{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T09:20:57Z","timestamp":1775985657780,"version":"3.50.1"},"posted":{"date-parts":[[2024,4,12]]},"group-title":"Neurology","reference-count":48,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,4,12]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Mutations in the\n                  <jats:italic>MAPT<\/jats:italic>\n                  gene encoding tau protein can cause autosomal dominant neurodegenerative tauopathies including frontotemporal dementia (often with Parkinsonism). In Alzheimer\u2019s disease, the most common tauopathy, synapse loss is the strongest pathological correlate of cognitive decline. Recently, PET imaging with synaptic tracers revealed clinically relevant loss of synapses in primary tauopathies; however, the molecular mechanisms leading to synapse degeneration in primary tauopathies remain largely unknown. In this study, we examined post-mortem brain tissue from people who died with frontotemporal dementia with tau pathology (FTDtau) caused by the\n                  <jats:italic>MAPT<\/jats:italic>\n                  intronic exon 10+16 mutation, which increases splice variants containing exon 10 resulting in higher levels of tau with four microtubule binding domains. We used RNA sequencing and histopathology to examine temporal cortex and visual cortex, to look for molecular phenotypes compared to age, sex, and RNA integrity matched participants who died without neurological disease (n=12 per group). Bulk tissue RNA sequencing reveals substantial downregulation of gene expression associated with synaptic function. Upregulated biological pathways in human\n                  <jats:italic>MAPT<\/jats:italic>\n                  10+16 brain included those involved in transcriptional regulation, DNA damage response, and neuroinflammation. Histopathology confirmed increased pathological tau accumulation in FTDtau cortex as well as a loss of presynaptic protein staining, and region-specific increased colocalization of phospho-tau with synapses in temporal cortex. Our data indicate that synaptic pathology likely contributes to pathogenesis in FTDtau caused by the\n                  <jats:italic>MAPT<\/jats:italic>\n                  10+16 mutation.\n                <\/jats:p>","DOI":"10.1101\/2024.04.09.24305501","type":"posted-content","created":{"date-parts":[[2024,4,12]],"date-time":"2024-04-12T23:25:20Z","timestamp":1712964320000},"source":"Crossref","is-referenced-by-count":2,"title":["Synaptic gene expression changes in frontotemporal dementia due to the\n                  <i>MAPT<\/i>\n                  10+16 mutation"],"prefix":"10.64898","author":[{"given":"Owen","family":"Dando","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"McGeachan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jamie","family":"McQueen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Baxter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Nathan","family":"Rockley","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hannah","family":"McAlister","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adharsh","family":"Prasad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"He","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Declan","family":"King","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jamie","family":"Rose","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0525-6323","authenticated-orcid":false,"given":"Phillip B","family":"Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane","family":"Tulloch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siddharthan","family":"Chandran","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Colin","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giles","family":"Hardingham","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2530-0598","authenticated-orcid":false,"given":"Tara L","family":"Spires-Jones","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2024041511251282000_2024.04.09.24305501v1.1","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btl140"},{"key":"2024041511251282000_2024.04.09.24305501v1.2","doi-asserted-by":"crossref","unstructured":"Bertucci T , Bowles KR , Lotz S , Qi L , Stevens K , Goderie SK , Borden S , Oja LM , Lane K , Lotz R , Lotz H , Chowdhury R , Joy S , Arduini BL , Butler DC , Miller M , Baron H , Sandhof CA , Silva MC , Haggarty SJ , Karch CM , Geschwind DH , Goate AM , Temple S (2023) Improved Protocol for Reproducible Human Cortical Organoids Reveals Early Alterations in Metabolism with MAPT Mutations. 2023.07.11.548571","DOI":"10.1101\/2023.07.11.548571"},{"key":"2024041511251282000_2024.04.09.24305501v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.07.003"},{"key":"2024041511251282000_2024.04.09.24305501v1.4","doi-asserted-by":"publisher","DOI":"10.1007\/BF00308809"},{"key":"2024041511251282000_2024.04.09.24305501v1.5","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0289-8"},{"key":"2024041511251282000_2024.04.09.24305501v1.6","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2023.04.020"},{"key":"2024041511251282000_2024.04.09.24305501v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.10.014"},{"key":"2024041511251282000_2024.04.09.24305501v1.8","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bts635"},{"key":"2024041511251282000_2024.04.09.24305501v1.9","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.64.10.1535"},{"key