{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T18:23:22Z","timestamp":1787682202229,"version":"build-2784847793"},"reference-count":84,"publisher":"Public Library of Science (PLoS)","issue":"8","license":[{"start":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T00:00:00Z","timestamp":1787616000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100007793","name":"Stiftelsen Kristian Gerhard Jebsen","doi-asserted-by":"publisher","award":["SKGJ-MED-022"],"award-info":[{"award-number":["SKGJ-MED-022"]}],"id":[{"id":"10.13039\/100007793","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Department of Neurology and Clinical Neurophysiology, University Hospital of Trondheim"},{"DOI":"10.13039\/501100004590","name":"Helse Midt-Norge","doi-asserted-by":"publisher","award":["P-103253-02-01-04"],"award-info":[{"award-number":["P-103253-02-01-04"]}],"id":[{"id":"10.13039\/501100004590","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001201","name":"Kavli Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001201","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100013263","name":"Nasjonalforeningen for Folkehelsen","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100013263","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100005416","name":"Norges Forskningsr\u00e5d","doi-asserted-by":"publisher","award":["332640"],"award-info":[{"award-number":["332640"]}],"id":[{"id":"10.13039\/501100005416","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.ploscompbiol.org"],"crossmark-restriction":false},"short-container-title":["PLoS Comput Biol"],"abstract":"\n The entorhinal cortex (EC) plays a crucial role in memory functions. Long before the clinical symptoms of Alzheimer\u2019s disease (AD) emerge, it has already undergone significant degeneration, making it a primary site for the onset of the disease. The reasons for this remain elusive. Layer II (LII) neurons of the anterolateral EC are especially prone to display a very early increase in intracellular amounts of amyloid-\n \n \n \n \n \n \u03b2<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n peptide (A\n \n \n \n \n \n \u03b2<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n ) and hyperphosphorylated tau protein (p-tau). The expression of the large glycoprotein reelin is extraordinarily high in ECLII neurons compared to most other cortical neurons and proximity ligation assay data and other immunohistochemical data strongly support the notion that reelin binds to A\n \n \n \n \n \n \u03b2<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n in these neurons. Here, based on the premise that reelin may function as a sink for intracellular A\n \n \n \n \n \n \u03b2<\/mml:mi>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n , we show by computational modeling that, in a senescent physiology predisposing to frequent inflammation-driven A\n \n \n \n \n \n \u03b2<\/mml:mi>\n 42<\/mml:mn>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n production bursts over a decades-long period, the intracellular amount of A\n \n \n \n \n \n \u03b2<\/mml:mi>\n 42<\/mml:mn>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n -reelin complexes can accumulate to extraordinarily high levels in anterolaterally positioned LII neurons compared to the vast majority of cortical neurons. This is consistent with experimental data showing that intracellular accumulations of A\n \n \n \n \n \n \u03b2<\/mml:mi>\n 42<\/mml:mn>\n <\/mml:mrow>\n <\/mml:math>\n <\/jats:alternatives>\n <\/jats:inline-formula>\n positive material ranged from 20 to 80% of total soma volume in EC neurons from patients with idiopathic AD. Based on known tau protein biology, we also show that this extreme intracellular aggregation that overloads the lysosomal degradation machinery, manifesting chronic homeostatic dysregulation, can lead to the production of p-tau fragments prone to aggregation. Together, our findings may contribute to the resolution of why the EC is so strongly associated with the very early etiology of AD.