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Chile","award":["CHL18-04"],"award-info":[{"award-number":["CHL18-04"]}]},{"name":"CRP-ICGEB","award":["11160288"],"award-info":[{"award-number":["11160288"]}]},{"name":"CRP-ICGEB","award":["1200459"],"award-info":[{"award-number":["1200459"]}]},{"name":"CRP-ICGEB","award":["1191003"],"award-info":[{"award-number":["1191003"]}]},{"name":"CRP-ICGEB","award":["11180546"],"award-info":[{"award-number":["11180546"]}]},{"name":"CRP-ICGEB","award":["11171061"],"award-info":[{"award-number":["11171061"]}]},{"name":"CRP-ICGEB","award":["1190958"],"award-info":[{"award-number":["1190958"]}]},{"name":"CRP-ICGEB","award":["1200287"],"award-info":[{"award-number":["1200287"]}]},{"name":"CRP-ICGEB","award":["1190743"],"award-info":[{"award-number":["1190743"]}]},{"name":"CRP-ICGEB","award":["15130011"],"award-info":[{"award-number":["15130011"]}]},{"name":"CRP-ICGEB","award":["URG-035\/1"],"award-info":[{"award-number":["URG-035\/1"]}]},{"name":"CRP-ICGEB","award":["CHL18-04"],"award-info":[{"award-number":["CHL18-04"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Alzheimer\u2019s disease (AD) is the most prevalent age-associated neurodegenerative disease. A decrease in autophagy during aging contributes to brain disorders by accumulating potentially toxic substrates in neurons. Rubicon is a well-established inhibitor of autophagy in all cells. However, Rubicon participates in different pathways depending on cell type, and little information is currently available on neuronal Rubicon\u2019s role in the AD context. Here, we investigated the cell-specific expression of Rubicon in postmortem brain samples from AD patients and 5xFAD mice and its impact on amyloid \u03b2 burden in vivo and neuroblastoma cells. Further, we assessed Rubicon levels in human-induced pluripotent stem cells (hiPSCs), derived from early-to-moderate AD and in postmortem samples from severe AD patients. We found increased Rubicon levels in AD-hiPSCs and postmortem samples and a notable Rubicon localization in neurons. In AD transgenic mice lacking Rubicon, we observed intensified amyloid \u03b2 burden in the hippocampus and decreased Pacer and p62 levels. In APP-expressing neuroblastoma cells, increased APP\/amyloid \u03b2 secretion in the medium was found when Rubicon was absent, which was not observed in cells depleted of Atg5, essential for autophagy, or Rab27a, required for exosome secretion. Our results propose an uncharacterized role of Rubicon on APP\/amyloid \u03b2 homeostasis, in which neuronal Rubicon is a repressor of APP\/amyloid \u03b2 secretion, defining a new way to target AD and other similar diseases therapeutically.<\/jats:p>","DOI":"10.3390\/cells11121860","type":"journal-article","created":{"date-parts":[[2022,6,9]],"date-time":"2022-06-09T10:49:14Z","timestamp":1654771754000},"page":"1860","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Neuronal Rubicon Represses Extracellular APP\/Amyloid \u03b2 Deposition in Alzheimer\u2019s Disease"],"prefix":"10.3390","volume":"11","author":[{"given":"Sandra","family":"Espinoza","sequence":"first","affiliation":[{"name":"Laboratory of Neuroprotection and Autophagy, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"},{"name":"Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felipe","family":"Grunenwald","sequence":"additional","affiliation":[{"name":"Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wileidy","family":"Gomez","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroprotection and Autophagy, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"},{"name":"Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Felipe","family":"Garc\u00eda","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroprotection and Autophagy, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lorena","family":"Abarz\u00faa-Catalan","sequence":"additional","affiliation":[{"name":"Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1023-8891","authenticated-orcid":false,"given":"Sebasti\u00e1n","family":"Oyarce-Pezoa","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroprotection and Autophagy, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"},{"name":"Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Fernanda","family":"Hernandez","sequence":"additional","affiliation":[{"name":"Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Basti\u00e1n