{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T18:58:17Z","timestamp":1791313097770,"version":"4.3.1"},"reference-count":64,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T00:00:00Z","timestamp":1718928000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"French Ministry of Higher Education, Research and Innovation (MESRI)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Docosahexaenoic acid (DHA, C22:6 \u03c93) may be involved in various neuroprotective mechanisms that could prevent Alzheimer\u2019s disease (AD). Its influence has still been little explored regarding the dysfunction of the endolysosomal pathway, known as an early key event in the physiopathological continuum triggering AD. This dysfunction could result from the accumulation of degradation products of the precursor protein of AD, in particular the C99 fragment, capable of interacting with endosomal proteins and thus contributing to altering this pathway from the early stages of AD. This study aims to evaluate whether neuroprotection mediated by DHA can also preserve the endolysosomal function. AD-typical endolysosomal abnormalities were recorded in differentiated human SH-SY5Y neuroblastoma cells expressing the Swedish form of human amyloid precursor protein. This altered phenotype included endosome enlargement, the reduced secretion of exosomes, and a higher level of apoptosis, which confirmed the relevance of the cellular model chosen for studying the associated deleterious mechanisms. Second, neuroprotection mediated by DHA was associated with a reduced interaction of C99 with the Rab5 GTPase, lower endosome size, restored exosome production, and reduced neuronal apoptosis. Our data reveal that DHA may influence protein localization and interactions in the neuronal membrane environment, thereby correcting the dysfunction of endocytosis and vesicular trafficking associated with AD.<\/jats:p>","DOI":"10.3390\/ijms25136816","type":"journal-article","created":{"date-parts":[[2024,6,21]],"date-time":"2024-06-21T05:33:28Z","timestamp":1718948008000},"page":"6816","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Increasing the Survival of a Neuronal Model of Alzheimer\u2019s Disease Using Docosahexaenoic Acid, Restoring Endolysosomal Functioning by Modifying the Interactions between the Membrane Proteins C99 and Rab5"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9719-1402","authenticated-orcid":false,"given":"Maxime","family":"Vigier","sequence":"first","affiliation":[{"name":"Unit\u00e9 de Recherche Animal et Fonctionnalit\u00e9s des Produits Animaux (UR AFPA), Qualivie Project, UA 3998, USC INRAE 340, Campus INP, University of Lorraine, 54500 Vand\u0153uvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magalie","family":"Uriot","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de Recherche Animal et Fonctionnalit\u00e9s des Produits Animaux (UR AFPA), Qualivie Project, UA 3998, USC INRAE 340, Campus INP, University of Lorraine, 54500 Vand\u0153uvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0163-3198","authenticated-orcid":false,"given":"Fathia","family":"Djelti-Delbarba","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de Recherche Animal et Fonctionnalit\u00e9s des Produits Animaux (UR AFPA), Qualivie Project, UA 3998, USC INRAE 340, Campus INP, University of Lorraine, 54500 Vand\u0153uvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6968-8518","authenticated-orcid":false,"given":"Thomas","family":"Claudepierre","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de Recherche Animal et Fonctionnalit\u00e9s des Produits Animaux (UR AFPA), Qualivie Project, UA 3998, USC INRAE 340, Campus INP, University of Lorraine, 54500 Vand\u0153uvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aseel","family":"El Hajj","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de Recherche Animal et Fonctionnalit\u00e9s des Produits Animaux (UR AFPA), Qualivie Project, UA 3998, USC INRAE 340, Campus INP, University of Lorraine, 54500 Vand\u0153uvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8740-4304","authenticated-orcid":false,"given":"Frances T.","family":"Yen","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de Recherche Animal et Fonctionnalit\u00e9s des Produits Animaux (UR AFPA), Qualivie Project, UA 3998, USC INRAE 340, Campus INP, University of Lorraine, 54500 