{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:17:45Z","timestamp":1785406665956,"version":"3.56.0"},"posted":{"date-parts":[[2025,9,20]]},"group-title":"Neuroscience","reference-count":127,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T00:00:00Z","timestamp":1758326400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"award":["R01AG070193"],"award-info":[{"award-number":["R01AG070193"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["T32AG00026624"],"award-info":[{"award-number":["T32AG00026624"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000957","name":"Alzheimer's Association","doi-asserted-by":"crossref","award":["AARFD-21-850893"],"award-info":[{"award-number":["AARFD-21-850893"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,20]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Synapse function is critical for cognition, and synapse loss is highly correlated with cognitive decline in Alzheimer\u2019s disease and related dementias. Tau oligomers, which accumulate in the brain in Alzheimer\u2019s disease, can acutely inhibit synaptic plasticity and cause synapse loss. Coordinated presynaptic and postsynaptic function is essential for effective synaptic transmission, and both compartments can be dysregulated by pathogenic tau. However, the series of pathophysiological events triggered by tau oligomers to cause the dysfunction and deterioration of presynaptic terminals and postsynaptic sites remain unclear.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We developed a proximity labeling tool to map the postsynaptic proteome by fusing PSD-95 with APEX2 (APEX2-PSD-95) which was expressed in human induced pluripotent stem cell (iPSC)-derived neurons. We used APEX2-PSD-95 to map the dynamic changes in the postsynaptic proteome with precise temporal resolution after an acute exposure of human iPSC-derived neurons to recombinant tau oligomers for 30 min. Leveraging immunocytochemistry, electrophysiology and electron microscopy, we further delineated the impact of the acute tau oligomer exposure on presynaptic and postsynaptic compartments over time for up to 14 days.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>The brief exposure of human iPSC-derived neurons to tau oligomers caused a progressive deterioration of synapses, marked by both presynaptic and postsynaptic dysregulation. Postsynaptic proteome mapping revealed an immediate tau oligomer-triggered downregulation of the postsynaptic actin motor proteins Myosin-Va and Myosin-10, which coincided with impaired AMPA receptor (AMPAR) trafficking during synaptic plasticity. This was followed 24 hours later by the upregulation of disease-related proteins, including GSK3\u03b2, at postsynaptic sites. The loss of PSD-95-labeled postsynaptic sites at 7 days after tau oligomer exposure preceded the loss of Synapsin-labeled presynaptic terminals at 14 days. The postsynaptic sites that remained exhibited a long-term downregulation of postsynaptic AMPAR levels and sustained synaptic plasticity impairment. Moreover, the remaining presynaptic terminals contained less clusters of vesicles at the presynaptic active zone which was associated with reduced vesicle release probability at synapses.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our findings reveal the series of events underlying tau oligomer-induced bipartite synapse deterioration. The progressive decline of synapses involves the emergence of two synapse fates. One synapse fate involves the persistent weakening of both presynaptic and postsynaptic function, and the other results in synaptic loss.