":"2024041511251282000_2024.04.09.24305501v1.10","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0298-7"},{"key":"2024041511251282000_2024.04.09.24305501v1.11","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2016.12.023"},{"key":"2024041511251282000_2024.04.09.24305501v1.12","doi-asserted-by":"publisher","DOI":"10.1002\/cm.21812"},{"key":"2024041511251282000_2024.04.09.24305501v1.13","doi-asserted-by":"publisher","DOI":"10.1002\/cm.21812"},{"key":"2024041511251282000_2024.04.09.24305501v1.14","doi-asserted-by":"publisher","DOI":"10.1038\/7454"},{"key":"2024041511251282000_2024.04.09.24305501v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41583-018-0113-1"},{"key":"2024041511251282000_2024.04.09.24305501v1.16","doi-asserted-by":"publisher","DOI":"10.1186\/s40478-019-0847-7"},{"key":"2024041511251282000_2024.04.09.24305501v1.17","doi-asserted-by":"publisher","DOI":"10.1002\/mds.28188"},{"key":"2024041511251282000_2024.04.09.24305501v1.18","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awab282"},{"key":"2024041511251282000_2024.04.09.24305501v1.19","doi-asserted-by":"publisher","DOI":"10.1038\/31508"},{"key":"2024041511251282000_2024.04.09.24305501v1.20","doi-asserted-by":"publisher","DOI":"10.1126\/science.6474172"},{"key":"2024041511251282000_2024.04.09.24305501v1.21","doi-asserted-by":"publisher","DOI":"10.1038\/s41436-021-01260-4"},{"key":"2024041511251282000_2024.04.09.24305501v1.22","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2019.09.006"},{"key":"2024041511251282000_2024.04.09.24305501v1.23","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02196-w"},{"key":"2024041511251282000_2024.04.09.24305501v1.24","doi-asserted-by":"publisher","DOI":"10.1002\/alz.12894"},{"key":"2024041511251282000_2024.04.09.24305501v1.25","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/aws127"},{"key":"2024041511251282000_2024.04.09.24305501v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2019.05.002"},{"key":"2024041511251282000_2024.04.09.24305501v1.27","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-03759-9"},{"key":"2024041511251282000_2024.04.09.24305501v1.28","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0080834"},{"key":"2024041511251282000_2024.04.09.24305501v1.29","doi-asserted-by":"publisher","DOI":"10.1007\/s00401-020-02158-2"},{"key":"2024041511251282000_2024.04.09.24305501v1.30","doi-asserted-by":"publisher","DOI":"10.1111\/ene.15043"},{"key":"2024041511251282000_2024.04.09.24305501v1.31","doi-asserted-by":"publisher","DOI":"10.1186\/s13024-017-0192-x"},{"key":"2024041511251282000_2024.04.09.24305501v1.32","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btt656"},{"key":"2024041511251282000_2024.04.09.24305501v1.33","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2018.10.031"},{"key":"2024041511251282000_2024.04.09.24305501v1.34","doi-asserted-by":"publisher","DOI":"10.1186\/s13059-014-0550-8"},{"key":"2024041511251282000_2024.04.09.24305501v1.35","doi-asserted-by":"publisher","DOI":"10.1002\/ana.26543"},{"key":"2024041511251282000_2024.04.09.24305501v1.36","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.55374"},{"key":"2024041511251282000_2024.04.09.24305501v1.37","doi-asserted-by":"publisher","DOI":"10.1111\/bpa.12486"},{"key":"2024041511251282000_2024.04.09.24305501v1.38","doi-asserted-by":"crossref","unstructured":"McGeachan RI , Keavey L , Rose JL , Simzer EM , Chang YY , Spires-Jones MP , Gilmore M , Ravingerova N , Scutariu C , Taylor L , King D , Tzioras M , Tulloch J , Booker SA , Liaquat I , Hindley-Pollock N , Geary B , Smith C , Brennan PM , Durrant CS , Spires-Jones TL (2024) Evidence for trans-synaptic propagation of oligomeric tau in Progressive Supranuclear Palsy. 2022.09.20.22280086","DOI":"10.1101\/2022.09.20.22280086"},{"key":"2024041511251282000_2024.04.09.24305501v1.39","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2015.01.025"},{"key":"2024041511251282000_2024.04.09.24305501v1.40","doi-asserted-by":"publisher","DOI":"10.1016\/j.neuron.2022.06.021"},{"key":"2024041511251282000_2024.04.09.24305501v1.41","doi-asserted-by":"publisher","DOI":"10.1093\/brain\/awf069"},{"key":"2024041511251282000_2024.04.09.24305501v1.42","doi-asserted-by":"publisher","DOI":"10.1016\/j.expneurol.2009.07.029"},{"key":"2024041511251282000_2024.04.09.24305501v1.43","doi-asserted-by":"publisher","DOI":"10.1111\/jcmm.17136"},{"key":"2024041511251282000_2024.04.09.24305501v1.44","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2880-19.2020"},{"key":"2024041511251282000_2024.04.09.24305501v1.45","doi-asserted-by":"publisher","DOI":"10.1016\/j.xcrm.2023.101175"},{"key":"2024041511251282000_2024.04.09.24305501v1.46","doi-asserted-by":"publisher","DOI":"10.1038\/s41582-022-00749-z"},{"key":"2024041511251282000_2024.04.09.24305501v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.ajpath.2013.03.015"},{"key":"2024041511251282000_2024.04.09.24305501v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2023.114619"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2024.04.09.24305501","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T19:57:56Z","timestamp":1768507076000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2024.04.09.24305501"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,12]]},"references-count":48,"URL":"https:\/\/doi.org\/10.1101\/2024.04.09.24305501","relation":{},"subject":[],"published":{"date-parts":[[2024,4,12]]},"subtype":"preprint"}}