{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T21:42:49Z","timestamp":1788385369474,"version":"build-2803163510"},"reference-count":135,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T00:00:00Z","timestamp":1610582400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2020R1A2B5B02002032"],"award-info":[{"award-number":["NRF-2020R1A2B5B02002032"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Microglia are brain-dwelling macrophages and major parts of the neuroimmune system that broadly contribute to brain development, homeostasis, ageing and injury repair in the central nervous system (CNS). Apart from other brain macrophages, they have the ability to constantly sense changes in the brain\u2019s microenvironment, functioning as housekeepers for neuronal well-being and providing neuroprotection in normal physiology. Microglia use a set of genes for these functions that involve proinflammatory cytokines. In response to specific stimuli, they release these proinflammatory cytokines, which can damage and kill neurons via neuroinflammation. However, alterations in microglial functioning are a common pathophysiology in age-related neurodegenerative diseases, such as Alzheimer\u2019s, Parkinson\u2019s, Huntington\u2019s and prion diseases, as well as amyotrophic lateral sclerosis, frontotemporal dementia and chronic traumatic encephalopathy. When their sentinel or housekeeping functions are severely disrupted, they aggravate neuropathological conditions by overstimulating their defensive function and through neuroinflammation. Several pathways are involved in microglial functioning, including the Trem2, Cx3cr1 and progranulin pathways, which keep the microglial inflammatory response under control and promote clearance of injurious stimuli. Over time, an imbalance in this system leads to protective microglia becoming detrimental, initiating or exacerbating neurodegeneration. Correcting such imbalances might be a potential mode of therapeutic intervention in neurodegenerative diseases.<\/jats:p>","DOI":"10.3390\/cells10010150","type":"journal-article","created":{"date-parts":[[2021,1,14]],"date-time":"2021-01-14T11:39:14Z","timestamp":1610624354000},"page":"150","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Microglial Turnover in Ageing-Related Neurodegeneration: Therapeutic Avenue to Intervene in Disease Progression"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4707-3488","authenticated-orcid":false,"given":"Shofiul","family":"Azam","sequence":"first","affiliation":[{"name":"Department of Applied Life Science &amp; Integrated Bioscience, Graduate School, BK21 Program, Konkuk University, Chungju 27478, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5625-3547","authenticated-orcid":false,"given":"Md. Ezazul","family":"Haque","sequence":"additional","affiliation":[{"name":"Department of Applied Life Science &amp; Integrated Bioscience, Graduate School, BK21 Program, Konkuk University, Chungju 27478, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"In-Su","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Integrated Bioscience &amp; Biotechnology, College of Biomedical and Health Science, Research Institute of Inflammatory Disease (RID), Konkuk University, Chungju 27478, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7041-1524","authenticated-orcid":false,"given":"Dong-Kug","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Applied Life Science &amp; Integrated Bioscience, Graduate School, BK21 Program, Konkuk University, Chungju 27478, Korea"},{"name":"Department of Integrated Bioscience &amp; Biotechnology, College of Biomedical and Health Science, Research Institute of Inflammatory Disease (RID), Konkuk University, Chungju 27478, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,1,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.immuni.2016.02.013","article-title":"Microglial Physiology and Pathophysiology: Insights from Genome-wide Transcriptional Profiling","volume":"44","author":"Crotti","year":"2016","journal-title":"Immunity"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1126\/science.1194637","article-title":"Fate mapping analysis reveals that adult microglia derive from primitive macrophages","volume":"330","author":"Ginhoux","year":"2010","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"382","DOI":"10.1016\/j.immuni.2015.07.016","article-title":"Most Tissue-Resident Macrophages Except Microglia Are Derived from Fetal Hematopoietic Stem Cells","volume":"43","author":"Sheng","year":"2015","journal-title":"Immunity"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"792","DOI":"10.1016\/j.immuni.2013.04.004","article-title":"Tissue-resident macrophages self-maintain locally throughout adult life with minimal contribution from circulating