Vand\u0153uvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4531-6458","authenticated-orcid":false,"given":"Thierry","family":"Oster","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de Recherche Animal et Fonctionnalit\u00e9s des Produits Animaux (UR AFPA), Qualivie Project, UA 3998, USC INRAE 340, Campus INP, University of Lorraine, 54500 Vand\u0153uvre-l\u00e8s-Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8361-4715","authenticated-orcid":false,"given":"Catherine","family":"Malaplate","sequence":"additional","affiliation":[{"name":"Unit\u00e9 de Recherche Animal et Fonctionnalit\u00e9s des Produits Animaux (UR AFPA), Qualivie Project, UA 3998, USC INRAE 340, Campus INP, University of Lorraine, 54500 Vand\u0153uvre-l\u00e8s-Nancy, France"},{"name":"Department of Biochemistry, Molecular Biology and Nutrition, Nancy University Hospital, 54000 Nancy, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"388","DOI":"10.1017\/S0029665120000129","article-title":"PUFA and their derivatives in neurotransmission and synapses: A new hallmark of synaptopathies","volume":"79","year":"2020","journal-title":"Proc. Nutr. Soc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1985","DOI":"10.1016\/j.bbamem.2018.04.016","article-title":"Docosahexaenoic acid regulates the formation of lipid rafts: A unified view from experiment and simulation","volume":"1860","author":"Wassall","year":"2018","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e13867","DOI":"10.1111\/acel.13867","article-title":"Molecular and biophysical features of hippocampal \u201clipid rafts aging\u201d are modified by dietary n-3 long-chain polyunsaturated fatty acids","volume":"22","author":"Santos","year":"2023","journal-title":"Aging Cell"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Girych, M., Kulig, W., Enkavi, G., and Vattulainen, I. (2023). How neuromembrane lipids modulate membrane proteins: Insights from G-protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs). Cold Spring Harb. Perspect. Biol., 15.","DOI":"10.1101\/cshperspect.a041419"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1017\/S0954422416000184","article-title":"Dietary DHA and health: Cognitive function ageing","volume":"29","author":"Cardoso","year":"2016","journal-title":"Nutr. Res. Rev."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1002\/2211-5463.13661","article-title":"Novel insights into brain lipid metabolism in Alzheimer\u2019s disease: Oligodendrocytes and white matter abnormalities","volume":"14","author":"Kawade","year":"2024","journal-title":"FEBS Open Bio"},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Chappus-McCendie, H., Chevalier, L., Roberge, C., and Plourde, M. (2019). Omega-3 PUFA metabolism and brain modifications during aging. Prog. Neuropsychopharmacol. Biol. Psychiatry, 94.","DOI":"10.1016\/j.pnpbp.2019.109662"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Petermann, A.B., Reyna-Jeldes, M., Ortega, L., Coddou, C., and Y\u00e9venes, G.E. (2022). Roles of the unsaturated fatty acid docosahexaenoic acid in the central nervous system: Molecular and cellular insights. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23105390"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Checler, F., Afram, E., Pardossi-Piquard, R., and Lauritzen, I. (2021). Is \u03b3-secretase a beneficial inactivating enzyme of the toxic APP C-terminal fragment C99?. J. Biol. Chem., 296.","DOI":"10.1016\/j.jbc.2021.100489"},{"key":"ref_10","first-page":"201","article-title":"Amyloid precursor protein: A regulatory hub in Alzheimer\u2019s disease","volume":"15","author":"Chen","year":"2024","journal-title":"Aging Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"14946","DOI":"10.1523\/JNEUROSCI.4305-10.2010","article-title":"Amyloid-independent mechanisms in Alzheimer\u2019s disease pathogenesis","volume":"30","author":"Pimplikar","year":"2010","journal-title":"J. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1016\/j.jalz.2019.09.002","article-title":"C99 selectively accumulates in vulnerable neurons in Alzheimer\u2019s disease","volume":"16","author":"Pulina","year":"2020","journal-title":"Alzheimers Dement."