I.","family":"Cort\u00e9s","sequence":"additional","affiliation":[{"name":"Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Markus","family":"Uhrig","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine, Facultad de Medicina Cl\u00ednica Alemana, Universidad del Desarrollo, Santiago 7550000, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Daniela P.","family":"Ponce","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Cl\u00ednica Avanzada, Universidad de Chile, Santiago 8380456, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2503-8366","authenticated-orcid":false,"given":"Claudia","family":"Dur\u00e1n-Aniotz","sequence":"additional","affiliation":[{"name":"Center for Social and Cognitive Neuroscience, School of Psychology, Universidad Adolfo Iba\u00f1ez, Santiago 7550313, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudio","family":"Hetz","sequence":"additional","affiliation":[{"name":"Center for Geroscience, Brain Health, and Metabolism, Santiago 8380453, Chile"},{"name":"Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago 8380453, Chile"},{"name":"Buck Institute for Research on Aging, Novato, CA 94945, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carol D.","family":"SanMart\u00edn","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Cl\u00ednica Avanzada, Universidad de Chile, Santiago 8380456, Chile"},{"name":"Departamento de Neurolog\u00eda y Neurocirug\u00eda, Hospital Cl\u00ednico Universidad de Chile, Santiago 8380456, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Victor H.","family":"Cornejo","sequence":"additional","affiliation":[{"name":"Program of Cellular and Molecular Biology, Institute of Biomedical Sciences, University of Chile, Santiago 8380453, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7696-4215","authenticated-orcid":false,"given":"Fernando","family":"Ezquer","sequence":"additional","affiliation":[{"name":"Center for Regenerative Medicine, Facultad de Medicina Cl\u00ednica Alemana, Universidad del Desarrollo, Santiago 7550000, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0080-6472","authenticated-orcid":false,"given":"Valentina","family":"Parra","sequence":"additional","affiliation":[{"name":"Autophagy Research Center, Universidad de Chile, Santiago 8380456, Chile"},{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular and Advanced Center for Chronic Diseases, Facultad de Ciencias Qu\u00edmicas y Farmac\u00e9uticas, Universidad de Chile, Santiago 8380456, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0964-426X","authenticated-orcid":false,"given":"Maria Isabel","family":"Behrens","sequence":"additional","affiliation":[{"name":"Centro de Investigaci\u00f3n Cl\u00ednica Avanzada, Universidad de Chile, Santiago 8380456, Chile"},{"name":"Departamento de Bioqu\u00edmica y Biolog\u00eda Molecular and Advanced Center for Chronic Diseases, Facultad de Ciencias Qu\u00edmicas y Farmac\u00e9uticas, Universidad de Chile, Santiago 8380456, Chile"},{"name":"Departamento de Neurociencia, Facultad de Medicina Universidad de Chile, Santiago 8380456, Chile"},{"name":"Cl\u00ednica Alemana de Santiago, Universidad del Desarrollo, Santiago 13132, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patricio A.","family":"Manque","sequence":"additional","affiliation":[{"name":"Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"},{"name":"Centro de Oncologia de Precision (COP), Escuela de Medicina, Universidad Mayor, Santiago 8580745, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8773-9830","authenticated-orcid":false,"given":"Diego","family":"Rojas-Rivera","sequence":"additional","affiliation":[{"name":"Escuela de Biotecnolog\u00eda, Facultad de Ciencias, Universidad Mayor, Santiago 8580745, Chile"},{"name":"Escuela de Tecnolog\u00eda M\u00e9dica, Facultad de Ciencias de la Salud, Universidad Mayor, Santiago 8580745, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4305-7387","authenticated-orcid":false,"given":"Ren\u00e9 L.","family":"Vidal","sequence":"additional","affiliation":[{"name":"Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"},{"name":"Center for Geroscience, Brain Health, and