{"id":"https://openalex.org/W7225159757","doi":"https://doi.org/10.64898/2026.11.01.763365","title":"Apolipoprotein E4 Exacerbates A\u03b2 Oligomer-Induced Synaptotoxicity through Promoting Autophagic Degradation of Glutathione Peroxidase 4","display_name":"Apolipoprotein E4 Exacerbates A\u03b2 Oligomer-Induced Synaptotoxicity through Promoting Autophagic Degradation of Glutathione Peroxidase 4","publication_year":2026,"publication_date":"2026-11-03","ids":{"openalex":"https://openalex.org/W7225159757","doi":"https://doi.org/10.64898/2026.11.01.763365"},"language":"en","primary_location":{"id":"doi:10.64898/2026.11.01.763365","doi":"https://doi.org/10.64898/2026.11.01.763365","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.11.01.763365","pdf_url":"https://www.biorxiv.org/content/biorxiv/early/2026/11/03/2026.11.01.763365.full.pdf","source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by-nc","license_id":"https://openalex.org/licenses/cc-by-nc","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"},"volume":null,"type":"preprint","indexed_in":["crossref"],"open_access":{"is_oa":true,"oa_status":"green","oa_url":"https://www.biorxiv.org/content/biorxiv/early/2026/11/03/2026.11.01.763365.full.pdf","any_repository_has_fulltext":true},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5160407521","display_name":"Jing Zhou","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I27781120","display_name":"Wenzhou Medical University","ror":"https://ror.org/00rd5t069","country_code":"CN","type":"education","lineage":["https://openalex.org/I27781120"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Jing Zhou","raw_affiliation_strings":["Wenzhou Medical University"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Wenzhou Medical University","institution_ids":["https://openalex.org/I27781120"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5126814894","display_name":"Hongji Liao","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I27781120","display_name":"Wenzhou Medical University","ror":"https://ror.org/00rd5t069","country_code":"CN","type":"education","lineage":["https://openalex.org/I27781120"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Hongji Liao","raw_affiliation_strings":["Wenzhou Medical University"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Wenzhou Medical University","institution_ids":["https://openalex.org/I27781120"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5125722210","display_name":"Wenjing Liang","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I27781120","display_name":"Wenzhou Medical University","ror":"https://ror.org/00rd5t069","country_code":"CN","type":"education","lineage":["https://openalex.org/I27781120"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Wenjing Liang","raw_affiliation_strings":["Wenzhou Medical University"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Wenzhou Medical University","institution_ids":["https://openalex.org/I27781120"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5123534521","display_name":"Shuyi Liu","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I27781120","display_name":"Wenzhou Medical University","ror":"https://ror.org/00rd5t069","country_code":"CN","type":"education","lineage":["https://openalex.org/I27781120"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Shuyi Liu","raw_affiliation_strings":["Wenzhou Medical University"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Wenzhou Medical University","institution_ids":["https://openalex.org/I27781120"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5160462582","display_name":"Jingjing Cai","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I27781120","display_name":"Wenzhou Medical University","ror":"https://ror.org/00rd5t069","country_code":"CN","type":"education","lineage":["https://openalex.org/I27781120"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Jingjing