\n <\/jats:p>","DOI":"10.1371\/journal.pcbi.1014532","type":"journal-article","created":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T17:47:28Z","timestamp":1787680048000},"page":"e1014532","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["High reelin expression may explain why a subgroup of entorhinal cortex neurons functions as an initial nucleation site of Alzheimer\u2019s 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Berron","year":"2021","journal-title":"Brain"},{"issue":"14","key":"pcbi.1014532.ref003","doi-asserted-by":"crossref","first-page":"4491","DOI":"10.1523\/JNEUROSCI.16-14-04491.1996","article-title":"Profound loss of layer II entorhinal cortex neurons occurs in very mild Alzheimer\u2019s disease","volume":"16","author":"T G\u00f3mez-Isla","year":"1996","journal-title":"J Neurosci"},{"issue":"2","key":"pcbi.1014532.ref004","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/1531-8249(20010201)49:2<202::AID-ANA40>3.0.CO;2-3","article-title":"Loss and atrophy of layer II entorhinal cortex neurons in elderly people with mild cognitive impairment","volume":"49","author":"JH Kordower","year":"2001","journal-title":"Ann Neurol"},{"key":"pcbi.1014532.ref005","doi-asserted-by":"crossref","first-page":"101617","DOI":"10.1016\/j.nicl.2018.101617","article-title":"Cortical thickness atrophy in the transentorhinal cortex in mild cognitive impairment","volume":"21","author":"S Kulason","year":"2019","journal-title":"Neuroimage Clin"},{"issue":"1","key":"pcbi.1014532.ref006","article-title":"Anterolateral entorhinal cortex thickness as a new biomarker for early detection of Alzheimer\u2019s disease","volume":"12","author":"AJ Holbrook","year":"2020","journal-title":"Alzheimers Dement (Amst)"},{"issue":"2","key":"pcbi.1014532.ref007","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1046\/j.1365-2559.2001.01082.x","article-title":"Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer\u2019s disease","volume":"38","author":"MR D\u2019Andrea","year":"2001","journal-title":"Histopathology"},{"issue":"3","key":"pcbi.1014532.ref008","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1016\/S0304-3940(02)00875-3","article-title":"Consistent immunohistochemical detection of intracellular beta-amyloid42 in pyramidal neurons of Alzheimer\u2019s disease entorhinal cortex","volume":"333","author":"MR 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Detection of a protofibrillar intermediate","volume":"272","author":"DM Walsh","year":"1997","journal-title":"J Biol Chem"},{"issue":"1","key":"pcbi.1014532.ref012","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1007\/s12575-009-9008-x","article-title":"Size and shape of protein molecules at the nanometer level determined by sedimentation, gel filtration, and electron microscopy","volume":"11","author":"HP Erickson","year":"2009","journal-title":"Biol Proced Online"},{"issue":"1","key":"pcbi.1014532.ref013","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pcbi.1012709","article-title":"Intraneuronal binding of amyloid beta with reelin-Implications for the onset of Alzheimer\u2019s disease","volume":"21","author":"A Kobro-Flatmoen","year":"2025","journal-title":"PLoS Comput Biol"},{"issue":"10","key":"pcbi.1014532.ref014","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1103\/PhysRevLett.84.2064","article-title":"Is random close packing of spheres well defined?","volume":"84","author":"S Torquato","year":"2000","journal-title":"Phys Rev Lett"},{"issue":"35","key":"pcbi.1014532.ref015","doi-asserted-by":"crossref","first-page":"14745","DOI":"10.1073\/pnas.0905127106","article-title":"Structure-neurotoxicity relationships of amyloid beta-protein oligomers","volume":"106","author":"K Ono","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"14","key":"pcbi.1014532.ref016","doi-asserted-by":"crossref","first-page":"3051","DOI":"10.1111\/j.1742-4658.2010.07719.x","article-title":"Progressive accumulation of amyloid-beta oligomers in Alzheimer\u2019s disease and in amyloid precursor protein transgenic mice is accompanied by selective alterations in synaptic scaffold proteins","volume":"277","author":"E Pham","year":"2010","journal-title":"FEBS J"},{"issue":"3","key":"pcbi.1014532.ref017","doi-asserted-by":"crossref","first-page":"624","DOI":"10.1016\/j.cell.2014.02.033","article-title":"Quantifying Absolute Protein Synthesis Rates Reveals Principles Underlying Allocation of Cellular Resources","volume":"157","author":"GW Li","year":"2014","journal-title":"Cell"},{"issue":"50","key":"pcbi.1014532.ref018","doi-asserted-by":"crossref","first-page":"12943","DOI":"10.1523\/JNEUROSCI.2561-06.2006","article-title":"Differential reelin-induced enhancement of NMDA and AMPA receptor activity in the adult hippocampus","volume":"26","author":"S