Metabolism, Santiago 8380453, Chile"},{"name":"Escuela de Biotecnolog\u00eda, Facultad de Ciencias, Universidad Mayor, Santiago 8580745, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3114-9708","authenticated-orcid":false,"given":"Ute","family":"Woehlbier","sequence":"additional","affiliation":[{"name":"Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"},{"name":"Escuela de Biotecnolog\u00eda, Facultad de Ciencias, Universidad Mayor, Santiago 8580745, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5039-5245","authenticated-orcid":false,"given":"Melissa","family":"Nassif","sequence":"additional","affiliation":[{"name":"Laboratory of Neuroprotection and Autophagy, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"},{"name":"Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"},{"name":"Escuela de Biotecnolog\u00eda, Facultad de Ciencias, Universidad Mayor, Santiago 8580745, Chile"},{"name":"Escuela de Tecnolog\u00eda M\u00e9dica, Facultad de Ciencias de la Salud, Universidad Mayor, Santiago 8580745, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,7]]},"reference":[{"key":"ref_1","unstructured":"Patterson, C. (2018). World Alzheimer Report 2018\u2014The State of the Art of Dementia Research: New Frontiers, Alzheimer\u2019s Disease International (ADI)."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1007\/s11357-020-00153-9","article-title":"NIA Workshop on Senescence in Brain Aging and Alzheimer\u2019s Disease and Its Related Dementias","volume":"42","author":"DiBattista","year":"2020","journal-title":"Geroscience"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1186\/1752-0509-8-65","article-title":"A systems biology investigation of neurodegenerative dementia reveals a pivotal role of autophagy","volume":"8","author":"Caberlotto","year":"2014","journal-title":"BMC Syst. Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-019-39828-5","article-title":"Cross-disease analysis of Alzheimer\u2019s disease and type-2 Diabetes highlights the role of autophagy in the pathophysiology of two highly comorbid diseases","volume":"9","author":"Caberlotto","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"14164","DOI":"10.1073\/pnas.1009485107","article-title":"Genome-wide analysis reveals mechanisms modulating autophagy in normal brain aging and in Alzheimer\u2019s disease","volume":"107","author":"Saito","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1584","DOI":"10.1038\/s41588-018-0238-1","article-title":"Integrative transcriptome analyses of the aging brain implicate altered splicing in Alzheimer\u2019s disease susceptibility","volume":"50","author":"Raj","year":"2018","journal-title":"Nat. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1093\/brain\/awy197","article-title":"Genetic variation within endolysosomal system is associated with late-onset Alzheimer\u2019s disease","volume":"141","author":"Gao","year":"2018","journal-title":"Brain"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/s41586-019-1195-2","article-title":"Single-cell transcriptomic analysis of Alzheimer\u2019s disease","volume":"570","author":"Mathys","year":"2019","journal-title":"Nature"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/j.cels.2021.06.001","article-title":"Dysregulation of the secretory pathway connects Alzheimer\u2019s disease genetics to aggregate formation","volume":"12","author":"Kuo","year":"2021","journal-title":"Cell Syst."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1112","DOI":"10.1080\/15548627.2020.1760623","article-title":"NRBF2 is a RAB7 effector required for autophagosome maturation and mediates the association of APP-CTFs with active form of RAB7 for degradation","volume":"17","author":"Cai","year":"2021","journal-title":"Autophagy"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Burrinha, T., Martinsson, I., Gomes, R., Terrasso, A.P., Gouras, G.K., and Almeida, C.G. (2021). Upregulation of APP endocytosis by neuronal aging drives amyloid-dependent synapse loss. J. Cell Sci., 134.","DOI":"10.1242\/jcs.255752"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s00401-016-1577-6","article-title":"Intraneuronal aggregation of the \u03b2-CTF fragment of APP (C99) induces A\u03b2-independent lysosomal-autophagic pathology","volume":"132","author":"Lauritzen","year":"2016","journal-title":"Acta Neuropathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"5255","DOI":"10.1523\/JNEUROSCI.0578-19.2019","article-title":"Lysosomal dysfunction in down syndrome is app-dependent and mediated by APP-\u03b2CTF (c99)","volume":"39","author":"Jiang","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1083\/jcb.200505082","article-title":"Macroautophagy\u2014A novel \u03b2-amyloid peptide-generating pathway activated in Alzheimer\u2019s disease","volume":"171","author":"Haung","year":"2005","journal-title":"J. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1038\/s41556-018-0092-5","article-title":"A brief history of autophagy from cell biology to physiology and disease","volume":"20","author":"Mizushima","year":"2018","journal-title":"Nat. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41421-020-0141-7","article-title":"Lysosome biology in autophagy","volume":"6","author":"Yim","year":"2020","journal-title":"Cell Discov."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2696","DOI":"10.1016\/j.cell.2021.03.048","article-title":"Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome","volume":"184","author":"Bourdenx","year":"2021","journal-title":"Cell"},{"key":"ref_18","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_19","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_20","doi-asserted-by":"crossref","first-page":"5933","DOI":"10.1523\/JNEUROSCI.4401-15.2016","article-title":"Compartment-specific regulation of autophagy in primary neurons","volume":"36","author":"Maday","year":"2016","journal-title":"J. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cell.2018.09.048","article-title":"Biological Functions of Autophagy Genes: A Disease Perspective","volume":"176","author":"Levine","year":"2019","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1016\/j.molcel.2017.02.010","article-title":"Pacer Mediates the Function of Class III PI3K and HOPS Complexes in Autophagosome Maturation by Engaging Stx17","volume":"65","author":"Cheng","year":"2017","journal-title":"Mol. Cell"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"468","DOI":"10.1038\/ncb1854","article-title":"Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1\u2013phosphatidylinositol-3-kinase complex","volume":"11","author":"Zhong","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1038\/ncb1846","article-title":"Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages","volume":"11","author":"Matsunaga","year":"2009","journal-title":"Nat. Cell Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.molcel.2014.11.006","article-title":"PLEKHM1 regulates autophagosome-lysosome fusion through HOPS complex and LC3\/GABARAP proteins","volume":"57","author":"McEwan","year":"2015","journal-title":"Mol. Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/0014-5793(93)80398-E","article-title":"Isolation and characterization of autophagy-defective mutants of Saccharomyces cerevisiae","volume":"333","author":"Tsukada","year":"1993","journal-title":"FEBS Lett."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"19338","DOI":"10.1073\/pnas.1010554107","article-title":"Rubicon controls endosome maturation as a Rab7 effector","volume":"107","author":"Sun","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-019-08729-6","article-title":"Suppression of autophagic activity by Rubicon is a signature of aging","volume":"10","author":"Nakamura","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"110444","DOI":"10.1016\/j.celrep.2022.110444","article-title":"Age-associated decline of MondoA drives cellular senescence through impaired autophagy and mitochondrial homeostasis","volume":"38","author":"Minami","year":"2022","journal-title":"Cell Rep."