Cai","raw_affiliation_strings":["Wenzhou Medical University"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Wenzhou Medical University","institution_ids":["https://openalex.org/I27781120"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5160444626","display_name":"Yu Liu","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I27781120","display_name":"Wenzhou Medical University","ror":"https://ror.org/00rd5t069","country_code":"CN","type":"education","lineage":["https://openalex.org/I27781120"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Yu Liu","raw_affiliation_strings":["Wenzhou Medical University"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Wenzhou Medical University","institution_ids":["https://openalex.org/I27781120"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5126847792","display_name":"Yimei Liu","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I27781120","display_name":"Wenzhou Medical University","ror":"https://ror.org/00rd5t069","country_code":"CN","type":"education","lineage":["https://openalex.org/I27781120"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Yimei Liu","raw_affiliation_strings":["Wenzhou Medical University"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Wenzhou Medical University","institution_ids":["https://openalex.org/I27781120"]}]},{"author_position":"middle","author":{"id":"https://openalex.org/A5032241007","display_name":"\u5468\u4ef2\u697c","orcid":null,"observed_orcids":[]},"institutions":[{"id":"https://openalex.org/I27781120","display_name":"Wenzhou Medical University","ror":"https://ror.org/00rd5t069","country_code":"CN","type":"education","lineage":["https://openalex.org/I27781120"]}],"countries":["CN"],"is_corresponding":false,"raw_author_name":"Zhonglou Zhou","raw_affiliation_strings":["Wenzhou Medical University"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Wenzhou Medical University","institution_ids":["https://openalex.org/I27781120"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5021491883","display_name":"Shengzhou Wu","orcid":"https://orcid.org/0000-0003-1154-2369","observed_orcids":["https://orcid.org/0000-0003-1154-2369"]},"institutions":[{"id":"https://openalex.org/I27781120","display_name":"Wenzhou Medical University","ror":"https://ror.org/00rd5t069","country_code":"CN","type":"education","lineage":["https://openalex.org/I27781120"]}],"countries":["CN"],"is_corresponding":true,"raw_author_name":"Shengzhou Wu","raw_affiliation_strings":["Wenzhou Medical University"],"raw_orcid":"https://orcid.org/0000-0003-1154-2369","affiliations":[{"raw_affiliation_string":"Wenzhou Medical University","institution_ids":["https://openalex.org/I27781120"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":1,"corresponding_author_ids":["https://openalex.org/A5021491883"],"corresponding_institution_ids":["https://openalex.org/I27781120"],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":true,"cited_by_count":0,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T10086","display_name":"Alzheimer's disease research and treatments","score":0.9976000189781189,"subfield":{"id":"https://openalex.org/subfields/2737","display_name":"Physiology (medical)"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},"topics":[{"id":"https://openalex.org/T10086","display_name":"Alzheimer's disease research and treatments","score":0.9976000189781189,"subfield":{"id":"https://openalex.org/subfields/2737","display_name":"Physiology (medical)"},"field":{"id":"https://openalex.org/fields/27","display_name":"Medicine"},"domain":{"id":"https://openalex.org/domains/4","display_name":"Health Sciences"}},{"id":"https://openalex.org/T10077","display_name":"Neuroscience and Neuropharmacology Research","score":0.0006000000284984708,"subfield":{"id":"https://openalex.org/subfields/2804","display_name":"Cellular and Molecular