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.19.677215","type":"posted-content","created":{"date-parts":[[2025,9,20]],"date-time":"2025-09-20T16:15:18Z","timestamp":1758384918000},"source":"Crossref","is-referenced-by-count":0,"title":["Tau oligomers modulate synapse fate by eliciting progressive bipartite synapse dysregulation and synapse loss"],"prefix":"10.64898","author":[{"given":"Kristeen A.","family":"Pareja-Navarro","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina D.","family":"King","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grant","family":"Kauwe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yani Y.","family":"Ngwala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Doyle","family":"Lokitiyakul","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivy","family":"Wong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aaryan","family":"Vira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jackson H.","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mahima","family":"Sharma","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriel","family":"Navarro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olfat","family":"Malak","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9907-2749","authenticated-orcid":false,"given":"Birgit","family":"Schilling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3356-4091","authenticated-orcid":false,"given":"Tara E.","family":"Tracy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2025092311451055000_2025.09.19.677215v1.1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410270502"},{"key":"2025092311451055000_2025.09.19.677215v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410300410"},{"issue":"9","key":"2025092311451055000_2025.09.19.677215v1.3","doi-asserted-by":"crossref","first-page":"2799","DOI":"10.1038\/s41380-024-02501-z","article-title":"Tau pathology is associated with synaptic density and longitudinal synaptic loss in Alzheimer\u2019s disease","volume":"29","year":"2024","journal-title":"Mol Psychiatry"},{"key":"2025092311451055000_2025.09.19.677215v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/j.conb.2018.04.027"},{"issue":"1","key":"2025092311451055000_2025.09.19.677215v1.5","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1186\/s40035-021-00270-1","article-title":"The role of pathological tau in synaptic dysfunction in Alzheimer\u2019s diseases","volume":"10","year":"2021","journal-title":"Transl Neurodegener"},{"key":"2025092311451055000_2025.09.19.677215v1.6","doi-asserted-by":"crossref","unstructured":"Rawat, P. , et al., Phosphorylated Tau in Alzheimer\u2019s Disease and Other Tauopathies. Int J Mol Sci, 2022. 23(21).","DOI":"10.3390\/ijms232112841"},{"key":"2025092311451055000_2025.09.19.677215v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jbc.2021.101442"},{"issue":"21","key":"2025092311451055000_2025.09.19.677215v1.8","doi-asserted-by":"crossref","first-page":"3959","DOI":"10.1021\/acschemneuro.3c00578","article-title":"Identification of Aggregation Mechanism of Acetylated PHF6* and PHF6 Tau Peptides Based on Molecular Dynamics Simulations and Markov State Modeling","volume":"14","year":"2023","journal-title":"ACS Chem Neurosci"},{"key":"2025092311451055000_2025.09.19.677215v1.9","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2009.07.029"},{"key":"2025092311451055000_2025.09.19.677215v1.10","doi-asserted-by":"publisher","DOI":"10.1126\/science.1113694"},{"key":"2025092311451055000_2025.09.19.677215v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.neures.2005.11.009"},{"key":"2025092311451055000_2025.09.19.677215v1.12","doi-asserted-by":"publisher","DOI":"10.1096\/fj.11-199851"},{"key":"2025092311451055000_2025.09.19.677215v1.13","doi-asserted-by":"publisher","DOI":"10.1186\/1750-1326-6-39"},{"key":"2025092311451055000_2025.09.19.677215v1.14","doi-asserted-by":"publisher","DOI":"10.2353\/ajpath.2006.050840"},{"key":"2025092311451055000_2025.09.19.677215v1.15","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.0587-07.2007"},{"key":"2025092311451055000_2025.09.19.677215v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2012.06.033"},{"key":"2025092311451055000_2025.09.19.677215v1.17","doi-asserted-by":"publisher","DOI":"10.1111\/j.1750-3639.2012.00598.x"},{"issue":"11","key":"2025092311451055000_2025.09.19.677215v1.18","doi-asserted-by":"crossref","first-page":"1209","DOI":"10.1001\/jamaneurol.2023.3530","article-title":"Tau