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1038\/ncb3192","article-title":"Molecular characterization of LC3-associated phagocytosis reveals distinct roles for Rubicon, NOX2 and autophagy proteins","volume":"17","author":"Martinez","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/j.cell.2019.05.056","article-title":"LC3-Associated Endocytosis Facilitates \u03b2-Amyloid Clearance and Mitigates Neurodegeneration in Murine Alzheimer\u2019s Disease","volume":"178","author":"Heckmann","year":"2019","journal-title":"Cell"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2072","DOI":"10.1080\/15548627.2017.1380124","article-title":"RUBCN\/rubicon and EGFR regulate lysosomal degradative processes in the retinal pigment epithelium (RPE) of the eye","volume":"13","author":"Doggett","year":"2017","journal-title":"Autophagy"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"S163","DOI":"10.3233\/JAD-201264","article-title":"DEF8 and Autophagy-Associated Genes Are Altered in Mild Cognitive Impairment, Probable Alzheimer\u2019s Disease Patients, and a Transgenic Model of the Disease","volume":"82","author":"Leyton","year":"2021","journal-title":"J. Alzheimer's Dis."},{"key":"ref_34","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's Dement."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2412","DOI":"10.1212\/WNL.43.11.2412-a","article-title":"The clinical dementia rating (cdr): Current version and scoring rules","volume":"43","author":"Morris","year":"1993","journal-title":"Neurology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1038\/nmeth.1591","article-title":"A more efficient method to generate integration-free human iPS cells","volume":"8","author":"Okita","year":"2011","journal-title":"Nat. Methods"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e20","DOI":"10.1161\/CIRCRESAHA.117.311522","article-title":"Down syndrome critical region 1 gene, rcan1, helps maintain a more fused mitochondrial network","volume":"122","author":"Parra","year":"2018","journal-title":"Circ. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"815","DOI":"10.1016\/j.jalz.2015.05.010","article-title":"Brain collection, standardized neuropathologic assessment, and comorbidity in Alzheimer\u2019s Disease Neuroimaging Initiative 2 participants","volume":"7","author":"Franklin","year":"2015","journal-title":"Alzheimer\u2019s Dement."},{"key":"ref_39","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_40","doi-asserted-by":"crossref","first-page":"10129","DOI":"10.1523\/JNEUROSCI.1202-06.2006","article-title":"Intraneuronal \u03b2-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: Potential factors in amyloid plaque formation","volume":"26","author":"Oakley","year":"2006","journal-title":"J. Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"196.e29","DOI":"10.1016\/j.neurobiolaging.2010.05.027","article-title":"Motor deficits, neuron loss, and reduced anxiety coinciding with axonal degeneration and intraneuronal A\u03b2 aggregation in the 5XFAD mouse model of Alzheimer\u2019s disease","volume":"33","author":"Jawhar","year":"2012","journal-title":"Neurobiol. Aging"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/s13024-019-0313-9","article-title":"Network approach identifies Pacer as an autophagy protein involved in ALS pathogenesis","volume":"14","author":"Nassif","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"2339","DOI":"10.1091\/mbc.e11-11-0944","article-title":"Adaptor protein 2\u2013mediated endocytosis of the \u03b2-secretase BACE1 is dispensable for amyloid precursor protein processing","volume":"23","author":"Prabhu","year":"2012","journal-title":"Mol. Biol. Cell"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1007\/s00401-020-02183-1","article-title":"Insulin-like growth factor 2 (IGF2) protects against Huntington\u2019s disease through the extracellular disposal of protein aggregates","volume":"140","author":"Wu","year":"2020","journal-title":"Acta Neuropathol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1016\/j.stem.2013.01.009","article-title":"Modeling Alzheimer\u2019s Disease with iPSCs Reveals Stress Phenotypes Associated with Intracellular A\u03b2 and Differential Drug Responsiveness","volume":"12","author":"Kondo","year":"2013","journal-title":"Cell Stem Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2754","DOI":"10.1016\/j.jmb.2020.01.024","article-title":"Human Induced Pluripotent Stem Cell Models of Neurodegenerative Disorders for Studying the Biomedical Implications of Autophagy","volume":"432","author":"Seranova","year":"2020","journal-title":"J. Mol. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1038\/s41582-021-00465-0","article-title":"hiPSCs for predictive modelling of neurodegenerative diseases: Dreaming the possible","volume":"17","author":"Cervo","year":"2021","journal-title":"Nat. Rev. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"24131","DOI":"10.1074\/jbc.M702824200","article-title":"p62\/SQSTM1 binds directly to Atg8\/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy","volume":"282","author":"Pankiv","year":"2007","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1715","DOI":"10.1111\/j.1742-4658.2007.05717.x","article-title":"RCAN1-1L is overexpressed in neurons of Alzheimer's disease patients","volume":"274","author":"Harris","year":"2007","journal-title":"FEBS J."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1007\/s12311-013-0489-4","article-title":"The Salih Ataxia Mutation Impairs Rubicon Endosomal Localization","volume":"12","author":"Assoum","year":"2013","journal-title":"Cerebellum"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2439","DOI":"10.1093\/brain\/awq181","article-title":"Rundataxin, a novel protein with RUN and diacylglycerol binding domains, is mutant in a new recessive ataxia","volume":"133","author":"Assoum","year":"2010","journal-title":"Brain"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2941","DOI":"10.4103\/0366-6999.220311","article-title":"Distinct Rab7-related endosomal-autophagic-lysosomal dysregulation observed in cortex and hippocampus in APPswe\/PSEN1dE9 mouse model of Alzheimer\u2019s disease","volume":"130","author":"Ba","year":"2017","journal-title":"Chin. Med. J."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/emm.2006.40","article-title":"Microglia, major player in the brain inflammation: Their roles in the pathogenesis of Parkinson\u2019s disease","volume":"4","author":"Kim","year":"2006","journal-title":"Exp. Mol. Med."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1186\/s40478-021-01126-5","article-title":"Iron loading is a prominent feature of activated microglia in Alzheimer\u2019s disease patients","volume":"9","author":"Kenkhuis","year":"2021","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12974-015-0332-6","article-title":"Systemic inflammation and microglial activation: Systematic review of animal experiments","volume":"12","author":"Hoogland","year":"2015","journal-title":"J. Neuroinflammation"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"788","DOI":"10.1016\/j.molcel.2018.12.017","article-title":"Pacer Is a Mediator of mTORC1 and GSK3-TIP60 Signaling in Regulation of Autophagosome Maturation and Lipid Metabolism","volume":"73","author":"Cheng","year":"2019","journal-title":"Mol. Cell"},{"key":"ref_57","first-page":"2190","article-title":"The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid beta accumulation in mice","volume":"118","author":"Pickford","year":"2008","journal-title":"J. Clin. Invest."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1038\/ncb2000","article-title":"Rab27a and Rab27b control different steps of the exosome secretion pathway","volume":"12","author":"Ostrowski","year":"2010","journal-title":"Nat. Cell Biol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.ijcard.2019.07.074","article-title":"Loss of Rubicon ameliorates doxorubicin-induced cardiotoxicity through enhancement of mitochondrial quality","volume":"296","author":"Liu","year":"2019","journal-title":"Int. J. Cardiol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1097\/FJC.0000000000000188","article-title":"Rubicon deficiency enhances cardiac autophagy and protects mice from lipopolysaccharide-induced lethality and reduction in stroke volume","volume":"65","author":"Zi","year":"2015","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1994","DOI":"10.1002\/hep.28820","article-title":"Rubicon inhibits autophagy and accelerates hepatocyte apoptosis and lipid accumulation in nonalcoholic fatty liver disease in mice","volume":"64","author":"Tanaka","year":"2016","journal-title":"Hepatology"},{"key":"ref_62","first-page":"1","article-title":"Loss of RUBCN\/rubicon in adipocytes mediates the upregulation of autophagy to promote the fasting response","volume":"14","author":"Yamamuro","year":"2022","journal-title":"Autophagy"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-020-17985-w","article-title":"Age-dependent loss of adipose Rubicon promotes metabolic disorders via excess autophagy","volume":"11","author":"Yamamuro","year":"2020","journal-title":"Nat. Commun."