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1007\/s00401-014-1379-7","article-title":"Early etiology of Alzheimer\u2019s disease: Tipping the balance toward autophagy or endosomal dysfunction?","volume":"129","author":"Peric","year":"2015","journal-title":"Acta Neuropathol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"B\u00e9cot, A., Volgers, C., and van Niel, G. (2020). Transmissible endosomal intoxication: A balance between exosomes and lysosomes at the basis of intercellular amyloid propagation. Biomedicines, 8.","DOI":"10.3390\/biomedicines8080272"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2577","DOI":"10.1007\/s00018-018-2825-9","article-title":"Impact of late-onset Alzheimer\u2019s genetic risk factors on beta-amyloid endocytic production","volume":"75","author":"Burrinha","year":"2018","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"102","DOI":"10.15252\/embr.201642738","article-title":"Bin1 and CD2AP polarise the endocytic generation of beta-amyloid","volume":"18","author":"Ubelmann","year":"2017","journal-title":"EMBO Rep."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1038\/nature10821","article-title":"Probing sporadic and familial Alzheimer\u2019s disease using induced pluripotent stem cells","volume":"482","author":"Israel","year":"2012","journal-title":"Nature"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1186\/s40035-015-0041-1","article-title":"The endosomal-lysosomal system: From acidification and cargo sorting to neurodegeneration","volume":"4","author":"Hu","year":"2015","journal-title":"Transl. Neurodegener."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"9269","DOI":"10.1523\/JNEUROSCI.0147-18.2019","article-title":"Extracellular vesicles and neurodegenerative diseases","volume":"39","author":"Hill","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.3389\/fnins.2019.01347","article-title":"Exosome production is key to neuronal endosomal Pathway Integrity in Neurodegenerative Diseases","volume":"13","author":"Mathews","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"370","DOI":"10.2353\/ajpath.2008.071053","article-title":"Down syndrome fibroblast model of Alzheimer-related endosome pathology","volume":"173","author":"Cataldo","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1038\/mp.2015.97","article-title":"Evidence that the Rab5 effector APPL1 mediates APP-\u03b2CTF-induced dysfunction of endosomes in Down syndrome and Alzheimer\u2019s disease","volume":"21","author":"Kim","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref_23","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."},{"key":"ref_24","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_25","doi-asserted-by":"crossref","first-page":"16243","DOI":"10.1523\/JNEUROSCI.2775-12.2012","article-title":"The \u03b2-secretase-derived C-terminal fragment of APP, C99, but not A\u03b2, is a key contributor to early intraneuronal lesions in triple-transgenic mouse hippocampus","volume":"32","author":"Lauritzen","year":"2012","journal-title":"J. Neurosci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.biochi.2016.08.014","article-title":"Membrane raft domains and remodeling in aging brain","volume":"130","author":"Colin","year":"2016","journal-title":"Biochimie"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1016\/j.neurobiolaging.2017.02.015","article-title":"Maintenance of membrane organization in the aging mouse brain as the determining factor for preventing receptor dysfunction and for improving response to anti-Alzheimer treatments","volume":"54","author":"Colin","year":"2017","journal-title":"Neurobiol. Aging"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"23380","DOI":"10.1074\/jbc.271.38.23380","article-title":"Enhanced amyloidogenic processing of the beta-amyloid precursor protein in gene-targeted mice bearing the Swedish familial Alzheimer\u2019s disease mutations and a \u201chumanized\u201d A\u03b2 sequence","volume":"271","author":"Reaume","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1016\/j.bbalip.2010.05.010","article-title":"Clathrin-dependent APP endocytosis and A\u03b2 secretion are highly sensitive to the level of plasma membrane cholesterol","volume":"1801","author":"Cossec","year":"2010","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/1750-1326-9-60","article-title":"Increasing membrane cholesterol of neurons in culture recapitulates Alzheimer\u2019s disease early phenotypes","volume":"9","author":"Marquer","year":"2014","journal-title":"Mol. Neurodegener"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1111\/j.1750-3639.1996.tb00878.x","article-title":"Mechanisms of neuronal death in Alzheimer\u2019s disease","volume":"6","author":"Cotman","year":"1996","journal-title":"Brain Pathol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2301","DOI":"10.1007\/s11064-014-1454-4","article-title":"Apoptosis in Alzheimer\u2019s disease: An understanding of the physiology, pathology and therapeutic avenues","volume":"39","author":"Obulesu","year":"2014","journal-title":"Neurochem. Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"665","DOI":"10.2353\/ajpath.2008.071176","article-title":"Neuronal apoptosis and autophagy cross talk in aging PS\/APP mice, a model of Alzheimer\u2019s disease","volume":"173","author":"Yang","year":"2008","journal-title":"Am. J. Pathol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1515\/revneuro-2017-0063","article-title":"Amyloid toxicity in Alzheimer\u2019s disease","volume":"29","author":"Reiss","year":"2018","journal-title":"Rev. Neurosci."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1111\/j.1471-4159.2005.03541.x","article-title":"Docosahexaenoic acid prevents neuronal apoptosis induced by soluble amyloid-\u03b2 oligomers","volume":"96","author":"Florent","year":"2006","journal-title":"J. Neurochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"253","DOI":"10.1111\/tra.12547","article-title":"Dysregulation of Rab5-mediated endocytic pathways in Alzheimer\u2019s disease","volume":"19","author":"Xu","year":"2018","journal-title":"Traffic"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Herman, M., Randall, G.W., Spiegel, J.L., Maldonado, D.J., and Simoes, S. (2024). Endo-lysosomal dysfunction in neurodegenerative diseases: Opinion on current progress and future direction in the use of exosomes as biomarkers. Philos. Trans. R. Soc. Lond. B Biol. Sci., 379.","DOI":"10.1098\/rstb.2022.0387"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"728","DOI":"10.1126\/science.1738847","article-title":"Processing of the amyloid protein precursor to potentially amyloidogenic derivatives","volume":"255","author":"Golde","year":"1992","journal-title":"Science"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e595","DOI":"10.1038\/tp.2015.87","article-title":"Modifications of the endosomal compartment in peripheral blood mononuclear cells and fibroblasts from Alzheimer\u2019s disease patients","volume":"5","author":"Corlier","year":"2015","journal-title":"Transl. Psychiatry"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"629891","DOI":"10.3389\/fnagi.2021.629891","article-title":"Enhanced autolysosomal function ameliorates the inflammatory response mediated by the NLRP3 inflammasome in Alzheimer\u2019s disease","volume":"13","author":"Zhou","year":"2021","journal-title":"Front. Aging Neurosci."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1007\/s12017-013-8269-3","article-title":"Lysosomal network proteins as potential novel CSF biomarkers for Alzheimer\u2019s disease","volume":"16","author":"Armstrong","year":"2014","journal-title":"Neuromol Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1111\/j.1365-2990.2006.00756.x","article-title":"Lysosome-associated membrane protein 1 (LAMP-1) in Alzheimer\u2019s disease","volume":"32","author":"Barrachina","year":"2006","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1186\/s13195-019-0533-9","article-title":"Endo-lysosomal proteins and ubiquitin CSF concentrations in Alzheimer\u2019s and Parkinson\u2019s disease","volume":"11","author":"Brinkmalm","year":"2019","journal-title":"Alz Res. Therapy"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"289","DOI":"10.1093\/gerona\/glx135","article-title":"Proteins involved in endocytosis are upregulated by ageing in the normal human brain: Implications for the development of Alzheimer\u2019s disease","volume":"73","author":"Alsaqati","year":"2018","journal-title":"J. Gerontol. Ser. A"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"611","DOI":"10.1007\/s13311-019-00742-3","article-title":"Preserving Lysosomal Function in the Aging Brain: Insights from Neurodegeneration","volume":"16","author":"Peng","year":"2019","journal-title":"Neurotherapeutics"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1279","DOI":"10.3233\/JAD-220360","article-title":"Endosomal-lysosomal and autophagy pathway in Alzheimer\u2019s disease: A systematic review and meta-analysis","volume":"88","author":"Krance","year":"2022","journal-title":"J. Alzheimer\u2019s Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"757","DOI":"10.1007\/s00018-017-2664-0","article-title":"Amyloid precursor protein products concentrate in a subset of exosomes specifically endocytosed by neurons","volume":"75","author":"Laulagnier","year":"2018","journal-title":"Cell