Cordella, F. | Search bioRxiv

bioRxiv2024

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

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

neuroscience↗

bioRxiv2020

Novel fragile X syndrome 2D and 3D brain models based on human isogenic FMRP-KO iPSCs

Fragile X syndrome (FXS) is a neurodevelopmental disorder, characterized by intellectual disability and sensory deficits, caused by epigenetic silencing of the FMR1 gene and subsequent loss of its protein product, fragile X mental retardation protein (FMRP). Delays in synaptic and neuronal development in the cortex have been reported in FXS mouse models, however, the main goal of translating lab research into pharmacological treatments in clinical trials has been so far largely unsuccessful, leaving FXS a still incurable disease. Here, we generated 2D and 3D in vitro human FXS model systems based on isogenic FMR1 knock-out mutant and wild-type human induced pluripotent stem cell (hiPSC) lines. Phenotypical and functional characterization of cortical neurons derived from FMRP-deficient hiPSCs display altered gene expression and impaired differentiation when compared with the healthy counterpart. FXS cortical cultures show increased proliferation of GFAP positive cells, likely astrocytes, increased spontaneous network activity and depolarizing GABAergic transmission. Cortical brain organoid models show increased proliferation of glial cells, and bigger organoid size. Our findings demonstrate that FMRP is required to correctly support neuronal and glial cell proliferation, and to set the correct excitation/inhibition ratio in human brain development.

neuroscience↗