{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T23:33:51Z","timestamp":1790638431738,"version":"4.1.0"},"reference-count":74,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,2,6]],"date-time":"2023-02-06T00:00:00Z","timestamp":1675641600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["GR-2016-02362548"],"award-info":[{"award-number":["GR-2016-02362548"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003196","name":"Italian Ministry of Health","doi-asserted-by":"publisher","award":["Ricerca Corrente 2021"],"award-info":[{"award-number":["Ricerca Corrente 2021"]}],"id":[{"id":"10.13039\/501100003196","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Intracerebral accumulation of amyloid-\u03b2 in the extracellular plaques of Alzheimer\u2019s disease (AD) brains represents the main cause of reactive astrogliosis and neuroinflammatory response. Of relevance, leucine-rich repeat kinase 2 (LRRK2), a kinase linked to genetic and sporadic Parkinson\u2019s disease (PD), has been identified as a positive mediator of neuroinflammation upon different inflammatory stimuli, however its pathogenicity in AD remains mainly unexplored. In this study, by using pharmacological inhibition of LRRK2 and murine primary astrocytes, we explored whether LRRK2 regulates astrocytic activation in response to amyloid-\u03b21-42 (A\u03b21-42). Our results showed that murine primary astrocytes become reactive and recruit serine 935 phosphorylated LRRK2 upon A\u03b21-42 fibril exposure. Moreover, we found that pharmacological inhibition of LRRK2, with two different kinase inhibitors, can attenuate A\u03b21-42-mediated inflammation and favor the clearance of A\u03b21-42 fibrils in astrocytes. Overall, our findings report that LRRK2 kinase activity modulates astrocytic reactivity and functions in the presence of A\u03b21-42 deposits and indicate that PD-linked LRRK2 might contribute to AD-related neuroinflammation and pathogenesis.<\/jats:p>","DOI":"10.3390\/biom13020307","type":"journal-article","created":{"date-parts":[[2023,2,7]],"date-time":"2023-02-07T01:56:48Z","timestamp":1675735008000},"page":"307","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["LRRK2 Kinase Inhibition Attenuates Astrocytic Activation in Response to Amyloid \u03b21-42 Fibrils"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6271-148X","authenticated-orcid":false,"given":"Alice","family":"Filippini","sequence":"first","affiliation":[{"name":"IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Salvi","sequence":"additional","affiliation":[{"name":"Oncology and Experimental Immunology Unit, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8493-6188","authenticated-orcid":false,"given":"Vincenzo","family":"Dattilo","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9933-8666","authenticated-orcid":false,"given":"Chiara","family":"Magri","sequence":"additional","affiliation":[{"name":"Biology and Genetics Unit, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefania","family":"Castrezzati","sequence":"additional","affiliation":[{"name":"Human Anatomy Unit, Department of Biomedical Sciences and Biotechnologies, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0869-621X","authenticated-orcid":false,"given":"Robert","family":"Veerhuis","sequence":"additional","affiliation":[{"name":"Amsterdam UMC, Psychiatry, Amsterdam Public Health Research Institute and Neuroscience Amsterdam, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"},{"name":"Amsterdam UMC, Department of Clinical Chemistry, Vrije Universiteit Amsterdam, 1081 HV Amsterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6276-5365","authenticated-orcid":false,"given":"Daniela","family":"Bosisio","sequence":"additional","affiliation":[{"name":"Oncology and Experimental Immunology Unit, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Massimo","family":"Gennarelli","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"},{"name":"Biology and Genetics Unit, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Russo","sequence":"additional","affiliation":[{"name":"IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, 25125 Brescia, Italy"},{"name":"Biology and Genetics Unit, Department of Molecular and Translational Medicine, University of Brescia, 25123 Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,2,6]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"137","DOI":"10.1038\/nrneurol.2011.2","article-title":"Epidemiology of Alzheimer disease","volume":"7","author":"Reitz","year":"2011","journal-title":"Nat. Rev. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1126\/science.1132814","article-title":"A century of Alzheimer\u2019s disease","volume":"314","author":"Goedert","year":"2006","journal-title":"Science"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"663","DOI":"10.1007\/s10787-019-00580-x","article-title":"Activation of microglia and astrocytes: A roadway to neuroinflammation and Alzheimer\u2019s disease","volume":"27","author":"Kaur","year":"2019","journal-title":"Inflammopharmacology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"918","DOI":"10.1016\/j.cell.2010.02.016","article-title":"Mechanisms underlying inflammation in neurodegeneration","volume":"140","author":"Glass","year":"2010","journal-title":"Cell"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"419","DOI":"10.1016\/S0896-6273(02)00794-8","article-title":"Inflammation in neurodegenerative disease\u2014A double-edged sword","volume":"35","author":"Mucke","year":"2002","journal-title":"Neuron"},{"key":"ref_6","first-page":"1003","article-title":"Neuroinflammation Induces Neurodegeneration","volume":"1","author":"Kempuraj","year":"2016","journal-title":"J. Neurol. Neurosurg. Spine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"101622","DOI":"10.1016\/j.arr.2022.101622","article-title":"Glial cells in Alzheimer\u2019s disease: From neuropathological changes to therapeutic implications","volume":"78","author":"Uddin","year":"2022","journal-title":"Ageing Res. Rev."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2678","DOI":"10.1007\/s12035-021-02661-x","article-title":"Microglia in Alzheimer\u2019s Disease: An Unprecedented Opportunity as Prospective Drug Target","volume":"59","author":"Kulkarni","year":"2022","journal-title":"Mol. Neurobiol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1146\/annurev-immunol-032713-120240","article-title":"Microglia development and function","volume":"32","author":"Nayak","year":"2014","journal-title":"Annu. Rev. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/1567205018666211029164106","article-title":"Astrocyte Reactivity in Alzheimer\u2019s Disease: Therapeutic Opportunities to Promote Repair","volume":"19","author":"Mirzaei","year":"2022","journal-title":"Curr. Alzheimer Res."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1007\/s00424-019-02310-2","article-title":"Astroglial atrophy in Alzheimer\u2019s disease","volume":"471","author":"Verkhratsky","year":"2019","journal-title":"Pflugers Arch."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1002\/glia.20967","article-title":"Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer\u2019s disease","volume":"58","author":"Olabarria","year":"2010","journal-title":"Glia"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s40035-020-00221-2","article-title":"Neuroinflammation in neurodegenerative disorders: The roles of microglia and astrocytes","volume":"9","author":"Kwon","year":"2020","journal-title":"Transl. Neurodegener."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"e167","DOI":"10.1038\/cddis.2011.50","article-title":"Astrocytes are important mediators of A\u03b2-induced neurotoxicity and tau phosphorylation in primary culture","volume":"2","author":"Garwood","year":"2011","journal-title":"Cell Death Dis."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1186\/1742-2094-3-5","article-title":"Interleukin-1 mediates Alzheimer and Lewy body pathologies","volume":"3","author":"Griffin","year":"2006","journal-title":"J. Neuroinflammation"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"9796","DOI":"10.1523\/JNEUROSCI.23-30-09796.2003","article-title":"Nonsteroidal anti-inflammatory drugs and peroxisome proliferator-activated receptor-\u03b3 agonists modulate immunostimulated processing of amyloid precursor protein through regulation of \u03b2-secretase","volume":"23","author":"Sastre","year":"2003","journal-title":"J. Neurosci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"49523","DOI":"10.1074\/jbc.M402034200","article-title":"Tumor necrosis factor-\u03b1, interleukin-1\u03b2, and interferon-\u03b3 stimulate \u03b3-secretase-mediated cleavage of amyloid precursor protein through a JNK-dependent MAPK pathway","volume":"279","author":"Liaoi","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1016\/j.neuron.2004.11.005","article-title":"Mutations in LRRK2 cause autosomal-dominant parkinsonism with pleomorphic pathology","volume":"44","author":"Zimprich","year":"2004","journal-title":"Neuron"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1303","DOI":"10.1038\/ng.485","article-title":"Genome-wide association study identifies common variants at four loci as genetic risk factors for Parkinson\u2019s disease","volume":"41","author":"Satake","year":"2009","journal-title":"Nat. Genet."},{"key":"ref_20","first-page":"85","article-title":"LRRK2: Cause, risk, and mechanism","volume":"3","author":"Lewis","year":"2013","journal-title":"J. Park. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1042\/BST20201092","article-title":"Leucine-rich repeat kinase 2-related functions in GLIA: An update of the last years","volume":"49","author":"Filippini","year":"2021","journal-title":"Biochem. Soc. Trans."