Mol. Life Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s00401-018-1868-1","article-title":"Alzheimer\u2019s disease pathology propagation by exosomes containing toxic amyloid-beta oligomers","volume":"136","author":"Sinha","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Hiroaki, H. (2023). Molecular mechanisms of amyloid-beta peptide fibril and oligomer formation: NMR-based challenges. Biophys. Physicobiol, 20.","DOI":"10.2142\/biophysico.bppb-v20.0007"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Ghosh, S., Ali, R., and Verma, S. (2023). Abeta-oligomers: A potential therapeutic target for Alzheimer\u2019s disease. Int. J. Biol. Macromol., 239.","DOI":"10.1016\/j.ijbiomac.2023.124231"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"981","DOI":"10.1038\/mp.2016.189","article-title":"Lysosomal dysfunction in the brain of a mouse model with intraneuronal accumulation of carboxyl terminal fragments of the amyloid precursor protein","volume":"22","author":"Kaur","year":"2017","journal-title":"Mol. Psychiatry"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"103869","DOI":"10.1016\/j.isci.2022.103869","article-title":"Lipid flippase dysfunction as a therapeutic target for endosomal anomalies in Alzheimer\u2019s disease","volume":"25","author":"Kaneshiro","year":"2022","journal-title":"iScience"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2729","DOI":"10.1096\/fj.201700359","article-title":"Amyloid precursor protein and endosomal-lysosomal dysfunction in Alzheimer\u2019s disease: Inseparable partners in a multifactorial disease","volume":"31","author":"Nixon","year":"2017","journal-title":"FASEB J."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.1172\/JCI82409","article-title":"Amyloid precursor protein\u2013mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration","volume":"126","author":"Xu","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Behl, T., Kaur, D., Sehgal, A., Singh, S., Makeen, H.A., Albratty, M., Abdellatif, A.A.H., Dachani, S.R., and Bungau, S. (2022). Exploring the potential role of rab5 protein in endo-lysosomal impairment in Alzheimer\u2019s disease. Biomed. Pharmacother., 148.","DOI":"10.1016\/j.biopha.2022.112773"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"7141","DOI":"10.1523\/JNEUROSCI.4599-06.2007","article-title":"Rab5 mediates an amyloid precursor protein signaling pathway that leads to apoptosis","volume":"27","author":"Laifenfeld","year":"2007","journal-title":"J. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Kim, H.-Y., Huang, B.X., and Spector, A.A. (2022). Molecular and signaling mechanisms for docosahexaenoic acid-derived neurodevelopment and neuroprotection. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23094635"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1126\/science.1255288","article-title":"Polyunsaturated phospholipids facilitate membrane deformation and fission by endocytic proteins","volume":"345","author":"Pinot","year":"2014","journal-title":"Science"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1016\/j.cell.2006.10.030","article-title":"Molecular anatomy of a trafficking organelle","volume":"127","author":"Takamori","year":"2006","journal-title":"Cell"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1091\/mbc.e07-07-0719","article-title":"Polyunsaturated fatty acids influence synaptojanin localization to regulate synaptic vesicle recycling","volume":"19","author":"Marza","year":"2008","journal-title":"Mol. Biol. Cell"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"173595","DOI":"10.1016\/j.ejphar.2020.173595","article-title":"Effect of docosahexaenoic acid, phorbol myristate acetate, and insulin on the interaction of the FFA4 (short isoform) receptor with Rab proteins","volume":"889","year":"2020","journal-title":"Eur. J. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.bbrc.2021.11.097","article-title":"Docosahexaenoic acid-containing phosphatidic acid interacts with clathrin coat assembly protein AP180 and regulates its interaction with clathrin","volume":"587","author":"Hoshino","year":"2022","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"14028","DOI":"10.1074\/jbc.M110.182329","article-title":"Docosahexaenoic acid reduces amyloid \u03b2 production via multiple pleiotropic mechanisms","volume":"286","author":"Grimm","year":"2011","journal-title":"J. Biol. 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