Qiu","year":"2006","journal-title":"J Neurosci"},{"key":"pcbi.1014532.ref019","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1016\/j.nbd.2016.05.012","article-title":"Reelin-immunoreactive neurons in entorhinal cortex layer II selectively express intracellular amyloid in early Alzheimer\u2019s disease","volume":"93","author":"A Kobro-Flatmoen","year":"2016","journal-title":"Neurobiol Dis"},{"issue":"2","key":"pcbi.1014532.ref020","doi-asserted-by":"crossref","DOI":"10.1093\/braincomms\/fcad115","article-title":"Lowering levels of reelin in entorhinal cortex layer II-neurons results in lowered levels of intracellular amyloid-\u03b2","volume":"5","author":"A Kobro-Flatmoen","year":"2023","journal-title":"Brain Commun"},{"issue":"10","key":"pcbi.1014532.ref021","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41574-018-0059-4","article-title":"Inflammaging: a new immune-metabolic viewpoint for age-related diseases","volume":"14","author":"C Franceschi","year":"2018","journal-title":"Nat Rev Endocrinol"},{"issue":"8","key":"pcbi.1014532.ref022","doi-asserted-by":"crossref","first-page":"3340","DOI":"10.1021\/acschemneuro.9b00333","article-title":"Understanding the Role of Systemic Inflammation in Alzheimer\u2019s Disease","volume":"10","author":"KA Walker","year":"2019","journal-title":"ACS Chem Neurosci"},{"key":"pcbi.1014532.ref023","doi-asserted-by":"crossref","first-page":"108190","DOI":"10.1155\/2010\/108190","article-title":"Selective vulnerability of neurons in layer II of the entorhinal cortex during aging and Alzheimer\u2019s disease","volume":"2010","author":"AM Stranahan","year":"2010","journal-title":"Neural Plast"},{"issue":"340","key":"pcbi.1014532.ref024","article-title":"Amyloid-\u03b2 peptide protects against microbial infection in mouse and worm models of Alzheimer\u2019s disease","volume":"8","author":"DKV Kumar","year":"2016","journal-title":"Sci Transl Med"},{"key":"pcbi.1014532.ref025","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1016\/j.trci.2018.06.014","article-title":"Inflammation as a central mechanism in Alzheimer\u2019s disease","volume":"4","author":"JW Kinney","year":"2018","journal-title":"Alzheimers Dement (N Y)"},{"issue":"5","key":"pcbi.1014532.ref026","doi-asserted-by":"crossref","first-page":"1243","DOI":"10.1038\/s41591-023-02318-3","article-title":"Resilience to autosomal dominant Alzheimer\u2019s disease in a Reelin-COLBOS heterozygous man","volume":"29","author":"F Lopera","year":"2023","journal-title":"Nat Med"},{"issue":"1","key":"pcbi.1014532.ref027","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1016\/S0002-9440(10)64700-1","article-title":"Intraneuronal A\u03b242 accumulation in human brain","volume":"156","author":"GK Gouras","year":"2000","journal-title":"Am J Pathol"},{"issue":"1","key":"pcbi.1014532.ref028","doi-asserted-by":"crossref","first-page":"5189","DOI":"10.1038\/s41467-025-60328-w","article-title":"Intracellular accumulation of amyloid-\u00df is a marker of selective neuronal vulnerability in Alzheimer\u2019s disease","volume":"16","author":"A Caramello","year":"2025","journal-title":"Nat Commun"},{"issue":"12","key":"pcbi.1014532.ref029","doi-asserted-by":"crossref","first-page":"826","DOI":"10.1038\/nri2873","article-title":"Sterile inflammation: sensing and reacting to damage","volume":"10","author":"GY Chen","year":"2010","journal-title":"Nat Rev 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Int"},{"issue":"3","key":"pcbi.1014532.ref033","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1038\/s41592-019-0686-2","article-title":"SciPy 1.0: fundamental algorithms for scientific computing in Python","volume":"17","author":"P Virtanen","year":"2020","journal-title":"Nat Methods"},{"issue":"3","key":"pcbi.1014532.ref034","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0009505","article-title":"The Alzheimer\u2019s disease-associated amyloid beta-protein is an antimicrobial peptide","volume":"5","author":"SJ Soscia","year":"2010","journal-title":"PLoS One"},{"issue":"7","key":"pcbi.1014532.ref035","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0101364","article-title":"Alzheimer\u2019s associated \u03b2-amyloid protein inhibits influenza A virus and modulates viral interactions with phagocytes","volume":"9","author":"MR White","year":"2014","journal-title":"PLoS One"},{"key":"pcbi.1014532.ref036","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1007\/s10522-014-9538-8","article-title":"\u03b2-Amyloid