to Cell Adhesion","volume":"17","author":"Bos","year":"2005","journal-title":"Curr. Opin. Cell Biol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1146\/annurev-cellbio-100109-104104","article-title":"Regulation of Integrin Activation","volume":"27","author":"Kim","year":"2011","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13024-018-0283-3","article-title":"Modifying Rap1-Signalling by Targeting Pde6\u03b4 Is Neuroprotective in Models of Alzheimer\u2019s Disease","volume":"13","author":"Dumbacher","year":"2018","journal-title":"Mol. Neurodegener."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"4195","DOI":"10.1242\/jcs.023820","article-title":"The Extracellular Matrix at a Glance","volume":"123","author":"Frantz","year":"2010","journal-title":"J. Cell Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1223","DOI":"10.1007\/s00018-008-8561-9","article-title":"Collagens in the Developing and Diseased Nervous System","volume":"66","author":"Hubert","year":"2008","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_40","first-page":"a005108","article-title":"Extracellular Matrix: Functions in the Nervous System","volume":"3","author":"Barros","year":"2010","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1946","DOI":"10.1016\/j.biotechadv.2018.08.002","article-title":"Neural Stem Cell Differentiation into Mature Neurons: Mechanisms of Regulation and Biotechnological Applications","volume":"36","author":"Vieira","year":"2018","journal-title":"Biotechnol. Adv."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1016\/j.brainresbull.2017.03.003","article-title":"Crosstalk between Glia, Extracellular Matrix and Neurons","volume":"136","author":"Song","year":"2018","journal-title":"Brain Res. Bull."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1038\/s41583-019-0196-3","article-title":"The Roles of Perineuronal Nets and the Perinodal Extracellular Matrix in Neuronal Function","volume":"20","author":"Fawcett","year":"2019","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.pneurobio.2018.02.002","article-title":"Cell Adhesion and Matricellular Support by Astrocytes of the Tripartite Synapse","volume":"165-167","author":"Hillen","year":"2018","journal-title":"Prog. Neurobiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"673","DOI":"10.1002\/jnr.490300411","article-title":"Association between Vascular Basement Membrane Components and the Lesions of Alzheimer\u2019s Disease","volume":"30","author":"Perlmutter","year":"1991","journal-title":"J. Neurosci. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s12974-020-1723-x","article-title":"Frontal Cortex Chitinase and Pentraxin Neuroinflammatory Alterations during the Progression of Alzheimer\u2019s Disease","volume":"17","author":"Perez","year":"2020","journal-title":"J. Neuroinflam."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.pharmthera.2011.12.008","article-title":"Integrins as Receptor Targets for Neurological Disorders","volume":"134","author":"Wu","year":"2012","journal-title":"Pharmacol. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1038\/nrn1115","article-title":"Extracellular Matrix Molecules and Synaptic Plasticity","volume":"4","author":"Dityatev","year":"2003","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1038\/nrn2898","article-title":"The Dual Role of the Extracellular Matrix in Synaptic Plasticity and Homeostasis","volume":"11","author":"Dityatev","year":"2010","journal-title":"Nat. Rev. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Gall, C.M., and Lynch, G. (2004). Integrins, Synaptic Plasticity and Epileptogenesis. Adv. Exp. Med. Biol., 12\u201333.","DOI":"10.1007\/978-1-4757-6376-8_2"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"925","DOI":"10.1016\/S0306-4522(02)00990-9","article-title":"Integrins Regulate Neuronal Neurotrophin Gene Expression through Effects on Voltage-Sensitive Calcium Channels","volume":"118","author":"Gall","year":"2003","journal-title":"Neuroscience"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"e22264","DOI":"10.7554\/eLife.22264","article-title":"The Fibronectin Synergy Site Re-Enforces Cell Adhesion and Mediates a Crosstalk between Integrin Classes","volume":"6","author":"Klapproth","year":"2017","journal-title":"eLife"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1146\/annurev-cellbio-100109-104020","article-title":"Assembly of Fibronectin Extracellular Matrix","volume":"26","author":"Singh","year":"2010","journal-title":"Annu. Rev. Cell Dev. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"7104","DOI":"10.1074\/jbc.270.13.7104","article-title":"Extracellular Matrix Influences the Biogenesis of Amyloid Precursor Protein in Microglial Cells","volume":"270","author":"Banati","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1007\/s00401-011-0801-7","article-title":"Perivascular Drainage of Solutes Is Impaired in the Ageing Mouse Brain and in the Presence of Cerebral Amyloid Angiopathy","volume":"121","author":"Hawkes","year":"2011","journal-title":"Acta Neuropathol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1385\/1-59259-671-1:315","article-title":"MAPK Cascades in the Brain: Lessons from Learning","volume":"Volume 205","author":"Berman","year":"2004","journal-title":"MAP Kinase Signaling Protocols"},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Lee, J.K., and Kim, N.