Oligomer-Containing Synapse Elimination by Microglia and Astrocytes in Alzheimer Disease","volume":"80","year":"2023","journal-title":"JAMA Neurol"},{"key":"2025092311451055000_2025.09.19.677215v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.04.020"},{"issue":"4","key":"2025092311451055000_2025.09.19.677215v1.20","doi-asserted-by":"crossref","first-page":"1661","DOI":"10.3233\/JAD-200716","article-title":"Functional Integrity of Synapses in the Central Nervous System of Cognitively Intact Individuals with High Alzheimer\u2019s Disease Neuropathology Is Associated with Absence of Synaptic Tau Oligomers","volume":"78","year":"2020","journal-title":"J Alzheimers Dis"},{"key":"2025092311451055000_2025.09.19.677215v1.21","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2013.00093"},{"key":"2025092311451055000_2025.09.19.677215v1.22","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-019-03349-1"},{"issue":"4","key":"2025092311451055000_2025.09.19.677215v1.23","doi-asserted-by":"crossref","first-page":"226","DOI":"10.1002\/acn3.382","article-title":"Tau oligomers in cerebrospinal fluid in Alzheimer\u2019s disease","volume":"4","year":"2017","journal-title":"Ann Clin Transl Neurol"},{"key":"2025092311451055000_2025.09.19.677215v1.24","doi-asserted-by":"publisher","DOI":"10.1038\/srep00700"},{"key":"2025092311451055000_2025.09.19.677215v1.25","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2020.579434"},{"key":"2025092311451055000_2025.09.19.677215v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2503-3"},{"key":"2025092311451055000_2025.09.19.677215v1.27","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.1523-15.2015"},{"key":"2025092311451055000_2025.09.19.677215v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.12.015"},{"key":"2025092311451055000_2025.09.19.677215v1.29","doi-asserted-by":"publisher","DOI":"10.1038\/srep19393"},{"key":"2025092311451055000_2025.09.19.677215v1.30","doi-asserted-by":"crossref","unstructured":"Puzzo, D. , et al., LTP and memory impairment caused by extracellular A\u03b2 and Tau oligomers is APP-dependent. Elife, 2017. 6.","DOI":"10.7554\/eLife.26991"},{"key":"2025092311451055000_2025.09.19.677215v1.31","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-019-0326-4"},{"key":"2025092311451055000_2025.09.19.677215v1.32","doi-asserted-by":"crossref","unstructured":"Hill, E. , et al., Introduction of Tau Oligomers into Cortical Neurons Alters Action Potential Dynamics and Disrupts Synaptic Transmission and Plasticity. eNeuro, 2019. 6(5).","DOI":"10.1523\/ENEURO.0166-19.2019"},{"issue":"1","key":"2025092311451055000_2025.09.19.677215v1.33","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s40478-025-01930-3","article-title":"Tau oligomers impair memory and synaptic plasticity through the cellular prion protein","volume":"13","year":"2025","journal-title":"Acta Neuropathol Commun"},{"issue":"1","key":"2025092311451055000_2025.09.19.677215v1.34","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1186\/s13041-025-01208-8","article-title":"Divergent disruptive effects of soluble recombinant tau assemblies on synaptic plasticity in vivo","volume":"18","year":"2025","journal-title":"Mol Brain"},{"key":"2025092311451055000_2025.09.19.677215v1.35","first-page":"464","article-title":"Tau Oligomers: The Toxic Player at Synapses in Alzheimer\u2019s Disease","volume":"9","year":"2015","journal-title":"Front Cell Neurosci"},{"key":"2025092311451055000_2025.09.19.677215v1.36","doi-asserted-by":"publisher","DOI":"10.1016\/j.jalz.2017.04.002"},{"key":"2025092311451055000_2025.09.19.677215v1.37","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2006.05032.x"},{"issue":"1633","key":"2025092311451055000_2025.09.19.677215v1.38","doi-asserted-by":"crossref","first-page":"20130138","DOI":"10.1098\/rstb.2013.0138","article-title":"Long-term depression: a cell biological view","volume":"369","year":"2014","journal-title":"Philos Trans R Soc Lond B Biol Sci"},{"key":"2025092311451055000_2025.09.19.677215v1.39","doi-asserted-by":"publisher","DOI":"10.1177\/1073858418769644"},{"key":"2025092311451055000_2025.09.19.677215v1.40","doi-asserted-by":"crossref","unstructured":"Hu, N.W. , et al., Patient-derived tau and amyloid-\u03b2 facilitate long-term depression in vivo: role of tumour necrosis factor-\u03b1 and the integrated stress response. Brain Commun, 2024. 