monocytes","volume":"38","author":"Hashimoto","year":"2013","journal-title":"Immunity"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1016\/j.neurobiolaging.2007.04.013","article-title":"Neocortical glial cell numbers in human brains","volume":"29","author":"Pelvig","year":"2008","journal-title":"Neurobiol. Aging"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1111\/acel.12149","article-title":"Homeostatic and injury-induced microglia behavior in the aging brain","volume":"13","author":"Hefendehl","year":"2014","journal-title":"Aging Cell"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1146\/annurev-immunol-051116-052358","article-title":"Microglia Function in the Central Nervous System during Health and Neurodegeneration","volume":"35","author":"Colonna","year":"2017","journal-title":"Annu. Rev. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1359","DOI":"10.1038\/s41593-018-0242-x","article-title":"Microglia in neurodegeneration","volume":"21","author":"Hickman","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1523\/JNEUROSCI.4440-12.2013","article-title":"Regulation of microglial proliferation during chronic neurodegeneration","volume":"33","author":"Fransen","year":"2013","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1371","DOI":"10.1038\/nn.4631","article-title":"Microglia turnover with aging and in an Alzheimer\u2019s model via long-term in vivo single-cell imaging","volume":"20","author":"Hefendehl","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1016\/0306-4522(92)90500-2","article-title":"Turnover of resident microglia in the normal adult mouse brain","volume":"48","author":"Lawson","year":"1992","journal-title":"Neuroscience"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.celrep.2016.12.041","article-title":"Coupled Proliferation and Apoptosis Maintain the Rapid Turnover of Microglia in the Adult Brain","volume":"18","author":"Askew","year":"2017","journal-title":"Cell Rep."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1038\/nn.4547","article-title":"A new fate mapping system reveals context-dependent random or clonal expansion of microglia","volume":"20","author":"Tay","year":"2017","journal-title":"Nat. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1126\/science.288.5467.771a","article-title":"New neurons: Extraordinary evidence or extraordinary conclusion?","volume":"288","author":"Nowakowski","year":"2000","journal-title":"Science"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1016\/S0079-6123(02)38067-1","article-title":"Neurogenesis in adult primates","volume":"138","author":"Rakic","year":"2002","journal-title":"Prog. Brain Res."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1038\/nrneurol.2014.187","article-title":"Maternal immune activation and abnormal brain development across CNS disorders","volume":"10","author":"Knuesel","year":"2014","journal-title":"Nat. Rev. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"217","DOI":"10.1038\/nrneurol.2014.38","article-title":"Microglial priming in neurodegenerative disease","volume":"10","author":"Perry","year":"2014","journal-title":"Nat. Rev. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1186\/s40478-014-0142-6","article-title":"Microglial pathology","volume":"2","author":"Streit","year":"2014","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1016\/0306-4522(90)90229-W","article-title":"Heterogeneity in the distribution and morphology of microglia in the normal adult mouse brain","volume":"39","author":"Lawson","year":"1990","journal-title":"Neuroscience"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1369","DOI":"10.1038\/nm1210-1369","article-title":"Neurodegeneration and the neuroimmune system","volume":"16","year":"2010","journal-title":"Nat. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"a020560","DOI":"10.1101\/cshperspect.a020560","article-title":"Microglia in Health and Disease","volume":"8","author":"Ransohoff","year":"2015","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/nn.3318","article-title":"Microglia emerge from erythromyeloid precursors via Pu.1- and Irf8-dependent pathways","volume":"16","author":"Kierdorf","year":"2013","journal-title":"Nat. Neurosci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1038\/ni.2360","article-title":"IL-34 is a tissue-restricted ligand of CSF1R required for the development of Langerhans cells and microglia","volume":"13","author":"Wang","year":"2012","journal-title":"Nat. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1896","DOI":"10.1038\/nn.3554","article-title":"The microglial sensome revealed by direct RNA sequencing","volume":"16","author":"Hickman","year":"2013","journal-title":"Nat. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1512","DOI":"10.1038\/nn1805","article-title":"The P2Y12 receptor regulates microglial activation by extracellular nucleotides","volume":"9","author":"Haynes","year":"2006","journal-title":"Nat. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1038\/nature17630","article-title":"TAM receptors regulate multiple features of microglial physiology","volume":"532","author":"Fourgeaud","year":"2016","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1038\/nature18283","article-title":"A complement-microglial axis drives synapse loss during virus-induced memory impairment","volume":"534","author":"Vasek","year":"2016","journal-title":"Nature"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1016\/j.cell.2016.04.001","article-title":"Progranulin Deficiency Promotes Circuit-Specific Synaptic Pruning by Microglia via Complement Activation","volume":"165","author":"Lui","year":"2016","journal-title":"Cell"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nn.2511","article-title":"Microglial Cx3cr1 knockout prevents neuron loss in a mouse model of Alzheimer\u2019s disease","volume":"13","author":"Fuhrmann","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"566","DOI":"10.1016\/j.immuni.2017.08.008","article-title":"The TREM2-APOE Pathway Drives the Transcriptional Phenotype of Dysfunctional Microglia in Neurodegenerative Diseases","volume":"47","author":"Krasemann","year":"2017","journal-title":"Immunity"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"3375","DOI":"10.4049\/jimmunol.1502562","article-title":"MerTK Is a Functional Regulator of Myelin Phagocytosis by Human Myeloid Cells","volume":"196","author":"Healy","year":"2016","journal-title":"J. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.cell.2020.06.026","article-title":"Microglia Require CD4 T Cells to Complete the Fetal-to-Adult Transition","volume":"182","author":"Pasciuto","year":"2020","journal-title":"Cell"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1657","DOI":"10.1084\/jem.20021546","article-title":"CD36 mediates the innate host response to beta-amyloid","volume":"197","author":"Moore","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"8354","DOI":"10.1523\/JNEUROSCI.0616-08.2008","article-title":"Microglial dysfunction and defective beta-amyloid clearance pathways in aging Alzheimer\u2019s disease mice","volume":"28","author":"Hickman","year":"2008","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"432","DOI":"10.1038\/nm1555","article-title":"Ccr2 deficiency impairs microglial accumulation and accelerates progression of Alzheimer-like disease","volume":"13","author":"Toft","year":"2007","journal-title":"Nat. Med."},{"key":"ref_36","first-page":"1327","article-title":"Age-related total gray matter and white matter changes in normal adult brain. Part I: Volumetric MR imaging analysis","volume":"23","author":"Ge","year":"2002","journal-title":"Ajnr. Am. J. Neuroradiol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1038\/nn1008","article-title":"Mapping cortical change across the human life span","volume":"6","author":"Sowell","year":"2003","journal-title":"Nat. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"721","DOI":"10.1093\/cercor\/bhh032","article-title":"Thinning of the cerebral cortex in aging","volume":"14","author":"Salat","year":"2004","journal-title":"Cerebral Cortex"},{"key":"ref_39","first-page":"124","article-title":"Microglial cell dysregulation in brain aging and neurodegeneration","volume":"7","year":"2015","journal-title":"Front. Aging Neurosci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1111\/j.1474-9726.2007.00294.x","article-title":"Oxidative stress and aberrant signaling in aging and cognitive decline","volume":"6","author":"Schipper","year":"2007","journal-title":"Aging Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1065","DOI":"10.1038\/nature07216","article-title":"Puzzles, promises and a cure for ageing","volume":"454","author":"Vijg","year":"2008","journal-title":"Nature"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.expneurol.2015.08.001","article-title":"Age decreases macrophage IL-10 expression: Implications for functional recovery and tissue repair in spinal cord injury","volume":"273","author":"Zhang","year":"2015","journal-title":"Exp. Neurol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1287","DOI":"10.1023\/B:NERE.0000023615.89699.63","article-title":"Gene expression profiling in fetal, aged, and Alzheimer hippocampus: A continuum of stress-related signaling","volume":"29","author":"Lukiw","year":"2004","journal-title":"Neurochem. Res."},{"key":"ref_44","first-page":"1329","article-title":"Exaggerated neuroinflammation and sickness behavior in aged mice following activation of the peripheral innate immune system","volume":"19","author":"Godbout","year":"2005","journal-title":"Faseb J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1016\/j.redox.2016.10.015","article-title":"Macroautophagy is impaired in old murine brain tissue as well as in senescent human fibroblasts","volume":"10","author":"Ott","year":"2016","journal-title":"Redox Biol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Plaza-Zabala, A., Sierra-Torre, V., and Sierra, A. (2017). Autophagy and Microglia: Novel Partners in Neurodegeneration and Aging. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18030598"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1038\/nature04724","article-title":"Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice","volume":"441","author":"Hara","year":"2006","journal-title":"Nature"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"880","DOI":"10.1038\/nature04723","article-title":"Loss of autophagy in the central nervous system causes neurodegeneration in mice","volume":"441","author":"Komatsu","year":"2006","journal-title":"Nature"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1386","DOI":"10.1038\/s41467-020-15119-w","article-title":"Microglia clear neuron-released \u03b1-synuclein via selective autophagy and prevent neurodegeneration","volume":"11","author":"Choi","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s40478-015-0203-5","article-title":"Induction of a common microglia gene expression signature by aging and neurodegenerative conditions: A co-expression meta-analysis","volume":"3","author":"Holtman","year":"2015","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"22","DOI":"10.3389\/fncel.2013.00022","article-title":"Microglial aging in the healthy CNS: Phenotypes, drivers, and rejuvenation","volume":"7","author":"Wong","year":"2013","journal-title":"Front. Cell. Neurosci."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1007\/s00401-009-0556-6","article-title":"Dystrophic (senescent) rather than activated microglial cells are associated with tau pathology and likely precede neurodegeneration in Alzheimer\u2019s disease","volume":"118","author":"Streit","year":"2009","journal-title":"Acta Neuropathol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1002\/glia.10319","article-title":"Dystrophic microglia in the aging human brain","volume":"45","author":"Streit","year":"2004","journal-title":"Glia"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1002\/glia.22966","article-title":"Dark microglia: A new phenotype predominantly associated with pathological states","volume":"64","author":"Bisht","year":"2016","journal-title":"Glia"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Koellhoffer, E.C., McCullough, L.D., and Ritzel, R.M. (2017). Old Maids: Aging and Its Impact on Microglia Function. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18040769"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbr.2009.02.001","article-title":"Microglia-aging: Roles of microglial lysosome- and mitochondria-derived reactive oxygen species in brain aging","volume":"201","author":"Nakanishi","year":"2009","journal-title":"Behav. Brain Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1269","DOI":"10.1097\/00005072-199712000-00001","article-title":"Aging-associated changes in human brain","volume":"56","author":"Mrak","year":"1997","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_58","first-page":"re1","article-title":"Lipofuscin and aging: A matter of toxic waste","volume":"2005","author":"Gray","year":"2005","journal-title":"Sci. Aging Knowl. Environ. Sage Ke"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"311","DOI":"10.2353\/ajpath.2010.090915","article-title":"Accelerated lipofuscinosis and ubiquitination in granulin knockout mice suggest a role for progranulin in successful aging","volume":"177","author":"Ahmed","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"2443.e9","DOI":"10.1016\/j.neurobiolaging.2015.04.008","article-title":"Microglia recapitulate a hematopoietic master regulator network in the aging human frontal cortex","volume":"36","author":"Wehrspaun","year":"2015","journal-title":"Neurobiol. Aging"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"595","DOI":"10.15252\/emmm.201606210","article-title":"The amyloid hypothesis of Alzheimer\u2019s disease at 25 years","volume":"8","author":"Selkoe","year":"2016","journal-title":"Embo Mol. Med."},{"key":"ref_62","first-page":"307","article-title":"Microglial response to amyloid plaques in APPsw transgenic mice","volume":"152","author":"Frautschy","year":"1998","journal-title":"Am. J. Pathol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1056\/NEJMoa1211103","article-title":"Variant of TREM2 associated with the risk of Alzheimer\u2019s disease","volume":"368","author":"Jonsson","year":"2013","journal-title":"New Engl. J. Med."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1038\/ng.2802","article-title":"Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer\u2019s disease","volume":"45","author":"Lambert","year":"2013","journal-title":"Nat. Genet."