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In Alzheimer's disease, the most common tauopathy, synapse loss is the strongest pathological correlate of cognitive decline. Recently, Positron Emission Tomography (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\u2010mortem 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\u00a0+\u200916 mutation, which increases splice variants containing exon 10 resulting in higher levels of tau with four microtubule\u2010binding domains.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      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                      <jats:italic>n<\/jats:italic>\n                      \u00a0=\u200912 FTDtau10\u00a0+\u200916 and 13 controls).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      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\u00a0+\u200916 brain included those involved in transcriptional regulation, DNA damage response and neuroinflammation. Histopathology confirmed increased pathological tau accumulation in FTDtau10\u2009+\u200916 cortex as well as a loss of presynaptic protein staining and region\u2010specific increased colocalization of phospho\u2010tau with synapses in temporal cortex.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our data indicate that synaptic pathology likely contributes to pathogenesis in FTDtau10\u2009+\u200916 caused by the\n                      <jats:italic>MAPT<\/jats:italic>\n                      10\u00a0+\u200916 mutation.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/nan.13006","type":"journal-article","created":{"date-parts":[[2024,8,21]],"date-time":"2024-08-21T22:54:58Z","timestamp":1724280898000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Synaptic gene expression changes in frontotemporal dementia due to the\n                    <i>MAPT<\/i>\n                    10\u00a0+\u200916 mutation"],"prefix":"10.1111","volume":"50","author":[{"given":"Owen","family":"Dando","sequence":"first","affiliation":[{"name":"UK Dementia Research Institute The University of Edinburgh  Edinburgh UK"},{"name":"Centre for Discovery Brain Sciences, School of Biomedical Sciences, College of Medicine and Veterinary Medicine The University of Edinburgh  Edinburgh UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"McGeachan","sequence":"additional","affiliation":[{"name":"UK Dementia Research Institute The University of Edinburgh  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