6(5): p. fcae333.","DOI":"10.1093\/braincomms\/fcae333"},{"key":"2025092311451055000_2025.09.19.677215v1.41","doi-asserted-by":"publisher","DOI":"10.3389\/fnins.2018.00963"},{"issue":"4","key":"2025092311451055000_2025.09.19.677215v1.42","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1016\/j.stemcr.2017.08.019","article-title":"Scalable Production of iPSC-Derived Human Neurons to Identify Tau-Lowering Compounds by High-Content Screening","volume":"9","year":"2017","journal-title":"Stem Cell Reports"},{"issue":"3","key":"2025092311451055000_2025.09.19.677215v1.43","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1017\/S1551929513000485","article-title":"Handling Cell Culture Monolayers for Transmission Electron Microscopy","volume":"21","year":"2013","journal-title":"Microscopy Today"},{"key":"2025092311451055000_2025.09.19.677215v1.44","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.3179"},{"key":"2025092311451055000_2025.09.19.677215v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.11.027"},{"issue":"6","key":"2025092311451055000_2025.09.19.677215v1.46","first-page":"O111","article-title":"Targeted data extraction of the MS\/MS spectra generated by data-independent acquisition: a new concept for consistent and accurate proteome analysis","volume":"11","year":"2012","journal-title":"Mol Cell Proteomics"},{"key":"2025092311451055000_2025.09.19.677215v1.47","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.RA117.000314"},{"key":"2025092311451055000_2025.09.19.677215v1.48","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-017-00249-5"},{"key":"2025092311451055000_2025.09.19.677215v1.49","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.7b00170"},{"key":"2025092311451055000_2025.09.19.677215v1.50","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jproteome.7b00170"},{"key":"2025092311451055000_2025.09.19.677215v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.05.002.SynGO"},{"key":"2025092311451055000_2025.09.19.677215v1.52","doi-asserted-by":"publisher","DOI":"10.1038\/ng1180"},{"key":"2025092311451055000_2025.09.19.677215v1.53","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0506580102"},{"key":"2025092311451055000_2025.09.19.677215v1.54","doi-asserted-by":"publisher","DOI":"10.1093\/NAR\/GKAC1000"},{"key":"2025092311451055000_2025.09.19.677215v1.55","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btp101"},{"key":"2025092311451055000_2025.09.19.677215v1.56","doi-asserted-by":"crossref","unstructured":"Kauwe, G. , et al., KIBRA repairs synaptic plasticity and promotes resilience to tauopathy-related memory loss. J Clin Invest, 2024. 134(3).","DOI":"10.1172\/JCI169064"},{"key":"2025092311451055000_2025.09.19.677215v1.57","doi-asserted-by":"crossref","unstructured":"Kauwe, G. , et al., Pathogenic tau inhibits synaptic plasticity by blocking eIF4B-mediated local protein synthesis. bioRxiv, 2025: p. 2025.09.11.675671.","DOI":"10.1101\/2025.09.11.675671"},{"key":"2025092311451055000_2025.09.19.677215v1.58","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.07.041"},{"key":"2025092311451055000_2025.09.19.677215v1.59","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.12.041"},{"key":"2025092311451055000_2025.09.19.677215v1.60","doi-asserted-by":"crossref","unstructured":"Liao, S. , et al., Identification of the B7-H3 Interaction Partners Using a Proximity Labeling Strategy. Int J Mol Sci, 2025. 