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"245","DOI":"10.4062\/biomolther.2012.20.3.245","article-title":"Mechanisms of Amyloid-\u03b2 Peptide Clearance: Potential Therapeutic Targets for Alzheimer\u2019s Disease","volume":"20","author":"Yoon","year":"2012","journal-title":"Biomol. Ther."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2030","DOI":"10.1038\/ncomms3030","article-title":"Scara1 deficiency impairs clearance of soluble amyloid-\u03b2 by mononuclear phagocytes and accelerates Alzheimer\u2019s-like disease progression","volume":"4","author":"Frenkel","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1038\/382716a0","article-title":"Scavenger receptor-mediated adhesion of microglia to beta-amyloid fibrils","volume":"382","author":"Hickman","year":"1996","journal-title":"Nature"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1126\/science.aad8373","article-title":"Complement and microglia mediate early synapse loss in Alzheimer mouse models","volume":"352","author":"Hong","year":"2016","journal-title":"Science"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"Mishra, V.K., Shih, H.H., Parveen, F., Lenzen, D., Ito, E., Chan, T.F., and Ke, L.Y. (2020). Identifying the Therapeutic Significance of Mesenchymal Stem Cells. Cells, 9.","DOI":"10.3390\/cells9051145"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1038\/nature25158","article-title":"Microglia-derived ASC specks cross-seed amyloid-\u03b2 in Alzheimer\u2019s disease","volume":"552","author":"Venegas","year":"2017","journal-title":"Nature"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"S295","DOI":"10.3233\/JAD-2012-129027","article-title":"The neuroimmune system in Alzheimer\u2019s disease: The glass is half full","volume":"33","author":"Hickman","year":"2013","journal-title":"J. Alzheimer\u2019s Dis. Jad"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"1276","DOI":"10.1016\/j.cell.2017.05.018","article-title":"A Unique Microglia Type Associated with Restricting Development of Alzheimer\u2019s Disease","volume":"169","author":"Spinrad","year":"2017","journal-title":"Cell"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"S30","DOI":"10.1016\/j.parkreldis.2017.07.033","article-title":"Neuropathology of Parkinson disease","volume":"46","author":"Dickson","year":"2018","journal-title":"Parkinsonism Relat. Disord."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1212\/WNL.38.8.1285","article-title":"Reactive microglia are positive for HLA-DR in the substantia nigra of Parkinson\u2019s and Alzheimer\u2019s disease brains","volume":"38","author":"McGeer","year":"1988","journal-title":"Neurology"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"ra45","DOI":"10.1126\/scisignal.2005965","article-title":"Activation of MyD88-dependent TLR1\/2 signaling by misfolded \u03b1-synuclein, a protein linked to neurodegenerative disorders","volume":"8","author":"Daniele","year":"2015","journal-title":"Sci. Signal."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"R32","DOI":"10.1093\/hmg\/ddv236","article-title":"Pathways to Parkinsonism Redux: Convergent pathobiological mechanisms in genetics of Parkinson\u2019s disease","volume":"24","author":"Kumaran","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"9289","DOI":"10.1073\/pnas.1403215111","article-title":"Abrogation of \u03b1-synuclein-mediated dopaminergic neurodegeneration in LRRK2-deficient rats","volume":"111","author":"Daher","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1002\/mds.23455","article-title":"Glia: Initiators and progressors of pathology in Parkinson\u2019s disease","volume":"26","author":"Halliday","year":"2011","journal-title":"Mov. Disord. Off. J. Mov. Disord. Soc."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.nbd.2003.12.012","article-title":"Evidence of widespread cerebral microglial activation in amyotrophic lateral sclerosis: An [11C](R)-PK11195 positron emission tomography study","volume":"15","author":"Turner","year":"2004","journal-title":"Neurobiol. Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"221","DOI":"10.1002\/ana.10805","article-title":"Presence of dendritic cells, MCP-1, and activated microglia\/macrophages in amyotrophic lateral sclerosis spinal cord tissue","volume":"55","author":"Henkel","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"16021","DOI":"10.1073\/pnas.0607423103","article-title":"Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis","volume":"103","author":"Beers","year":"2006","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"1389","DOI":"10.1126\/science.1123511","article-title":"Onset and progression in inherited ALS determined by motor neurons and microglia","volume":"312","author":"Yamanaka","year":"2006","journal-title":"Science"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1772","DOI":"10.1126\/science.8209258","article-title":"Motor neuron