Neuroscience"},"field":{"id":"https://openalex.org/fields/28","display_name":"Neuroscience"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T11266","display_name":"Neuroinflammation and Neurodegeneration Mechanisms","score":0.0006000000284984708,"subfield":{"id":"https://openalex.org/subfields/2808","display_name":"Neurology"},"field":{"id":"https://openalex.org/fields/28","display_name":"Neuroscience"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/apoe-epsilon4","display_name":"APOE \u03b54","score":0.9909999966621399},{"id":"https://openalex.org/keywords/amyloid-beta-oligomers","display_name":"amyloid-beta oligomers","score":0.8759999871253967},{"id":"https://openalex.org/keywords/synaptotoxicity","display_name":"synaptotoxicity","score":0.9929999709129333},{"id":"https://openalex.org/keywords/store-operated-calcium-entry","display_name":"store-operated calcium entry","score":0.8830000162124634},{"id":"https://openalex.org/keywords/stromal-interaction-molecule-1","display_name":"STIM1","score":0.9990000128746033},{"id":"https://openalex.org/keywords/stim2","display_name":"STIM2","score":0.7549999952316284},{"id":"https://openalex.org/keywords/gpx4","display_name":"GPX4","score":0.9909999966621399},{"id":"https://openalex.org/keywords/bcl-2","display_name":"Bcl-2","score":0.9240000247955322},{"id":"https://openalex.org/keywords/reactive-oxygen-species","display_name":"reactive oxygen species","score":0.9200000166893005},{"id":"https://openalex.org/keywords/mitochondrial-cristae","display_name":"mitochondrial cristae","score":0.8799999952316284},{"id":"https://openalex.org/keywords/alzheimer-s-disease","display_name":"Alzheimer's disease","score":0.8190000057220459},{"id":"https://openalex.org/keywords/neurodegeneration","display_name":"neurodegeneration","score":0.640999972820282}],"concepts":[{"id":"https://openalex.org/C203522944","wikidata":"https://www.wikidata.org/wiki/Q288322","display_name":"Autophagy","level":3,"score":0.7263000011444092},{"id":"https://openalex.org/C95444343","wikidata":"https://www.wikidata.org/wiki/Q7141","display_name":"Cell biology","level":1,"score":0.6998999714851379},{"id":"https://openalex.org/C2776925932","wikidata":"https://www.wikidata.org/wiki/Q1755122","display_name":"Neurodegeneration","level":3,"score":0.6315000057220459},{"id":"https://openalex.org/C127561419","wikidata":"https://www.wikidata.org/wiki/Q224527","display_name":"Downregulation and upregulation","level":3,"score":0.621999979019165},{"id":"https://openalex.org/C185592680","wikidata":"https://www.wikidata.org/wiki/Q2329","display_name":"Chemistry","level":0,"score":0.5120999813079834},{"id":"https://openalex.org/C53345823","wikidata":"https://www.wikidata.org/wiki/Q5531554","display_name":"Gene isoform","level":3,"score":0.41260001063346863},{"id":"https://openalex.org/C174884520","wikidata":"https://www.wikidata.org/wiki/Q902079","display_name":"Dendritic spine","level":3,"score":0.4020000100135803},{"id":"https://openalex.org/C48349386","wikidata":"https://www.wikidata.org/wiki/Q424361","display_name":"Reactive oxygen species","level":2,"score":0.39079999923706055},{"id":"https://openalex.org/C201571599","wikidata":"https://www.wikidata.org/wiki/Q5018840","display_name":"Calcium signaling","level":3,"score":0.36250001192092896},{"id":"https://openalex.org/C28859421","wikidata":"https://www.wikidata.org/wiki/Q39572","display_name":"Mitochondrion","level":2,"score":0.35740000009536743},{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.3553999960422516},{"id":"https://openalex.org/C2780942790","wikidata":"https://www.wikidata.org/wiki/Q372016","display_name":"Pathogenesis","level":2,"score":0.3328999876976013},{"id":"https://openalex.org/C57089818","wikidata":"https://www.wikidata.org/wiki/Q424728","display_name":"Apolipoprotein