Biology subjects

Guedj, F.

Publications and source records attributed to Guedj, F..

4 recordsLinked to original sources

bioRxiv2026

Anti-inflammatory and pro-proliferative effects of fasudil in human trisomy 21 neural progenitor cells

Down syndrome (DS) results from trisomy for human chromosome 21 and is the most frequent genetic cause of intellectual disability. No effective treatments currently exist that improve neurodevelopment and cognition. Atypical brain development in individuals with DS is apparent before birth, which suggests that the optimal time to begin administration of therapies is prenatally. Human neural progenitor cell (NPC) cultures provide a tractable in vitro model system to examine the effects of trisomy 21 (T21) on neurodevelopment and to measure the effects of pharmacological interventions. Here we report the results of preclinical studies evaluating 24 candidate therapies. RNA-Seq analyses found that euploid and T21 NPCs showed different transcriptomic responses to five candidate pharmacotherapies. The Rho-associated coiled-coil kinase (ROCK) inhibitor fasudil increased proliferation of T21 NPCs, reduced expression of inflammatory pathway genes in T21 NPCs, and reduced markers of inflammation in LPS-stimulated microglia model systems. These results demonstrate that fasudil can alter multiple T21-associated abnormalities in a beneficial manner, suggesting that fasudil warrants further study as a candidate prenatal pharmacotherapy for DS.

pharmacology and toxicology↗

bioRxiv2022

The impact of Mmu17 non-Hsa21 orthologous genes in the Ts65Dn mouse model of Down syndrome: the "gold standard" revisited

Despite many successful preclinical treatment studies to improve neurocognition in the Ts65Dn mouse model of Down syndrome (DS), translation to humans has failed. This raises critical questions about the appropriateness of the Ts65Dn mouse as the "gold standard" for DS research given that it carries, in addition to Mmu16 orthologous genes, triplication of 50 Mmu17 non-orthologous genes that might contribute to the observed brain and behavioral phenotypes. We used the novel Ts66Yah mouse that carries both an extra mini chromosome and the identical segmental Mmu16 trisomy as Ts65Dn, but in which the Mmu17 non-orthologous region was removed using CRISPR/Cas9 technology. We demonstrate that the Ts65Dn exhibits a more severe phenotype throughout the lifespan compared to the Ts66Yah mouse. Several Mmu17 non-orthologous genes were uniquely overexpressed in Ts65Dn embryonic forebrain; this produced major differences in dysregulated genes and pathways. Despite these genome-wide differences, the primary Mmu16 trisomic effects were highly conserved in both models, resulting in several commonly dysregulated disomic genes and pathways. During the neonatal period, delays in motor development, communication and olfactory spatial memory were observed in both Ts66Yah and Ts65Dn pups but were more pronounced in Ts65Dn. Adult Ts66Yah mice showed working memory deficits and sex-specific effects in exploratory behavior and spatial hippocampal memory, while long-term memory was preserved. Like the neonates, adult Ts66Yah mice exhibited fewer and milder behavioral deficits when compared to Ts65Dn mice. Our findings suggest that trisomy of the non-orthologous Mmu17 genes significantly contributes to the phenotype of the Ts65Dn mouse and may be one major reason why preclinical trials that used this model have unsuccessfully translated to human therapies.

neuroscience↗

bioRxiv2020

Translating the Human CANTAB Touchscreen Based Tasks to Evaluate Learning and Memory in Mouse Models of Down Syndrome

Humans with Down syndrome (DS) exhibit hippocampal learning deficits in the Cambridge Neuropsychological Test Automated Battery (CANTAB). Here we translated the CANTAB Visual Discrimination (VD) and Extinction tasks to investigate hippocampal learning and cortical inhibitory control in the Dp(16)1/Yey, Ts65Dn and Ts1Cje mouse models of DS. No food or water restriction was used prior to testing. The number of days to reach 70% correct answers and percent of correct responses were analyzed. All Dp(16)1/Yey, Ts1Cje and WT mice reached Stage 5 of pre-training. No differences between genotypes were found in percent of correct responses. Five Ts65Dn and one WT animals reached Stage 5 and only one Ts65Dn mouse reached VD. Ts1Cje mice took longer (17.86{+/-}3.19 days) to move to VD vs. WT (11.44{+/-}1.96 days, P=0.09). There were no differences between Dp(16)1/Yey and WT mice. At VD, the average percent of correct answers was significantly lower in Dp(16)1/Yey (22.70{+/-}1.93%) and Ts1Cje (34.39{+/-}1.98%) compared to WT littermates (32.18{+/-}1.49% and 41.11{+/-}1.45%, respectively, P<0.05). In another set of experiments, we demonstrated that mild food restriction significantly reduced the time needed to complete pre-training in C57BL/6J mice compared to C67BL/6J mice that had ad libitum access to food and water. In conclusion, we were able to apply human cognitive tests to evaluate hippocampal learning and cortical inhibitory control in three mouse models of DS. These studies demonstrate significant cognitive differences between strains. Future experiments will evaluate whether food restriction and/or pre- and postnatal therapy decreases the time intervals to achieve training mile.

animal behavior and cognition↗

bioRxiv2018

Apigenin as a Candidate Prenatal Treatment for Trisomy 21: Effects in Human Amniocytes and the Ts1Cje Mouse Model

Human fetuses with trisomy 21 (T21) have atypical brain development that is apparent sonographically in the second trimester. Prenatal diagnosis provides a potential opportunity to begin treatment in utero. We hypothesize that by analyzing and integrating dysregulated gene expression and pathways common to humans with DS and mouse models we can discover novel targets for therapy. Here, we tested the safety and efficacy of apigenin (4, 5, 7-trihydroxyflavone), identified using this approach, in both human amniocytes from fetuses with T21 and in the Ts1Cje mouse model. The experiments compared treated to untreated results in T21 and euploid cells, as well as in Ts1Cje mice and their wild-type littermate controls. T21 cells cultured with apigenin (2{micro}M) had significantly reduced oxidative stress and improved antioxidant defense response in vitro. Apigenin (333-400 mg/kg/day), mixed with chow, was initiated prenatally to the dams and fed to the pups over their lifetimes. There was no significant increase in birth defects or pup deaths resulting from prenatal apigenin treatment. Apigenin significantly improved several developmental milestones and spatial olfactory memory in Ts1Cje neonates. In addition, we noted sex-specific effects on exploratory behavior and long-term hippocampal memory in adult mice, with males showing significantly more improvement than females. Global gene expression analyses demonstrated that apigenin targets similar signaling pathways through common upstream regulators both in vitro and in vivo. These studies provide proof-of-principle that apigenin has therapeutic effects in preclinical models of Down syndrome.\n\nONE SENTENCE SUMMARYAs a candidate prenatal treatment for Down syndrome, apigenin improved oxidative stress/antioxidant capacity imbalance and reduced pathways associated with inflammation in human cells while improving aspects of behavior in the Ts1Cje mouse model.

genetics↗