degeneration in mice that express a human Cu,Zn superoxide dismutase mutation","volume":"264","author":"Gurney","year":"1994","journal-title":"Science"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1016\/j.neuron.2014.01.013","article-title":"Microglia induce motor neuron death via the classical NF-\u03baB pathway in amyotrophic lateral sclerosis","volume":"81","author":"Frakes","year":"2014","journal-title":"Neuron"},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"7594","DOI":"10.1073\/pnas.0802556105","article-title":"Mutant SOD1 in cell types other than motor neurons and oligodendrocytes accelerates onset of disease in ALS mice","volume":"105","author":"Yamanaka","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"4102","DOI":"10.1093\/hmg\/ddt259","article-title":"Ablation of P2 \u00d7 7 receptor exacerbates gliosis and motoneuron death in the SOD1-G93A mouse model of amyotrophic lateral sclerosis","volume":"22","author":"Apolloni","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.expneurol.2012.06.011","article-title":"Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS","volume":"237","author":"Liao","year":"2012","journal-title":"Exp. Neurol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"13046","DOI":"10.1073\/pnas.1002396107","article-title":"Mutant superoxide dismutase 1-induced IL-1beta accelerates ALS pathogenesis","volume":"107","author":"Meissner","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_89","first-page":"659","article-title":"SOD1 mutations disrupt redox-sensitive Rac regulation of NADPH oxidase in a familial ALS model","volume":"118","author":"Harraz","year":"2008","journal-title":"J. Clin. Investig."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1002\/glia.20919","article-title":"Extracellular mutant SOD1 induces microglial-mediated motoneuron injury","volume":"58","author":"Zhao","year":"2010","journal-title":"Glia"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1324","DOI":"10.1126\/science.aaf1064","article-title":"C9orf72 is required for proper macrophage and microglial function in mice","volume":"351","author":"Bogdanik","year":"2016","journal-title":"Science"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"892","DOI":"10.1016\/j.neuron.2015.10.027","article-title":"C9orf72 BAC Transgenic Mice Display Typical Pathologic Features of ALS\/FTD","volume":"88","author":"Bogdanik","year":"2015","journal-title":"Neuron"},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1038\/s41593-018-0083-7","article-title":"Microglia-mediated recovery from ALS-relevant motor neuron degeneration in a mouse model of TDP-43 proteinopathy","volume":"21","author":"Spiller","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.neuron.2017.05.037","article-title":"TDP-43 Depletion in Microglia Promotes Amyloid Clearance but Also Induces Synapse Loss","volume":"95","author":"Paolicelli","year":"2017","journal-title":"Neuron"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.molmed.2018.11.005","article-title":"Microglia in Central Nervous System Inflammation and Multiple Sclerosis Pathology","volume":"25","author":"Voet","year":"2019","journal-title":"Trends Mol. Med."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1007\/s00401-016-1653-y","article-title":"An updated histological classification system for multiple sclerosis lesions","volume":"133","author":"Kuhlmann","year":"2017","journal-title":"Acta Neuropathol."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"1533","DOI":"10.1084\/jem.20132477","article-title":"Differential roles of microglia and monocytes in the inflamed central nervous system","volume":"211","author":"Yamasaki","year":"2014","journal-title":"J. Exp. Med."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"258","DOI":"10.3389\/fnmol.2019.00258","article-title":"The Role of Microglia and Astrocytes in Huntington\u2019s Disease","volume":"12","author":"Palpagama","year":"2019","journal-title":"Front. Mol. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/B978-0-444-63233-3.00017-8","article-title":"Huntington disease","volume":"147","author":"Ghosh","year":"2018","journal-title":"Handb. Clin. Neurol."