E","level":3,"score":0.3305000066757202},{"id":"https://openalex.org/C127445978","wikidata":"https://www.wikidata.org/wiki/Q187181","display_name":"Synapse","level":2,"score":0.3181999921798706},{"id":"https://openalex.org/C2776151105","wikidata":"https://www.wikidata.org/wiki/Q898814","display_name":"Oxidative stress","level":2,"score":0.31369999051094055},{"id":"https://openalex.org/C2781452922","wikidata":"https://www.wikidata.org/wiki/Q2892805","display_name":"Proteostasis","level":2,"score":0.30379998683929443},{"id":"https://openalex.org/C31573885","wikidata":"https://www.wikidata.org/wiki/Q304484","display_name":"Programmed cell death","level":3,"score":0.30320000648498535},{"id":"https://openalex.org/C169760540","wikidata":"https://www.wikidata.org/wiki/Q207011","display_name":"Neuroscience","level":1,"score":0.2903999984264374},{"id":"https://openalex.org/C25274449","wikidata":"https://www.wikidata.org/wiki/Q1805481","display_name":"Long-term potentiation","level":3,"score":0.28189998865127563},{"id":"https://openalex.org/C162740809","wikidata":"https://www.wikidata.org/wiki/Q15334560","display_name":"STIM1","level":3,"score":0.27489998936653137},{"id":"https://openalex.org/C2780795997","wikidata":"https://www.wikidata.org/wiki/Q413283","display_name":"Superoxide","level":3,"score":0.2680000066757202},{"id":"https://openalex.org/C134018914","wikidata":"https://www.wikidata.org/wiki/Q162606","display_name":"Endocrinology","level":1,"score":0.2669000029563904},{"id":"https://openalex.org/C2992195973","wikidata":"https://www.wikidata.org/wiki/Q33123","display_name":"Protein degradation","level":2,"score":0.2624000012874603},{"id":"https://openalex.org/C62478195","wikidata":"https://www.wikidata.org/wiki/Q828130","display_name":"Signal transduction","level":2,"score":0.260699987411499},{"id":"https://openalex.org/C158617107","wikidata":"https://www.wikidata.org/wiki/Q79927","display_name":"Endoplasmic reticulum","level":2,"score":0.26030001044273376},{"id":"https://openalex.org/C2779719074","wikidata":"https://www.wikidata.org/wiki/Q2038057","display_name":"NADPH oxidase","level":3,"score":0.258899986743927},{"id":"https://openalex.org/C2779138974","wikidata":"https://www.wikidata.org/wiki/Q5332073","display_name":"Ebselen","level":5,"score":0.251800000667572}],"mesh":[],"locations_count":1,"locations":[{"id":"doi:10.64898/2026.11.01.763365","doi":"https://doi.org/10.64898/2026.11.01.763365","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.11.01.763365","pdf_url":"https://www.biorxiv.org/content/biorxiv/early/2026/11/03/2026.11.01.763365.full.pdf","source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by-nc","license_id":"https://openalex.org/licenses/cc-by-nc","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"}],"best_oa_location":{"id":"doi:10.64898/2026.11.01.763365","doi":"https://doi.org/10.64898/2026.11.01.763365","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.11.01.763365","pdf_url":"https://www.biorxiv.org/content/biorxiv/early/2026/11/03/2026.11.01.763365.full.pdf","source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by-nc","license_id":"https://openalex.org/licenses/cc-by-nc","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"},"sustainable_development_goals":[{"id":"https://metadata.un.org/sdg/3","display_name":"Good health and well-being","score":0.9391000270843506}],"study_designs":[],"awards":[],"funders":[{"id":"https://openalex.org/F4320310111","display_name":"Wenzhou Medical University","ror":"https://ror.org/00rd5t069"},{"id":"https://openalex.org/F4320321001","display_name":"National Natural Science Foundation of