peptides display protective activity against the human Alzheimer\u2019s disease-associated herpes simplex virus-1","volume":"16","author":"K Bourgade","year":"2015","journal-title":"Biogerontology"},{"issue":"340","key":"pcbi.1014532.ref037","article-title":"Amyloid-\u03b2 peptide protects against microbial infection in mouse and worm models of Alzheimer\u2019s disease","volume":"8","author":"DKV Kumar","year":"2016","journal-title":"Sci Transl Med"},{"key":"pcbi.1014532.ref038","doi-asserted-by":"crossref","first-page":"224","DOI":"10.3389\/fnagi.2018.00224","article-title":"Can an Infection Hypothesis Explain the Beta Amyloid Hypothesis of Alzheimer\u2019s Disease?","volume":"10","author":"T Fulop","year":"2018","journal-title":"Front Aging Neurosci"},{"key":"pcbi.1014532.ref039","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1007\/s40588-021-00168-6","article-title":"The role of chronic infection in Alzheimer\u2019s disease: instigators, co-conspirators, or bystanders?","volume":"8","author":"L Butler","year":"2021","journal-title":"Curr Clin Micro Rpt"},{"issue":"10","key":"pcbi.1014532.ref040","doi-asserted-by":"crossref","first-page":"5476","DOI":"10.1038\/s41380-021-01138-6","article-title":"The viral hypothesis: how herpesviruses may contribute to Alzheimer\u2019s disease","volume":"26","author":"M Wainberg","year":"2021","journal-title":"Mol Psychiatry"},{"issue":"2","key":"pcbi.1014532.ref041","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1080\/1040841X.2021.1876630","article-title":"The role of microbial infection in the pathogenesis of Alzheimer\u2019s disease and the opportunity for protection by anti-microbial peptides","volume":"47","author":"F Li","year":"2021","journal-title":"Crit Rev Microbiol"},{"issue":"3","key":"pcbi.1014532.ref042","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1038\/s41593-025-02157-0","article-title":"Phosphorylated tau exhibits antimicrobial activity capable of neutralizing herpes simplex virus 1 infectivity in human neurons","volume":"29","author":"WA Eimer","year":"2026","journal-title":"Nat Neurosci"},{"issue":"1","key":"pcbi.1014532.ref043","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41572-021-00269-y","article-title":"Alzheimer Disease","volume":"7","author":"DS Knopman","year":"2021","journal-title":"Nat Rev Dis Primers"},{"issue":"1","key":"pcbi.1014532.ref044","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s40035-020-00196-0","article-title":"The emerging roles of vacuolar-type ATPase-dependent Lysosomal acidification in neurodegenerative diseases","volume":"9","author":"Q Song","year":"2020","journal-title":"Transl Neurodegener"},{"issue":"30","key":"pcbi.1014532.ref045","volume":"9","author":"E Im","year":"2023","journal-title":"Sci Adv"},{"issue":"1","key":"pcbi.1014532.ref046","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1038\/ng1718","article-title":"APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy","volume":"38","author":"A Rovelet-Lecrux","year":"2006","journal-title":"Nat Genet"},{"key":"pcbi.1014532.ref047","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1159\/000170884","article-title":"Expression of transgenic APP mRNA is the key determinant for beta-amyloid deposition in PS2APP transgenic mice","volume":"6","author":"L Ozmen","year":"2009","journal-title":"Neurodegener Dis"},{"issue":"2","key":"pcbi.1014532.ref048","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1007\/s11044-018-9617-8","article-title":"Ball-and-Finger System: Modeling and Optimal Trajectories","volume":"44","author":"M Ghazaei Ardakani","year":"2018","journal-title":"Multibody Syst Dyn"},{"issue":"1","key":"pcbi.1014532.ref049","doi-asserted-by":"crossref","first-page":"86","DOI":"10.1038\/s41398-023-02376-8","article-title":"HSV-1 cellular model reveals links between aggresome formation and early step of Alzheimer\u2019s disease","volume":"13","author":"MA Albaret","year":"2023","journal-title":"Transl Psychiatry"},{"issue":"6","key":"pcbi.1014532.ref050","doi-asserted-by":"crossref","first-page":"943","DOI":"10.1007\/s00401-019-02046-4","article-title":"Granulovacuolar degeneration bodies are neuron-selective lysosomal structures induced by intracellular tau pathology","volume":"138","author":"VI Wiersma","year":"2019","journal-title":"Acta