Bezafibrate treatment rescues neurodevelopmental and neurodegenerative defects in 3D cortical organoid model of MAPT frontotemporal dementia

Abstract

INTRODUCTIONThe intronic MAPT mutation IVS10+16 is linked to familiar frontotemporal dementia, causing hyperphosphorylation and accumulation of tau protein, resulting in synaptic and neuronal loss and neuroinflammation in patients. This mutation disrupts MAPT gene splicing, increasing exon 10 inclusion and leading to an imbalance of 3R and 4R Tau isoforms. METHODSWe generated patterned cortical organoids from isogenic control and mutant human iPSC lines. Nanostring gene expression analysis immunofluorescence and calcium imaging recordings were used to study the impact of the MAPT IVS10+16 mutation on neuronal development and function. RESULTSTau mutant cortical organoids showed altered mitochondrial function and gene expression related to neuronal development, with synaptic markers and neuronal activity reduction. Bezafibrate treatment, which restored mitochondrial content, rescued synaptic functionality and tau physiology. DISCUSSIONThese findings suggest that targeting mitochondrial function with bezafibrate could potentially reverse tau-induced neurodevelopmental deficits, highlighting its therapeutic potential for tauopathies like FTD. HIGLIGHTSO_LIThe IVS 10+16 MAPT mutation significantly disrupts cortical differentiation and synaptic maturation, evidenced by downregulated genes associated with synapses and neuronal development. C_LIO_LITau-mutant cortical organoids exhibit mitochondrial dysfunction, with fewer and smaller mitochondria alongside with tau hyperphosphorylation and aggregation, which further contribute to neuronal damage and disease progression. C_LIO_LITreatment with bezafibrate effectively normalizes mitochondrial parameters, enhances neuronal integrity and synaptic maturation, and restores network functionality, showcasing its promise as a therapeutic strategy for tauopathies. C_LIO_LIThe 3D in vitro disease model used in this study proves valuable for studying tauopathies and testing new drugs, effectively mimicking key aspects of tau-related neurodegeneration. C_LI RESEARCH IN CONTEXTO_LISystematic Review: We searched PubMed, Google Scholar, and Web of Science for studies on the MAPT IVS10+16 mutations impact on tauopathies, focusing on neuronal development, synaptic function, and mitochondrial involvement. Key terms included "MAPT IVS10+16 mutation," "tauopathy," "neuronal development," "synaptic function," and "mitochondrial function." C_LIO_LIInterpretation: Our findings reveal that the MAPT IVS10+16 mutation disrupts mitochondrial function altering gene expression related to neuronal development, synaptic structures, impairing neuronal and glial maturation. Bezafibrate treatment restored mitochondrial content, synaptic functionality, and tau physiology in mutant-derived cortical organoids, suggesting it as a potential therapeutic strategy for tauopathies. C_LIO_LIFuture Directions: Future research should investigate the molecular mechanisms underlying the bezafibrates therapeutic effect and its long-term efficacy and safety in vivo, in humanized mouse models. Additionally, the possibility to combine bezafibrate with other therapeutic agents used to treat tauopathies will be worth to assess. C_LI