{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:53:10Z","timestamp":1787507590976,"version":"build-2736575974"},"posted":{"date-parts":[[2025,7,29]]},"group-title":"Neuroscience","reference-count":59,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T00:00:00Z","timestamp":1753747200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["R01AG080585"],"award-info":[{"award-number":["R01AG080585"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32AG52354"],"award-info":[{"award-number":["T32AG52354"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/05ewr7t48","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,7,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>\n                    Synaptic dysfunction is an early feature of Alzheimer\u2019s disease (AD) and a significant contributor to cognitive decline and neurodegeneration. Proper localization of proteins involved in pre-and post-synaptic composition is dependent on endosomal recycling and trafficking. Alterations in trafficking complexes, such as retromer, have been shown to impair neuronal synaptic function. The\n                    <jats:italic>SORL1<\/jats:italic>\n                    gene has been strongly implicated in AD pathogenesis and its protein product, SORLA, is an endosomal receptor that works in conjunction with retromer to regulate endosomal recycling.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>\n                    We utilized our established human induced pluripotent stem cell (hiPSC) derived excitatory cortical neuron model to examine\n                    <jats:italic>SORL1<\/jats:italic>\n                    \u2019s role in synaptic protein composition and neuronal function. We used Quantitative Multiplex co-Immunoprecipitation (QMI), a mesoscale proteomics assay to measure synaptic protein interactions, immunocytochemistry to assay synapses and AMPA receptor subunits, and multi-electrode arrays (MEAs) to measure neuronal function of\n                    <jats:italic>SORL1<\/jats:italic>\n                    KO and isogenic control hiPSC derived neurons.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We show that loss of\n                    <jats:italic>SORL1<\/jats:italic>\n                    expression significantly changes many synaptic protein-protein interactions and patterns of expression. We demonstrate that\n                    <jats:italic>SORL1<\/jats:italic>\n                    deficient neurons are hyperactive and that the increased activity is driven by glutamatergic neurotransmission. Hyperexcitability has been seen in other models of AD with familial AD variants in amyloid precursor protein and presenilin genes, due to the increases in amyloid beta (A\u03b2) peptides. In the case of\n                    <jats:italic>SORL1<\/jats:italic>\n                    deficiency, the hyperexcitability we observe is primarily due to mis-trafficking of synaptic proteins, rather than an overall increase in A\u03b2. Finally, we find that\n                    <jats:italic>SORL1<\/jats:italic>\n                    deficient neurons have impaired synaptic plasticity.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>These findings further support a growing body of literature implicating early endosomal recycling defects as drivers of AD pathogenesis. Furthermore, our work supports further emphasis on exploring the SORL1-retromer pathway for therapeutic development in AD.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.07.28.667194","type":"posted-content","created":{"date-parts":[[2025,7,29]],"date-time":"2025-07-29T13:45:12Z","timestamp":1753796712000},"source":"Crossref","is-referenced-by-count":1,"title":["The Alzheimer\u2019s disease risk gene\n                  <i>SORL1<\/i>\n                  is a regulator of excitatory neuronal function"],"prefix":"10.64898","author":[{"given":"C. Andrew","family":"Williams","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shannon E.","family":"Rose","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vera","family":"Stamenkovic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4180-573X","authenticated-orcid":false,"given":"Stephen E.P.