Neuropathol"},{"issue":"4","key":"pcbi.1014532.ref051","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1007\/s00401-016-1546-0","article-title":"Phosphorylation of the amyloid \u03b2-peptide at Ser26 stabilizes oligomeric assembly and increases neurotoxicity","volume":"131","author":"S Kumar","year":"2016","journal-title":"Acta Neuropathol"},{"issue":"7","key":"pcbi.1014532.ref052","doi-asserted-by":"crossref","first-page":"1336","DOI":"10.1128\/MCB.00103-14","article-title":"Proteasome failure promotes positioning of lysosomes around the aggresome via local block of microtubule-dependent transport","volume":"34","author":"N Zaarur","year":"2014","journal-title":"Mol Cell Biol"},{"issue":"2","key":"pcbi.1014532.ref053","doi-asserted-by":"crossref","first-page":"481","DOI":"10.1016\/S0896-6273(00)80861-2","article-title":"Direct binding of Reelin to VLDL receptor and ApoE receptor 2 induces tyrosine phosphorylation of Disabled-1 and modulates Tau phosphorylation","volume":"24","author":"T Hiesberger","year":"1999","journal-title":"Neuron"},{"issue":"51","key":"pcbi.1014532.ref054","doi-asserted-by":"crossref","first-page":"49958","DOI":"10.1074\/jbc.M209205200","article-title":"Reelin-mediated signaling locally regulates protein kinase B\/Akt and glycogen synthase kinase 3","volume":"277","author":"U Beffert","year":"2002","journal-title":"J Biol Chem"},{"issue":"2","key":"pcbi.1014532.ref055","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1096\/fj.02-0434fje","article-title":"Apolipoprotein E and Reelin ligands modulate tau phosphorylation through an apolipoprotein E receptor\/disabled-1\/glycogen synthase kinase-3beta cascade","volume":"17","author":"N Ohkubo","year":"2003","journal-title":"FASEB J"},{"issue":"9","key":"pcbi.1014532.ref056","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1097\/00005072-199909000-00011","article-title":"Distribution of active glycogen synthase kinase 3 (GSK-3) in brains staged for Alzheimer disease neurofibrillary changes","volume":"58","author":"JJ Pei","year":"1999","journal-title":"J Neuropathol Exp Neurol"},{"issue":"8","key":"pcbi.1014532.ref057","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0072297","article-title":"Beta-amyloid impairs reelin signaling","volume":"8","author":"I Cuchillo-Ib\u00e1\u00f1ez","year":"2013","journal-title":"PLoS One"},{"issue":"40","key":"pcbi.1014532.ref058","doi-asserted-by":"crossref","first-page":"36955","DOI":"10.1074\/jbc.M206210200","article-title":"A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3 (GSK-3) and mediates protein kinase A-dependent inhibition of GSK-3","volume":"277","author":"C Tanji","year":"2002","journal-title":"Journal of Biological Chemistry"},{"key":"pcbi.1014532.ref059","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/j.pneurobio.2013.03.001","article-title":"Tau degradation: the ubiquitin-proteasome system versus the autophagy-lysosome system","volume":"105","author":"MJ Lee","year":"2013","journal-title":"Prog Neurobiol"},{"issue":"8","key":"pcbi.1014532.ref060","doi-asserted-by":"crossref","first-page":"656","DOI":"10.2174\/156720510793611592","article-title":"Tau in Alzheimer disease and related 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Chem"},{"issue":"3","key":"pcbi.1014532.ref064","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1093\/hmg\/ddi458","article-title":"Rapamycin alleviates toxicity of different aggregate-prone proteins","volume":"15","author":"Z Berger","year":"2006","journal-title":"Hum Mol Genet"},{"issue":"5","key":"pcbi.1014532.ref065","doi-asserted-by":"crossref","first-page":"1119","DOI":"10.1111\/j.1460-9568.2008.06084.x","article-title":"Autophagic-lysosomal perturbation enhances tau aggregation in transfectants with induced wild-type tau expression","volume":"27","author":"T Hamano","year":"2008","journal-title":"Eur J Neurosci"},{"key":"pcbi.1014532.ref066","doi-asserted-by":"crossref","first-page":"702788","DOI":"10.3389\/fnins.2021.702788","article-title":"Human Tau Isoforms and Proteolysis for Production of Toxic Tau Fragments in Neurodegeneration","volume":"15","author":"B Boyarko","year":"2021","journal-title":"Front Neurosci"},{"key":"pcbi.1014532.ref067","doi-asserted-by":"crossref","unstructured":"Murrell-Lagnado RD, Frick M. P2X4 and Lysosome Fusion. 