-J. (2017). Recent Advances in the Inhibition of P38 MAPK as a Potential Strategy for the Treatment of Alzheimer\u2019s Disease. Mol. A J. Synth. Chem. Nat. Prod. Chem., 22.","DOI":"10.3390\/molecules22081287"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.expneurol.2018.08.007","article-title":"Dephosphorylated rather than Hyperphosphorylated Tau Triggers a Pro-Inflammatory Profile in Microglia through the P38 MAPK Pathway","volume":"310","author":"Perea","year":"2018","journal-title":"Exp. Neurol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.redox.2014.03.002","article-title":"A\u03b2 and Tau Toxicities in Alzheimer\u2019s are Linked via Oxidative Stress-Induced P38 Activation: Protective Role of Vitamin E","volume":"2","author":"Giraldo","year":"2014","journal-title":"Redox Biol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s13195-020-00617-2","article-title":"A Selective P38\u03b1\/\u03b2 MAPK Inhibitor Alleviates Neuropathology and Cognitive Impairment, and Modulates Microglia Function in 5XFAD Mouse","volume":"12","author":"Gee","year":"2020","journal-title":"Alzheimer\u2019s Res. Ther."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"241","DOI":"10.15761\/JTS.1000146","article-title":"Forkhead Transcription Factors: New Considerations for Alzheimer\u2019s Disease and Dementia","volume":"2","author":"Maiese","year":"2016","journal-title":"J. Transl. Sci."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"223","DOI":"10.2174\/156720209789630302","article-title":"FoxO3a Governs Early Microglial Proliferation and Employs Mitochondrial Depolarization with Caspase 3, 8, and 9 Cleavage during Oxidant Induced Apoptosis","volume":"6","author":"Shang","year":"2009","journal-title":"Curr. Neurovasc. Res."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"e1233","DOI":"10.1038\/cddis.2014.196","article-title":"FoxO Mediates APP-Induced AICD-Dependent Cell Death","volume":"5","author":"Wang","year":"2014","journal-title":"Cell Death Dis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1242\/jcs.185009","article-title":"Cdk5-FOXO3a Axis: Initially Neuroprotective, Eventually Neurodegenerative in Alzheimer\u2019s Disease Models","volume":"129","author":"Shi","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0959-4388(00)00211-7","article-title":"Transcription-Dependent and -Independent Control of Neuronal Survival by the PI3K\u2013Akt Signaling Pathway","volume":"11","author":"Brunet","year":"2001","journal-title":"Curr. Opin. Neurobiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"3375","DOI":"10.1111\/j.1460-9568.2006.04859.x","article-title":"Signalling Mechanisms Mediated by the Phosphoinositide 3-Kinase\/Akt Cascade in Synaptic Plasticity and Memory in the Rat","volume":"23","author":"Horwood","year":"2006","journal-title":"Eur. J. Neurosci."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"7060","DOI":"10.1073\/pnas.0909314107","article-title":"PI3 Kinase Signaling Is Involved in a -Induced Memory Loss in Drosophila","volume":"107","author":"Chiang","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","first-page":"29","article-title":"A Neuroprotective Function for the Hematopoietic Protein Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF)","volume":"28","author":"Pitzer","year":"2007","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1091\/mbc.e08-07-0777","article-title":"The Insulin\/Akt Signaling Pathway Is Targeted by Intracellular \u03b2-Amyloid","volume":"20","author":"Lee","year":"2009","journal-title":"Mol. Biol. Cell."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"16743","DOI":"10.1073\/pnas.1208011109","article-title":"Epidermal Growth Factor Receptor Is a Preferred Target for Treating Amyloid-\u03b2-Induced Memory Loss","volume":"109","author":"Wang","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_71","first-page":"E3129","article-title":"ErbB2 Regulates Autophagic Flux to Modulate the Proteostasis of APP-CTFs in Alzheimer\u2019s Disease","volume":"114","author":"Wang","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"549","DOI":"10.1097\/00005072-198809000-00006","article-title":"Immunoreactive Epidermal Growth Factor Receptors in Neuritic Plaques from Patients with Alzheimer\u2019s Disease","volume":"47","author":"Birecree","year":"1988","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"7709","DOI":"10.1016\/S0021-9258(19)38983-5","article-title":"Epidermal Growth Factor","volume":"265","author":"Carpenter","year":"1990","journal-title":"J. Biol. Chem."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"3077","DOI":"10.1158\/0008-5472.CAN-14-3380","article-title":"EGF Receptor Promotes Prostate Cancer Bone Metastasis by Downregulating MiR-1 and Activating TWIST1","volume":"75","author":"Chang","year":"2015","journal-title":"Cancer Res."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"ENEURO.0149-16.2017","DOI":"10.1523\/ENEURO.0149-16.2017","article-title":"Activation of Ras-ERK Signaling and GSK-3 by Amyloid Precursor Protein and Amyloid Beta Facilitates Neurodegeneration in Alzheimer\u2019s Disease","volume":"4","author":"Kirouac","year":"2017","journal-title":"eNeuro"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/1\/163\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:36:10Z","timestamp":1760362570000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/1\/163"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,4]]},"references-count":75,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["cells11010163"],"URL":"https:\/\/doi.org\/10.3390\/cells11010163","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,4]]}}}