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2106-0339","authenticated-orcid":false,"given":"Jessica E.","family":"Young","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025073106000933000_2025.07.28.667194v1.1","doi-asserted-by":"publisher","DOI":"10.3233\/ADR-200177"},{"key":"2025073106000933000_2025.07.28.667194v1.2","doi-asserted-by":"publisher","DOI":"10.1016\/J.NEUROBIOLAGING.2017.07.001"},{"key":"2025073106000933000_2025.07.28.667194v1.3","doi-asserted-by":"publisher","DOI":"10.3791\/60029"},{"key":"2025073106000933000_2025.07.28.667194v1.4","doi-asserted-by":"publisher","DOI":"10.1126\/science.1162844"},{"key":"2025073106000933000_2025.07.28.667194v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/378075a0"},{"key":"2025073106000933000_2025.07.28.667194v1.6","doi-asserted-by":"publisher","DOI":"10.1002\/ana.24695"},{"key":"2025073106000933000_2025.07.28.667194v1.7","doi-asserted-by":"publisher","DOI":"10.1186\/S40035-024-00460-7"},{"key":"2025073106000933000_2025.07.28.667194v1.8","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-023-02652-3"},{"key":"2025073106000933000_2025.07.28.667194v1.9","doi-asserted-by":"publisher","DOI":"10.1098\/RSTB.2022.0377"},{"key":"2025073106000933000_2025.07.28.667194v1.10","doi-asserted-by":"publisher","DOI":"10.7554\/ELIFE.50333"},{"key":"2025073106000933000_2025.07.28.667194v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2022.05.028"},{"key":"2025073106000933000_2025.07.28.667194v1.12","doi-asserted-by":"publisher","DOI":"10.3233\/JAD-160702\/ASSET\/0269B2D7-0469-404A-8EA0-5C78E82AFF69\/ASSETS\/GRAPHIC\/10.3233_JAD-160702-FIG1.JPG"},{"key":"2025073106000933000_2025.07.28.667194v1.13","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2181-19.2020"},{"key":"2025073106000933000_2025.07.28.667194v1.14","doi-asserted-by":"publisher","DOI":"10.1126\/scisignal.abd7325"},{"key":"2025073106000933000_2025.07.28.667194v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2009.04.011"},{"key":"2025073106000933000_2025.07.28.667194v1.16","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-03134-2"},{"key":"2025073106000933000_2025.07.28.667194v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2017.87"},{"key":"2025073106000933000_2025.07.28.667194v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/nature10821"},{"key":"2025073106000933000_2025.07.28.667194v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2020.101208"},{"key":"2025073106000933000_2025.07.28.667194v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.yexcr.2017.03.002"},{"key":"2025073106000933000_2025.07.28.667194v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/S41467-025-57751-4"},{"key":"2025073106000933000_2025.07.28.667194v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2020.107719"},{"key":"2025073106000933000_2025.07.28.667194v1.23","doi-asserted-by":"publisher","DOI":"10.1111\/j.1440-1789.2009.01090.x"},{"key":"2025073106000933000_2025.07.28.667194v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2802"},{"key":"2025073106000933000_2025.07.28.667194v1.25","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-9-1"},{"key":"2025073106000933000_2025.07.28.667194v1.26","doi-asserted-by":"publisher","DOI":"10.1111\/jnc.14466"},{"key":"2025073106000933000_2025.07.28.667194v1.27","doi-asserted-by":"publisher","DOI":"10.1016\/J.CELREP.2021.110076"},{"key":"2025073106000933000_2025.07.28.667194v1.28","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts034"},{"key":"2025073106000933000_2025.07.28.667194v1.29","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1714409115"},{"key":"2025073106000933000_2025.07.28.667194v1.30","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.0050254"},{"key":"2025073106000933000_2025.07.28.667194v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2004.09.012"},{"key":"2025073106000933000_2025.07.28.667194v1.32","doi-asserted-by":"publisher","DOI":"10.1016\/J.STEMCR.2023.10.011"},{"key":"2025073106000933000_2025.07.28.667194v1.33","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-022-04225-1"},{"key":"2025073106000933000_2025.07.28.667194v1.34","doi-asserted-by":"publisher","DOI":"10.1002\/GLIA.70009;WGROUP:STRING:PUBLICATION"},{"key":"2025073106000933000_2025.07.28.667194v1.35","doi-asserted-by":"publisher","DOI":"10.1038\/srep26181"},{"key":"2025073106000933000_2025.07.28.667194v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2583"},{"key":"2025073106000933000_2025.07.28.667194v1.37","doi-asserted-by":"publisher","DOI":"10.1126\/science.1102026"},{"key":"2025073106000933000_2025.07.28.667194v1.38","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-819410-2.00022-9"},{"key":"2025073106000933000_2025.07.28.667194v1.39","doi-asserted-by":"publisher","DOI":"10.1371\/JOURNAL.PGEN.1005025"},{"key":"2025073106000933000_2025.07.28.667194v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-50226-9"},{"key":"2025073106000933000_2025.07.28.667194v1.41","doi-asserted-by":"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