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Design and Estimator for the Total Sensitivity Index","volume":"181","author":"A Saltelli","year":"2010","journal-title":"Comput Phys Commun"},{"issue":"2","key":"pcbi.1014532.ref074","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1615\/Int.J.UncertaintyQuantification.2024051475","article-title":"Variance-Based Sensitivity of Bayesian Inverse Problems to the Prior Distribution","volume":"15","author":"JE Darges","year":"2025","journal-title":"Int J Uncertain Quantif"},{"issue":"4","key":"pcbi.1014532.ref075","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1083\/jcb.141.4.1031","article-title":"Detection of a novel intraneuronal pool of insoluble amyloid beta protein that accumulates with time in culture","volume":"141","author":"DM Skovronsky","year":"1998","journal-title":"J Cell Biol"},{"issue":"13","key":"pcbi.1014532.ref076","doi-asserted-by":"crossref","first-page":"2930","DOI":"10.1093\/nar\/gkf401","article-title":"On the epigenetic regulation of the human reelin promoter","volume":"30","author":"Y Chen","year":"2002","journal-title":"Nucleic Acids Res"},{"issue":"16","key":"pcbi.1014532.ref077","doi-asserted-by":"crossref","first-page":"7437","DOI":"10.1073\/pnas.89.16.7437","article-title":"Intracellular accumulation and resistance to degradation of the Alzheimer amyloid A4\/beta protein","volume":"89","author":"MF Knauer","year":"1992","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"29","key":"pcbi.1014532.ref078","doi-asserted-by":"crossref","first-page":"20650","DOI":"10.1074\/jbc.274.29.20650","article-title":"Intracellular accumulation of insoluble, newly synthesized A\u03b2-42 in amyloid precursor protein-transfected cells that have been treated with A\u03b21\u201342","volume":"274","author":"AJ Yang","year":"1999","journal-title":"J Biol Chem"},{"issue":"10","key":"pcbi.1014532.ref079","doi-asserted-by":"crossref","first-page":"5691","DOI":"10.1007\/s12035-023-03434-4","article-title":"Pathological Impact of Tau Proteolytical Process on Neuronal and Mitochondrial Function: a Crucial Role in Alzheimer\u2019s Disease","volume":"60","author":"MA Olesen","year":"2023","journal-title":"Mol Neurobiol"},{"issue":"4","key":"pcbi.1014532.ref080","article-title":"In vivo mitochondrial and glycolytic impairments in patients with Alzheimer disease","volume":"94","author":"T Terada","year":"2020","journal-title":"Neurology"},{"issue":"1","key":"pcbi.1014532.ref081","doi-asserted-by":"crossref","DOI":"10.1242\/bio.056796","article-title":"Molecular mechanisms of neurodegeneration in the entorhinal cortex that underlie its selective vulnerability during the pathogenesis of Alzheimer\u2019s disease","volume":"10","author":"OJ Olajide","year":"2021","journal-title":"Biol Open"},{"issue":"7","key":"pcbi.1014532.ref082","doi-asserted-by":"crossref","first-page":"1617","DOI":"10.1007\/s00429-024-02816-1","article-title":"Bnip3 expression is strongly associated with reelin-positive entorhinal cortex layer II neurons","volume":"229","author":"SW Omholt","year":"2024","journal-title":"Brain Struct Funct"},{"issue":"26","key":"pcbi.1014532.ref083","doi-asserted-by":"crossref","DOI":"10.1126\/sciadv.aba3239","article-title":"Astrocytes and microglia play orchestrated roles and respect phagocytic territories during neuronal corpse removal in vivo","volume":"6","author":"EC Damisah","year":"2020","journal-title":"Sci Adv"},{"issue":"12","key":"pcbi.1014532.ref084","doi-asserted-by":"crossref","first-page":"115052","DOI":"10.1016\/j.celrep.2024.115052","article-title":"Microglia degrade Alzheimer\u2019s amyloid-beta deposits extracellularly via digestive exophagy","volume":"43","author":"RG Jacquet","year":"2024","journal-title":"Cell Rep"}],"container-title":["PLOS Computational Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1014532","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T17:47:46Z","timestamp":1787680066000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pcbi.1014532"}},"subtitle":[],"editor":[{"given":"Andrew","family":"Goryachev","sequence":"first","affiliation":[{"name":"University of Edinburgh","place":["UNITED KINGDOM OF GREAT BRITAIN AND NORTHERN IRELAND"]}],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2026,8,25]]},"references-count":84,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2026,8,25]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pcbi.1014532","relation":{},"ISSN":["1553-7358"],"issn-type":[{"value":"1553-7358","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,25]]}}}