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.nbd.2019.05.012","article-title":"Transcriptome analysis of LRRK2 knock-out microglia cells reveals alterations of inflammatory- and oxidative stress-related pathways upon treatment with \u03b1-synuclein fibrils","volume":"129","author":"Russo","year":"2019","journal-title":"Neurobiol. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"230","DOI":"10.1186\/s12974-015-0449-7","article-title":"Leucine-rich repeat kinase 2 positively regulates inflammation and down-regulates NF-\u03baB p50 signaling in cultured microglia cells","volume":"12","author":"Russo","year":"2015","journal-title":"J. Neuroinflammation"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Kim, B., Yang, M.S., Choi, D., Kim, J.H., Kim, H.S., Seol, W., Choi, S., Jou, I., Kim, E.Y., and Joe, E.H. (2012). Impaired inflammatory responses in murine lrrk2-knockdown brain microglia. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0034693"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1602","DOI":"10.1523\/JNEUROSCI.5601-11.2012","article-title":"LRRK2 inhibition attenuates microglial inflammatory responses","volume":"32","author":"Moehle","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"105724","DOI":"10.1016\/j.nbd.2022.105724","article-title":"LRRK2 as a target for modulating immune system responses","volume":"169","author":"Russo","year":"2022","journal-title":"Neurobiol. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12974-018-1337-8","article-title":"Leucine-rich repeat kinase 2 controls protein kinase A activation state through phosphodiesterase 4","volume":"15","author":"Russo","year":"2018","journal-title":"J. Neuroinflammation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1016\/j.ejmech.2015.03.003","article-title":"Optimisation of LRRK2 inhibitors and assessment of functional efficacy in cell-based models of neuroinflammation","volume":"95","author":"Munoz","year":"2015","journal-title":"Eur. J. Med. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1088","DOI":"10.1016\/j.bbrc.2016.11.163","article-title":"Phosphorylation of p53 by LRRK2 induces microglial tumor necrosis factor \u03b1-mediated neurotoxicity","volume":"482","author":"Ho","year":"2017","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"14474","DOI":"10.1038\/s41598-020-71329-8","article-title":"Metabolic alterations in Parkinson\u2019s disease astrocytes","volume":"10","author":"Sonninen","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2423","DOI":"10.1093\/molbev\/msl114","article-title":"The Parkinson disease gene LRRK2: Evolutionary and structural insights","volume":"23","year":"2006","journal-title":"Mol. Biol. Evol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"527","DOI":"10.3389\/fnins.2020.00527","article-title":"LRRK2 Phosphorylation, More Than an Epiphenomenon","volume":"14","author":"Marchand","year":"2020","journal-title":"Front. Neurosci."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/ncomms6827","article-title":"Phosphorylation of LRRK2 by casein kinase 1\u03b1 regulates trans-Golgi clustering via differential interaction with ARHGEF7","volume":"5","author":"Chia","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Dzamko, N., Inesta-Vaquera, F., Zhang, J., Xie, C., Cai, H., Arthur, S., Tan, L., Choi, H., Gray, N., and Cohen, P. (2012). The IkappaB kinase family phosphorylates the Parkinson\u2019s disease kinase LRRK2 at Ser935 and Ser910 during Toll-like receptor signaling. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0039132"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1042\/BJ20100784","article-title":"Inhibition of LRRK2 kinase activity leads to dephosphorylation of Ser(910)\/Ser(935), disruption of 14-3-3 binding and altered cytoplasmic localization","volume":"430","author":"Dzamko","year":"2010","journal-title":"Biochem. J."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"51","DOI":"10.3389\/fnmol.2014.00051","article-title":"In silico, in vitro and cellular analysis with a kinome-wide inhibitor panel correlates cellular LRRK2 dephosphorylation to inhibitor activity on LRRK2","volume":"7","author":"Vancraenenbroeck","year":"2014","journal-title":"Front. Mol. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.neulet.2007.01.052","article-title":"Minocycline does not affect amyloid \u03b2 phagocytosis by human microglial cells","volume":"416","author":"Familian","year":"2007","journal-title":"Neurosci. Lett."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Montoliu-Gaya, L., Mulder, S.D., Veerhuis, R., and Villegas, S. (2017). Effects of an A\u03b2-antibody fragment on A\u03b2 aggregation and astrocytic uptake are modulated by apolipoprotein E and J mimetic peptides. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0188191"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1002\/glia.21004","article-title":"Astrocytic A \u03b2 1-42 uptake is determined by A \u03b2-aggregation state and the presence of amyloid-associated proteins","volume":"58","author":"Nielsen","year":"2010","journal-title":"Glia"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1007\/s00401-021-02372-6","article-title":"Diverse human astrocyte and microglial transcriptional responses to Alzheimer\u2019s pathology","volume":"143","author":"Smith","year":"2022","journal-title":"Acta Neuropathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"581","DOI":"10.1016\/S0197-4580(99)00065-2","article-title":"Evidence for glial-mediated inflammation in aged APP(SW) transgenic mice","volume":"20","author":"Benzing","year":"1999","journal-title":"Neurobiol. Aging"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"5709","DOI":"10.1523\/JNEUROSCI.20-15-05709.2000","article-title":"Ibuprofen suppresses plaque pathology and inflammation in a mouse model for Alzheimer\u2019s disease","volume":"20","author":"Lim","year":"2000","journal-title":"J. Neurosci."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"13075","DOI":"10.1096\/fj.201900439","article-title":"Inflammasome-mediated innate immunity in Alzheimer\u2019s disease","volume":"33","author":"Venegas","year":"2019","journal-title":"FASEB J."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1111\/j.1750-3639.1998.tb00136.x","article-title":"Glial-neuronal interactions in Alzheimer\u2019s disease: The potential role of a \u201ccytokine cycle\u201d in disease progression","volume":"8","author":"Griffin","year":"1998","journal-title":"Brain Pathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"89","DOI":"10.1016\/j.brainresrev.2009.05.007","article-title":"Clusterin: A forgotten player in Alzheimer\u2019s disease","volume":"61","author":"Nuutinen","year":"2009","journal-title":"Brain Res. Rev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1186\/1742-2094-9-261","article-title":"LRRK2 kinase inhibition prevents pathological microglial phagocytosis in response to HIV-1 Tat protein","volume":"9","author":"Marker","year":"2012","journal-title":"J. Neuroinflammation"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Kim, J., Pajarillo, E., Rizor, A., Son, D.S., Lee, J., Aschner, M., and Lee, E. (2019). LRRK2 kinase plays a critical role in manganese-induced inflammation and apoptosis in microglia. PLoS ONE, 14.","DOI":"10.1371\/journal.pone.0210248"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4201","DOI":"10.1093\/hmg\/ddu138","article-title":"Membrane recruitment of endogenous LRRK2 precedes its potent regulation of autophagy","volume":"23","author":"Schapansky","year":"2014","journal-title":"Hum. Mol. Genet."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5271","DOI":"10.1523\/JNEUROSCI.0650-14.2015","article-title":"Leucine-rich repeat kinase 2 modulates neuroinflammation and neurotoxicity in models of human immunodeficiency virus 1-associated neurocognitive disorders","volume":"35","author":"Puccini","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"5625","DOI":"10.1016\/j.bmcl.2012.06.104","article-title":"GSK2578215A; a potent and highly selective 2-arylmethyloxy-5-substitutent-N-arylbenzamide LRRK2 kinase inhibitor","volume":"22","author":"Reith","year":"2012","journal-title":"Bioorganic Med. Chem. Lett."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1038\/nchembio.538","article-title":"Characterization of a selective inhibitor of the Parkinson\u2019s disease kinase LRRK2","volume":"7","author":"Deng","year":"2011","journal-title":"Nat. Chem. Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3119","DOI":"10.1007\/s12035-021-02327-8","article-title":"Parkinson\u2019s Disease-Associated LRRK2 Interferes with Astrocyte-Mediated Alpha-Synuclein Clearance","volume":"58","author":"Giusti","year":"2021","journal-title":"Mol. Neurobiol."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Maekawa, T., Sasaoka, T., Azuma, S., Ichikawa, T., Melrose, H.L., Farrer, M.J., and Obata, F. (2016). Leucine-rich repeat kinase 2 (LRRK2) regulates \u03b1-synuclein clearance in microglia. BMC Neurosci., 17.","DOI":"10.1186\/s12868-016-0315-2"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"885","DOI":"10.1042\/EBC20210021","article-title":"Inflammasome activation in neurodegenerative diseases","volume":"65","author":"Ravichandran","year":"2021","journal-title":"Essays Biochem."},{"key":"ref_55","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_56","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1186\/1742-2094-11-52","article-title":"LRRK2 and neuroinflammation: Partners in crime in Parkinson\u2019s disease?","volume":"11","author":"Russo","year":"2014","journal-title":"J. Neuroinflammation"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"484","DOI":"10.1002\/glia.20306","article-title":"Human amyloid \u03b2-induced neuroinflammation is an early event in neurodegeneration","volume":"53","author":"Craft","year":"2006","journal-title":"Glia"},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"Vignon, A., Salvador-Prince, L., Lehmann, S., Perrier, V., and Torrent, J. (2021). Deconstructing Alzheimer\u2019s Disease: How to Bridge the Gap between Experimental Models and the Human Pathology?. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22168769"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"199","DOI":"10.2147\/JIR.S86958","article-title":"Targeting neuroinflammation in Alzheimer\u2019s disease","volume":"9","author":"Bronzuoli","year":"2016","journal-title":"J. Inflamm. Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"357","DOI":"10.1016\/0006-8993(88)90410-6","article-title":"Lamina-specific arrangement of astrocytic gliosis and senile plaques in Alzheimer\u2019s disease visual cortex","volume":"463","author":"Beach","year":"1988","journal-title":"Brain Res."},{"key":"ref_61","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_62","doi-asserted-by":"crossref","first-page":"378","DOI":"10.1038\/cdd.2008.172","article-title":"Astroglia in dementia and Alzheimer\u2019s disease","volume":"16","author":"Olabarria","year":"2009","journal-title":"Cell Death Differ."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"105212","DOI":"10.1016\/j.neuint.2021.105212","article-title":"Cellular and molecular influencers of neuroinflammation in Alzheimer\u2019s disease: Recent concepts & roles","volume":"151","author":"Ghosh","year":"2021","journal-title":"Neurochem. Int."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"7","DOI":"10.1186\/1742-2094-5-7","article-title":"The role of interleukin-1 in neuroinflammation and Alzheimer disease: An evolving perspective","volume":"5","author":"Shaftel","year":"2008","journal-title":"J. Neuroinflammation"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"eaay0399","DOI":"10.1126\/scitranslmed.aay0399","article-title":"LRRK2 mediates microglial neurotoxicity via NFATc2 in rodent models of synucleinopathies","volume":"12","author":"Kim","year":"2020","journal-title":"Sci. Transl. Med."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1581","DOI":"10.1042\/BST20180463","article-title":"LRRK2 regulation of immune-pathways and inflammatory disease","volume":"47","author":"Wallings","year":"2019","journal-title":"Biochem. Soc. Trans."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1007\/s10571-019-00649-9","article-title":"\u03b1-Synuclein and Glia in Parkinson\u2019s Disease: A Beneficial or a Detrimental Duet for the Endo-Lysosomal System?","volume":"39","author":"Filippini","year":"2019","journal-title":"Cell. Mol. Neurobiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"165","DOI":"10.2217\/fnl.12.6","article-title":"Clearance of amyloid-\u03b2 peptides by microglia and macrophages: The issue of what, when and where","volume":"7","author":"Lai","year":"2012","journal-title":"Future Neurol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12974-022-02422-0","article-title":"Microglial VPS35 deficiency impairs A\u03b2 phagocytosis and A\u03b2-induced disease-associated microglia, and enhances A\u03b2 associated pathology","volume":"19","author":"Ren","year":"2022","journal-title":"J. Neuroinflammation"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1126\/science.1197623","article-title":"Decreased clearance of CNS beta-amyloid in Alzheimer\u2019s disease","volume":"330","author":"Mawuenyega","year":"2010","journal-title":"Science"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1016\/j.neurobiolaging.2020.02.017","article-title":"Leucine-rich repeat kinase-2 (LRRK2) modulates microglial phenotype and dopaminergic neurodegeneration","volume":"91","author":"Dwyer","year":"2020","journal-title":"Neurobiol. Aging"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"6013","DOI":"10.1093\/hmg\/ddv314","article-title":"Pathogenic LRRK2 mutations, through increased kinase activity, produce enlarged lysosomes with reduced degradative capacity and increase ATP13A2 expression","volume":"24","author":"Henry","year":"2015","journal-title":"Hum. Mol. Genet."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1016\/j.stemcr.2018.12.011","article-title":"Patient-Specific iPSC-Derived Astrocytes Contribute to Non-Cell-Autonomous Neurodegeneration in Parkinson\u2019s Disease","volume":"12","author":"Carola","year":"2019","journal-title":"Stem Cell Rep."},{"key":"ref_74","first-page":"1","article-title":"Accumulation of amyloid-\u03b2 by astrocytes result in enlarged endosomes and microvesicle-induced apoptosis of neurons","volume":"11","author":"Nikitidou","year":"2016","journal-title":"Mol. Neurodegener."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/2\/307\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T18:26:07Z","timestamp":1760120767000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/13\/2\/307"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,2,6]]},"references-count":74,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2023,2]]}},"alternative-id":["biom13020307"],"URL":"https:\/\/doi.org\/10.3390\/biom13020307","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,2,6]]}}}