26(4).","DOI":"10.3390\/ijms26041731"},{"key":"2025092311451055000_2025.09.19.677215v1.61","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-023-00673-w"},{"key":"2025092311451055000_2025.09.19.677215v1.62","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2013.04.017"},{"key":"2025092311451055000_2025.09.19.677215v1.63","doi-asserted-by":"publisher","DOI":"10.1038\/nn.2719"},{"key":"2025092311451055000_2025.09.19.677215v1.64","doi-asserted-by":"publisher","DOI":"10.1038\/nn2063"},{"issue":"8","key":"2025092311451055000_2025.09.19.677215v1.65","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1007\/s12264-023-01174-y","article-title":"Myosin Va-dependent Transport of NMDA Receptors in Hippocampal Neurons","volume":"40","year":"2024","journal-title":"Neurosci Bull"},{"key":"2025092311451055000_2025.09.19.677215v1.66","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3294-10.2011"},{"key":"2025092311451055000_2025.09.19.677215v1.67","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2010.07.016"},{"issue":"1","key":"2025092311451055000_2025.09.19.677215v1.68","doi-asserted-by":"crossref","first-page":"4466","DOI":"10.1038\/s41467-023-40208-x","article-title":"Compilation of reported protein changes in the brain in Alzheimer\u2019s disease","volume":"14","year":"2023","journal-title":"Nature Communications"},{"key":"2025092311451055000_2025.09.19.677215v1.69","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-021-00999-y"},{"key":"2025092311451055000_2025.09.19.677215v1.70","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/s42003-018-0254-9","article-title":"Regional protein expression in human Alzheimer\u2019s brain correlates with disease severity","volume":"2","year":"2019","journal-title":"Commun Biol"},{"issue":"1","key":"2025092311451055000_2025.09.19.677215v1.71","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.cels.2016.11.006","article-title":"A Multi-network Approach Identifies Protein-Specific Co-expression in Asymptomatic and Symptomatic Alzheimer\u2019s Disease","volume":"4","year":"2017","journal-title":"Cell Syst"},{"key":"2025092311451055000_2025.09.19.677215v1.72","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-018-0282-4"},{"key":"2025092311451055000_2025.09.19.677215v1.73","doi-asserted-by":"publisher","DOI":"10.1002\/prca.201100068"},{"key":"2025092311451055000_2025.09.19.677215v1.74","doi-asserted-by":"publisher","DOI":"10.1038\/S41591-020-0815-6"},{"key":"2025092311451055000_2025.09.19.677215v1.75","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-020-0635-5"},{"key":"2025092311451055000_2025.09.19.677215v1.76","doi-asserted-by":"publisher","DOI":"10.1074\/mcp.M115.056580"},{"key":"2025092311451055000_2025.09.19.677215v1.77","doi-asserted-by":"publisher","DOI":"10.1038\/srep11138"},{"issue":"1","key":"2025092311451055000_2025.09.19.677215v1.78","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1186\/s40478-018-0524-2","article-title":"Integrated proteomics and network analysis identifies protein hubs and network alterations in Alzheimer\u2019s disease","volume":"6","year":"2018","journal-title":"Acta Neuropathol Commun"},{"key":"2025092311451055000_2025.09.19.677215v1.79","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbagen.2012.09.008"},{"key":"2025092311451055000_2025.09.19.677215v1.80","doi-asserted-by":"publisher","DOI":"10.1016\/j.mam.2008.08.009"},{"key":"2025092311451055000_2025.09.19.677215v1.81","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M414635200"},{"key":"2025092311451055000_2025.09.19.677215v1.82","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-pharmtox-011112-140320"},{"key":"2025092311451055000_2025.09.19.677215v1.83","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M006219200"},{"key":"2025092311451055000_2025.09.19.677215v1.84","doi-asserted-by":"publisher","DOI":"10.1016\/0304-3940(92)90774-2"},{"key":"2025092311451055000_2025.09.19.677215v1.85","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamcr.2020.118664"},{"key":"2025092311451055000_2025.09.19.677215v1.86","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/4209475"},{"key":"2025092311451055000_2025.09.19.677215v1.87","doi-asserted-by":"crossref","unstructured":"Sayas, C.L. and J. \u00c1vila , GSK-3 and Tau: A Key Duet in Alzheimer\u2019s Disease. Cells, 2021. 