},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/B978-0-444-52014-2.00004-5","article-title":"Huntington\u2019s disease\u2014neuropathology","volume":"100","author":"Vonsattel","year":"2011","journal-title":"Handb. Clin. Neurol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1093\/jnen\/60.2.161","article-title":"Early and progressive accumulation of reactive microglia in the Huntington disease brain","volume":"60","author":"Sapp","year":"2001","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1093\/brain\/awm044","article-title":"Microglial activation in presymptomatic Huntington\u2019s disease gene carriers","volume":"130","author":"Tai","year":"2007","journal-title":"Brain A J. Neurol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1212\/01.wnl.0000222734.56412.17","article-title":"Microglial activation correlates with severity in Huntington disease: A clinical and PET study","volume":"66","author":"Pavese","year":"2006","journal-title":"Neurology"},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1038\/nn.3668","article-title":"Mutant Huntingtin promotes autonomous microglia activation via myeloid lineage-determining factors","volume":"17","author":"Crotti","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1007\/s00401-009-0612-2","article-title":"Nomenclature and nosology for neuropathologic subtypes of frontotemporal lobar degeneration: An update","volume":"119","author":"Mackenzie","year":"2010","journal-title":"Acta Neuropathol."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"2611","DOI":"10.1084\/jem.20160999","article-title":"Progranulin deficiency causes impairment of autophagy and TDP-43 accumulation","volume":"214","author":"Chang","year":"2017","journal-title":"J. Exp. Med."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"2341","DOI":"10.1523\/JNEUROSCI.3081-17.2018","article-title":"Progranulin Gene Therapy Improves Lysosomal Dysfunction and Microglial Pathology Associated with Frontotemporal Dementia and Neuronal Ceroid Lipofuscinosis","volume":"38","author":"Arrant","year":"2018","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1146\/annurev-neuro-071714-033828","article-title":"Neurodegenerative diseases: Expanding the prion concept","volume":"38","author":"Walker","year":"2015","journal-title":"Annu. Rev. Neurosci."},{"key":"ref_109","doi-asserted-by":"crossref","unstructured":"Yamasaki, T., Suzuki, A., Hasebe, R., and Horiuchi, M. (2018). Flow Cytometric Detection of PrP(Sc) in Neurons and Glial Cells from Prion-Infected Mouse Brains. J. Virol., 92.","DOI":"10.1128\/JVI.01457-17"},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1038\/nn2028","article-title":"A versatile prion replication assay in organotypic brain slices","volume":"11","author":"Falsig","year":"2008","journal-title":"Nat. Neurosci."},{"key":"ref_111","doi-asserted-by":"crossref","unstructured":"Sorce, S., Nuvolone, M., Keller, A., Falsig, J., Varol, A., Schwarz, P., Bieri, M., Budka, H., and Aguzzi, A. (2014). The role of the NADPH oxidase NOX2 in prion pathogenesis. PLoS Pathog., 10.","DOI":"10.1371\/journal.ppat.1004531"},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"3230","DOI":"10.1172\/JCI90605","article-title":"Microglia in prion diseases","volume":"127","author":"Aguzzi","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"4215","DOI":"10.1007\/s00018-012-1140-0","article-title":"NLRP3 inflammasome activation in macrophage cell lines by prion protein fibrils as the source of IL-1\u03b2 and neuronal toxicity","volume":"69","author":"Fitzgerald","year":"2012","journal-title":"Cell. Mol. Life Sci. Cmls"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"919","DOI":"10.1007\/s12031-013-0002-z","article-title":"Abnormal activation of microglia accompanied with disrupted CX3CR1\/CX3CL1 pathway in the brains of the hamsters infected with scrapie agent 263K","volume":"51","author":"Xie","year":"2013","journal-title":"J. Mol. Neurosci. Mn"},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"2017","DOI":"10.1002\/glia.21070","article-title":"Microglia in the degenerating brain are capable of phagocytosis of beads and of apoptotic cells, but do not efficiently remove PrPSc, even upon LPS stimulation","volume":"58","author":"Hughes","year":"2010","journal-title":"Glia"},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"13433","DOI":"10.1128\/JVI.02072-13","article-title":"Absence of CD14 delays progression of prion diseases accompanied by increased microglial activation","volume":"87","author":"Sakai","year":"2013","journal-title":"J. Virol."},{"key":"ref_117","doi-asserted-by":"crossref","unstructured":"Kouadir, M., Yang, L., Tan, R., Shi, F., Lu, Y., Zhang, S., Yin, X., Zhou, X., and Zhao, D. (2012). CD36 participates in PrP(106-126)-induced activation of microglia. PLoS ONE, 7.","DOI":"10.1371\/annotation\/f900d37b-3d36-4551-8680-cecf4bd1418d"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.neulet.2014.07.018","article-title":"Keratan sulfate expression is associated with activation of a subpopulation of microglia\/macrophages in Wallerian degeneration","volume":"579","author":"Shinjo","year":"2014","journal-title":"Neurosci. Lett."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.brainres.2014.09.008","article-title":"The role of the immune system in neurodegenerative disorders: Adaptive or maladaptive?","volume":"1617","author":"Doty","year":"2015","journal-title":"Brain Res."