A Model of Traumatic Brain Injury Oligomerizes Tau in Cortical Organoids and Induces Clinically Relevant Pathologies...

Traumatic brain injury (TBI) is the most important environmental risk factor for neurodegenerative disease. Tauopathy plays an important role in post-traumatic neurodegeneration. Human-induced pluripotent stem cell (hiPSC)-derived cortical organoids have exciting potential to reveal the influence of genotype on post-traumatic neurodegeneration because they permit manipulation of the genome in a human system. This study established an isogenic 3D cortical organoid model of TBI to investigate tau pathology and other clinically relevant injury phenotypes. Organoids generated from patient-derived hiPSC lines carrying the V337M or IVS10 + 16 Microtubule associated protein tau (MAPT) mutations and their clustered regularly interspaced short palindromic repeats (CRISPR)-corrected isogenic counterparts were subjected to consistent compressive injury. Mitochondrial dysfunction, cell viability, lactate dehydrogenase (LDH) release, neurofilament light chain (NF-L) release, tau hyperphosphorylation, and tau oligomerization were quantified using live-cell imaging, ELISA, Western blotting, and immunostaining post-injury. Pathology depended on the severity of the mechanical injury and the time since injury. The V337M mutation synergized with injury to exacerbate cell damage, increasing LDH release and reducing viability in 4- and 6-month-old organoids. Therefore, this model can reproduce gene-trauma interactions in vitro, so it has the capacity to answer important questions about why different patients have different outcomes after similar TBIs. MAPT mutation was not necessary for injury to induce tau hyperphosphorylation in 4-month-old organoids and both tau hyperphosphorylation and tau oligomerization in 6-month-old organoids. This capacity to induce advanced tau pathology in wild-type human organoids could have utility beyond the field of TBI research.