China","ror":"https://ror.org/01h0zpd94"}],"has_content":{"pdf":true,"grobid_xml":true},"content_urls":{"pdf":"https://content.openalex.org/works/W7225159757.pdf","grobid_xml":"https://content.openalex.org/works/W7225159757.grobid-xml"},"referenced_works_count":0,"referenced_works":[],"related_works":["https://openalex.org/W2791755620","https://openalex.org/W2169135478","https://openalex.org/W2157612361","https://openalex.org/W1966895399","https://openalex.org/W2031458272","https://openalex.org/W2059517195","https://openalex.org/W2061387301","https://openalex.org/W2023075118","https://openalex.org/W7159599586","https://openalex.org/W2126375117"],"abstract_inverted_index":{"Extensive":[0],"synaptic":[1,261],"loss":[2],"and":[3,20,63,75,89,95,127,181,201,218,252],"progressive":[4],"neurodegeneration":[5],"are":[6],"defining":[7],"pathological":[8,31,80],"hallmarks":[9],"of":[10,187,204,214,246],"Alzheimer's":[11],"disease":[12],"(AD),":[13],"primarily":[14],"driven":[15],"by":[16,179],"soluble":[17],"A\u03b2":[18],"oligomers":[19],"neurofibrillary":[21],"tangles.":[22],"The":[23],"apolipoprotein":[24],"E4":[25],"(APOE4)":[26],"isoform":[27],"further":[28,210],"aggravates":[29],"these":[30],"cascades,":[32],"yet":[33],"the":[34,134,169,184,239],"precise":[35],"molecular":[36],"mechanisms":[37],"underlying":[38],"AD":[39],"pathogenesis":[40],"remain":[41],"poorly":[42],"elucidated.":[43],"Store-operated":[44],"calcium":[45],"entry":[46],"(SOCE)":[47],"deficiency":[48],"in":[49,150,171,223],"neurons":[50,111],"has":[51],"been":[52],"proven":[53],"to":[54,72,113,197],"exert":[55],"a":[56,229],"detrimental":[57],"effect":[58],"on":[59,159],"dendritic":[60,97,172],"spine":[61],"integrity":[62],"function.":[64],"Herein,":[65],"we":[66],"investigated":[67],"whether":[68],"SOCE":[69,120,132],"dysregulation":[70],"contributes":[71],"A\u03b2O-induced":[73,236],"synaptotoxicity":[74],"how":[76],"APOE4":[77,90,116,182,234],"modulates":[78],"this":[79],"process.":[81],"In":[82,129],"primary":[83],"neuronal":[84,260],"cultures,":[85],"co-treatment":[86],"with":[87,101,105,125,131,146],"A\u03b2O":[88,102,114,126,180],"markedly":[91],"reduced":[92],"synapse":[93],"density":[94],"impaired":[96],"arbor":[98,173],"complexity,":[99],"compared":[100],"treatments":[103],"combined":[104],"APOE3":[106],"or":[107],"APOE2":[108],"isoforms.":[109],"Consistently,":[110],"exposed":[112],"plus":[115],"exhibited":[117],"significantly":[118],"lower":[119],"amplitudes":[121],"than":[122],"those":[123],"treated":[124],"APOE3.":[128],"line":[130],"suppression,":[133],"A\u03b2O/APOE4":[135],"combination":[136,240],"specifically":[137],"downregulated":[138],"stromal":[139],"interaction":[140],"molecule":[141],"1":[142],"(STIM1)":[143],"protein":[144],"expression,":[145],"no":[147],"observable":[148],"change":[149],"STIM2":[151],"levels.":[152],"Mechanistically,":[153],"A\u03b2O/APOE4-mediated":[154],"STIM1":[155,165,176],"reduction":[156],"was":[157,195],"dependent":[158],"p62-selective":[160],"autophagic":[161,185,244,257],"degradation.":[162],"Notably,":[163],"exogenous":[164],"overexpression":[166],"effectively":[167],"rescued":[168],"deficits":[170],"complexity.":[174],"Furthermore,":[175],"downregulation":[177],"induced":[178],"initiated":[183],"degradation":[186,245],"glutathione":[188],"peroxidase":[189],"4":[190],"(Gpx4).":[191],"This":[192],"autophagy":[193],"activation":[194],"attributed":[196],"decreased":[198],"Bcl2":[199,250],"expression":[200,251],"occurs":[202],"independently":[203],"STING":[205],"accumulation.":[206],"Subsequent":[207],"Gpx4":[208,256],"insufficiency":[209],"triggered":[211],"excessive":[212],"accumulation":[213],"reactive":[215],"oxygen":[216],"species":[217],"disrupted":[219],"mitochondrial":[220],"cristae":[221],"morphology":[222],"neurons.":[224],"Collectively,":[225],"our":[226],"findings":[227],"uncover":[228],"previously":[230],"unrecognized":[231],"mechanism":[232],"whereby":[233],"exacerbates":[235],"synaptotoxicity.":[237],"Specifically,":[238],"facilitates":[241],"p62-mediated":[242],"selective":[243],"STIM1,":[247],"which":[248],"suppresses":[249],"ultimately":[253],"promotes":[254],"robust":[255],"degradation,":[258],"driving":[259],"damage.":[262]},"counts_by_year":[],"updated_date":"2026-11-05T12:25:35.769452","created_date":"2026-11-04T00:00:00"}