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1016\/j.neuron.2017.03.042","article-title":"iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases","volume":"94","author":"Abud","year":"2017","journal-title":"Neuron"},{"key":"ref_121","doi-asserted-by":"crossref","unstructured":"Ryan, K.J., White, C.C., Patel, K., Xu, J., Olah, M., Replogle, J.M., Frangieh, M., Cimpean, M., Winn, P., and McHenry, A. (2017). A human microglia-like cellular model for assessing the effects of neurodegenerative disease gene variants. Sci. Transl. Med., 9.","DOI":"10.1126\/scitranslmed.aai7635"},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1084\/jem.20150479","article-title":"Impact of peripheral myeloid cells on amyloid-\u03b2 pathology in Alzheimer\u2019s disease-like mice","volume":"212","author":"Prokop","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"1803","DOI":"10.1084\/jem.20150478","article-title":"Replacement of brain-resident myeloid cells does not alter cerebral amyloid-\u03b2 deposition in mouse models of Alzheimer\u2019s disease","volume":"212","author":"Varvel","year":"2015","journal-title":"J. Exp. Med."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"1162","DOI":"10.1016\/j.neuron.2014.12.064","article-title":"Immunotherapeutic approaches for Alzheimer\u2019s disease","volume":"85","author":"Wisniewski","year":"2015","journal-title":"Neuron"},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/nature19323","article-title":"The antibody aducanumab reduces A\u03b2 plaques in Alzheimer\u2019s disease","volume":"537","author":"Sevigny","year":"2016","journal-title":"Nature"},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"992","DOI":"10.15252\/emmm.201606370","article-title":"TREM2 deficiency reduces the efficacy of immunotherapeutic amyloid clearance","volume":"8","author":"Xiang","year":"2016","journal-title":"Embo Mol. Med."},{"key":"ref_127","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.bbi.2016.07.003","article-title":"Inflammation in Alzheimer\u2019s disease: Lessons learned from microglia-depletion models","volume":"61","author":"Spangenberg","year":"2017","journal-title":"BrainBehav. Immun."},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1016\/j.neuron.2014.02.040","article-title":"Colony-stimulating factor 1 receptor signaling is necessary for microglia viability, unmasking a microglia progenitor cell in the adult brain","volume":"82","author":"Elmore","year":"2014","journal-title":"Neuron"},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1093\/brain\/awv379","article-title":"Pharmacological targeting of CSF1R inhibits microglial proliferation and prevents the progression of Alzheimer\u2019s-like pathology","volume":"139","author":"Schetters","year":"2016","journal-title":"Brain A J. Neurol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1084\/jem.20120412","article-title":"Colony-stimulating factor 1 receptor (CSF1R) signaling in injured neurons facilitates protection and survival","volume":"210","author":"Luo","year":"2013","journal-title":"J. Exp. Med."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"6532","DOI":"10.1523\/JNEUROSCI.4586-14.2015","article-title":"Nuclear receptors license phagocytosis by trem2+ myeloid cells in mouse models of Alzheimer\u2019s disease","volume":"35","author":"Savage","year":"2015","journal-title":"J. Neurosci. Off. J. Soc. Neurosci."},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"918","DOI":"10.2174\/1567205013666160404120817","article-title":"An Anti-apoE4 Specific Monoclonal Antibody Counteracts the Pathological Effects of apoE4 In Vivo","volume":"13","author":"Luz","year":"2016","journal-title":"Curr. Alzheimer Res."},{"key":"ref_133","doi-asserted-by":"crossref","unstructured":"Nixon, R.A., and Yang, D.S. (2012). Autophagy and neuronal cell death in neurological disorders. Cold Spring Harb. Perspect. Biol., 4.","DOI":"10.1101\/cshperspect.a008839"},{"key":"ref_134","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1016\/j.molmed.2016.04.006","article-title":"Human TBK1: A Gatekeeper of Neuroinflammation","volume":"22","author":"Ahmad","year":"2016","journal-title":"Trends Mol. Med."},{"key":"ref_135","doi-asserted-by":"crossref","first-page":"1761","DOI":"10.4161\/auto.29647","article-title":"Autophagy in microglia degrades extracellular \u03b2-amyloid fibrils and regulates the NLRP3 inflammasome","volume":"10","author":"Cho","year":"2014","journal-title":"Autophagy"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/1\/150\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T05:10:54Z","timestamp":1760159454000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/1\/150"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,14]]},"references-count":135,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,1]]}},"alternative-id":["cells10010150"],"URL":"https:\/\/doi.org\/10.3390\/cells10010150","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,14]]}}}