10(4).","DOI":"10.3390\/cells10040721"},{"key":"2025092311451055000_2025.09.19.677215v1.88","doi-asserted-by":"publisher","DOI":"10.1038\/bjp.2008.2"},{"key":"2025092311451055000_2025.09.19.677215v1.89","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2006.05245.x"},{"key":"2025092311451055000_2025.09.19.677215v1.90","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.3321-07.2007"},{"key":"2025092311451055000_2025.09.19.677215v1.91","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2007.01.029"},{"key":"2025092311451055000_2025.09.19.677215v1.92","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3759"},{"key":"2025092311451055000_2025.09.19.677215v1.93","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2011.09.034"},{"key":"2025092311451055000_2025.09.19.677215v1.94","doi-asserted-by":"publisher","DOI":"10.1152\/physiol.00009.2020"},{"key":"2025092311451055000_2025.09.19.677215v1.95","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgab790"},{"key":"2025092311451055000_2025.09.19.677215v1.96","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2022.02.028"},{"issue":"s1","key":"2025092311451055000_2025.09.19.677215v1.97","doi-asserted-by":"crossref","first-page":"S453","DOI":"10.3233\/JAD-220514","article-title":"The Novel Role of Mitochondrial Citrate Synthase and Citrate in the Pathophysiology of Alzheimer\u2019s Disease","volume":"94","year":"2023","journal-title":"J Alzheimers Dis"},{"key":"2025092311451055000_2025.09.19.677215v1.98","doi-asserted-by":"crossref","unstructured":"Han, R. , J. Liang , and B. Zhou , Glucose Metabolic Dysfunction in Neurodegenerative Diseases-New Mechanistic Insights and the Potential of Hypoxia as a Prospective Therapy Targeting Metabolic Reprogramming. Int J Mol Sci, 2021. 22(11).","DOI":"10.3390\/ijms22115887"},{"key":"2025092311451055000_2025.09.19.677215v1.99","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2024.03.015"},{"issue":"1","key":"2025092311451055000_2025.09.19.677215v1.100","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1186\/s13024-024-00786-w","article-title":"Distinct regulation of Tau Monomer and aggregate uptake and intracellular accumulation in human neurons","volume":"19","year":"2024","journal-title":"Mol Neurodegener"},{"key":"2025092311451055000_2025.09.19.677215v1.101","doi-asserted-by":"crossref","unstructured":"Pardo, E. , et al., Mitochondrial NADK2-dependent NADPH controls Tau oligomer uptake in human neurons. bioRxiv, 2024.","DOI":"10.1101\/2024.10.31.621392"},{"issue":"1","key":"2025092311451055000_2025.09.19.677215v1.102","doi-asserted-by":"crossref","first-page":"e12029","DOI":"10.1002\/trc2.12029","article-title":"A human induced pluripotent stem cell-derived cortical neuron human-on-a chip system to study A\u03b2(42) and tau-induced pathophysiological effects on long-term potentiation","volume":"6","year":"2020","journal-title":"Alzheimers Dement (N Y"},{"key":"2025092311451055000_2025.09.19.677215v1.103","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15295"},{"key":"2025092311451055000_2025.09.19.677215v1.104","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.01.022"},{"key":"2025092311451055000_2025.09.19.677215v1.105","doi-asserted-by":"publisher","DOI":"10.1016\/j.ceb.2021.02.007"},{"key":"2025092311451055000_2025.09.19.677215v1.106","doi-asserted-by":"publisher","DOI":"10.1038\/ncb2135"},{"key":"2025092311451055000_2025.09.19.677215v1.107","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.132969"},{"key":"2025092311451055000_2025.09.19.677215v1.108","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-019-52543-5"},{"key":"2025092311451055000_2025.09.19.677215v1.109","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M703269200"},{"key":"2025092311451055000_2025.09.19.677215v1.110","doi-asserted-by":"publisher","DOI":"10.1021\/acschemneuro.9b00459"},{"key":"2025092311451055000_2025.09.19.677215v1.111","doi-asserted-by":"crossref","unstructured":"Marcatti, M. , et al., Inhibition of Calcineurin with FK506 Reduces Tau Levels and Attenuates Synaptic Impairment Driven by Tau Oligomers in the Hippocampus of Male Mouse Models. Int J Mol Sci, 2024. 