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1016\/j.bbrc.2021.02.148","article-title":"Rubicon regulates A2E-induced autophagy impairment in the retinal pigment epithelium implicated in the pathology of age-related macular degeneration","volume":"551","author":"Ando","year":"2021","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"1","DOI":"10.3389\/fcell.2021.816829","article-title":"Rubicon in Metabolic Diseases and Ageing","volume":"9","author":"Minami","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pgen.1004278","article-title":"The Caenorhabditis elegans Myc-Mondo\/Mad complexes integrate diverse longevity signals","volume":"10","author":"Johnson","year":"2014","journal-title":"PLoS Genet."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Nakamura, S., Karalay, \u00d6., J\u00e4ger, P.S., Horikawa, M., Klein, C., Nakamura, K., Latza, C., Templer, S.E., Dieterich, C., and Antebi, A. (2016). Mondo Complexes Regulate TFEB via TOR Inhibition to Promote Longevity in Response to Gonadal Signals. Nat. Commun., 7, Available online: https:\/\/pubmed.ncbi.nlm.nih.gov\/27001890\/.","DOI":"10.1038\/ncomms10944"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"6912","DOI":"10.1073\/pnas.0712199105","article-title":"Glucose sensing by MondoA:Mlx complexes: A role for hexokinases and direct regulation of thioredoxin-interacting protein expression","volume":"105","author":"Stoltzman","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_69","doi-asserted-by":"crossref","unstructured":"McKnight, N., Zhong, Y., Wold, M.S., Gong, S., Phillips, G.R., Dou, Z., Zhao, Y., Heintz, N., Zong, W.-X., and Yue, Z. (2014). Beclin 1 Is Required for Neuron Viability and Regulates Endosome Pathways via the UVRAG-VPS34 Complex. PLoS Genet., 10.","DOI":"10.1371\/journal.pgen.1004626"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.cub.2018.12.021","article-title":"Autophagy Is Required for Memory Formation and Reverses Age-Related Memory Decline","volume":"29","author":"Glatigny","year":"2019","journal-title":"Curr. Biol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"1694","DOI":"10.1212\/WNL.38.11.1694","article-title":"The distribution of neuritic plaques and acetylcholinesterase staining in the amygdala in alzheimer\u2019s disease","volume":"38","author":"Brashear","year":"1988","journal-title":"Neurology"},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1093\/jnen\/nlx099","article-title":"The Amygdala as a Locus of Pathologic Misfolding in Neurodegenerative Diseases","volume":"77","author":"Nelson","year":"2018","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1212\/WNL.41.3.351","article-title":"Volumetrie atrophy of the amygdala in Alzheimer\u2019s disease: Quantitative serial reconstruction","volume":"41","author":"Scott","year":"1991","journal-title":"Neurology"},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Swart, C., Khoza, A., Khan, K., Le Roux, S., Du Plessis, A., and Loos, B. (2017). Investigating Basal Autophagic Activity in Brain Regions Associated with Neurodegeneration using In Vivo and Ex Vivo Models. J. Alzheimer\u2019s Dis. Park., 7.","DOI":"10.4172\/2161-0460.1000337"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1126\/sciadv.abb9036","article-title":"Noncanonical function of an autophagy protein prevents spontaneous Alzheimer\u2019s disease","volume":"6","author":"Heckmann","year":"2020","journal-title":"Sci. Adv."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"108420","DOI":"10.1016\/j.celrep.2020.108420","article-title":"Endosomal Dysfunction Induced by Directly Overactivating Rab5 Recapitulates Prodromal and Neurodegenerative Features of Alzheimer\u2019s Disease","volume":"33","author":"Pensalfini","year":"2020","journal-title":"Cell Rep."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/12\/1860\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:25:40Z","timestamp":1760138740000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/11\/12\/1860"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,7]]},"references-count":76,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2022,6]]}},"alternative-id":["cells11121860"],"URL":"https:\/\/doi.org\/10.3390\/cells11121860","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,7]]}}}