{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,9,19]],"date-time":"2026-09-19T00:11:13Z","timestamp":1789776673293,"version":"4.0.1"},"posted":{"date-parts":[[2024,6,29]]},"group-title":"Neuroscience","reference-count":68,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,6,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  TDP-43 proteinopathy, initially disclosed in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), coexists with tauopathy in a variety of neurodegenerative disorders, termed multiple etiology dementias (MEDs), including Alzheimer\u2019s Disease (AD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration and steeper cognitive decline, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. The loss of TDP-43 splicing repression that occurs in presymptomatic ALS-FTD individuals suggests that such early loss could facilitate the pathological conversion of tau to accelerate neuron loss. Here, we report that the loss of TDP-43 repression of cryptic exons in forebrain neurons (\n                  <jats:italic>\n                    CaMKII-CreER;Tardbp\n                    <jats:sup>f\/f<\/jats:sup>\n                  <\/jats:italic>\n                  mice) is necessary to exacerbate tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-dependent cleavage of endogenous tau to promote tauopathy. Corroborating this finding within the human context, we demonstrate that loss of TDP-43 function in iPSC-derived cortical neurons promotes early cryptic exon inclusion and subsequent caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in\n                  <jats:italic>\n                    CaMKII-CreER;Tardbp\n                    <jats:sup>f\/f<\/jats:sup>\n                  <\/jats:italic>\n                  mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed positively correlates with levels of caspase 3-cleaved tau. Importantly, we found that the vulnerability of hippocampal neurons to TDP-43 depletion is dependent on the amount of caspase 3-cleaved tau: from most vulnerable neurons in the CA2\/3, followed by those in the dentate gyrus, to the least in CA1. Taken together, our findings strongly support the view that TDP-43 loss-of-function exacerbates tauopathy-dependent brain atrophy by increasing the sensitivity of vulnerable neurons to caspase 3-mediated endoproteolysis of tau, resulting in a greater degree of neurodegeneration in human disorders with co-pathologies of tau and TDP-43. Our work thus discloses novel mechanistic insights and therapeutic targets for human tauopathies harboring co-pathology of TDP-43 and provides a new MED model for testing therapeutic strategies.\n                <\/jats:p>\n                <jats:sec>\n                  <jats:title>Highlights<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Loss of TDP-43 repression of cryptic exons is necessary for caspase 3-dependent endoproteolysis of tau at D421 in the mouse brain and human iPSC-derived cortical neurons.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>The level of caspase 3-dependent cleavage of tau is a major determinant of the vulnerability of mouse brain neurons lacking TDP-43.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>In a novel mouse model of multiple etiology dementia, TDP-43 loss-of-function exacerbates tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-mediated endoproteolysis of tau to drive tauopathy.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>In human tauopathies with co-pathology of TDP-43, dysfunction of TDP-43 may promote caspase 3-dependent cleavage of endogenous tau in vulnerable neurons and exacerbate tauopathy-dependent neurodegeneration.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Summary<\/jats:title>\n                  <jats:p>The pathogenic mechanism by which TDP-43 loss of repression function exacerbates tauopathy-dependent neurodegeneration in multiple etiology dementia (MED) with co-pathology of TDP-43 is unknown. In a novel mouse model of MED, loss of TDP-43 function exacerbates tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-dependent cleavage of endogenous tau to drive tauopathy. This mechanistic insight informs novel targets and therapeutic strategies for MEDs harboring the co-pathologies of tau and TDP-43, which can be validated using this mouse model of MED.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2024.06.26.600814","type":"posted-content","created":{"date-parts":[[2024,6,29]],"date-time":"2024-06-29T22:15:10Z","timestamp":1719699310000},"source":"Crossref","is-referenced-by-count":6,"title":["Depletion of TDP-43 exacerbates tauopathy-dependent brain atrophy by sensitizing vulnerable neurons to caspase 3-mediated endoproteolysis of tau in a mouse model of Multiple Etiology Dementia"],"prefix":"10.64898","author":[{"given":"Meghraj S","family":"Baghel","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace D","family":"Burns","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Margarita","family":"Tsapatsis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aswathy","family":"Peethambaran Mallika","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna Lourdes F","family":"Cruz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianyu","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoke K","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel De La","family":"Rosa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shaelyn R","family":"Marx","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingzhi","family":"Ye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuying","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8162-3274","authenticated-orcid":false,"given":"Philip 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