25(16).","DOI":"10.3390\/ijms25169092"},{"key":"2025092311451055000_2025.09.19.677215v1.112","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddab363"},{"key":"2025092311451055000_2025.09.19.677215v1.113","doi-asserted-by":"publisher","DOI":"10.3389\/fnagi.2017.00083"},{"key":"2025092311451055000_2025.09.19.677215v1.114","doi-asserted-by":"crossref","unstructured":"Spina, E. , et al., Mitochondrial Alterations, Oxidative Stress, and Therapeutic Implications in Alzheimer\u2019s Disease: A Narrative Review. Cells, 2025. 14(3).","DOI":"10.3390\/cells14030229"},{"key":"2025092311451055000_2025.09.19.677215v1.115","doi-asserted-by":"crossref","first-page":"148545","DOI":"10.1016\/j.brainres.2023.148545","article-title":"Identification of genes related to glucose metabolism and analysis of the immune characteristics in Alzheimer\u2019s disease","volume":"1819","year":"2023","journal-title":"Brain Res"},{"issue":"3","key":"2025092311451055000_2025.09.19.677215v1.116","doi-asserted-by":"crossref","first-page":"803","DOI":"10.3233\/JAD-170168","article-title":"Extracellular Tau Oligomers Induce Invasion of Endogenous Tau into the Somatodendritic Compartment and Axonal Transport Dysfunction","volume":"58","year":"2017","journal-title":"J Alzheimers Dis"},{"key":"2025092311451055000_2025.09.19.677215v1.117","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-32-9358-8_23"},{"key":"2025092311451055000_2025.09.19.677215v1.118","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-018-1937-5"},{"key":"2025092311451055000_2025.09.19.677215v1.119","doi-asserted-by":"publisher","DOI":"10.1038\/srep30498"},{"key":"2025092311451055000_2025.09.19.677215v1.120","doi-asserted-by":"publisher","DOI":"10.1016\/J.MOLCEL.2021.07.038"},{"issue":"3","key":"2025092311451055000_2025.09.19.677215v1.121","doi-asserted-by":"crossref","first-page":"1656","DOI":"10.1002\/alz.13535","article-title":"Structural and functional damage to neuronal nuclei caused by extracellular tau oligomers","volume":"20","year":"2024","journal-title":"Alzheimers Dement"},{"issue":"4","key":"2025092311451055000_2025.09.19.677215v1.122","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.3233\/JAD-221284","article-title":"Extracellular Tau Oligomers Damage the Axon Initial Segment","volume":"93","year":"2023","journal-title":"Journal of Alzheimer\u2019s Disease"},{"key":"2025092311451055000_2025.09.19.677215v1.123","doi-asserted-by":"crossref","first-page":"39","DOI":"10.1016\/j.nlm.2016.10.013","article-title":"Long-term depression-associated signaling is required for an in vitro model of NMDA receptor-dependent synapse pruning","volume":"138","year":"2017","journal-title":"Neurobiol Learn Mem"},{"key":"2025092311451055000_2025.09.19.677215v1.124","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2008.09.018"},{"key":"2025092311451055000_2025.09.19.677215v1.125","doi-asserted-by":"publisher","DOI":"10.1002\/alz.13682"},{"key":"2025092311451055000_2025.09.19.677215v1.126","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.10.014"},{"issue":"9","key":"2025092311451055000_2025.09.19.677215v1.127","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1038\/s43587-022-00281-1","article-title":"Complement C1q-dependent excitatory and inhibitory synapse elimination by astrocytes and microglia in Alzheimer\u2019s disease mouse models","volume":"2","year":"2022","journal-title":"Nat Aging"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.09.19.677215","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T05:05:05Z","timestamp":1782277505000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.1101\/2025.09.19.677215"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,9,20]]},"references-count":127,"URL":"https:\/\/doi.org\/10.1101\/2025.09.19.677215","relation":{"is-preprint-of":[{"id-type":"doi","id":"10.1186\/s13024-026-00928-2","asserted-by":"subject"}]},"subject":[],"published":{"date-parts":[[2025,9,20]]},"subtype":"preprint"}}