Reconsidering repurposing: long-term metformin treatment impairs cognition in Alzheimer’s model mice

Metformin, a primary anti-diabetic medication, has been anticipated to provide benefits for Alzheimer’s disease (AD), also known as “type 3 diabetes”. Nevertheless, some studies have demonstrated that metformin may trigger AD pathology and even elevate AD risk in humans. Despite this, limited research has elucidated the behavioral outcomes of metformin treatment, which would hold significant translational value. Thus, we aimed to perform thorough behavioral research on the prolonged administration of metformin to mice: We administered metformin (300 mg/kg/day) to transgenic 3xTg-AD and non-transgenic (NT) C57BL/6 mice over 1 and 2 years, respectively, and evaluated their behaviors across multiple domains via touchscreen operant chambers, including motivation, attention, memory, visual discrimination, and cognitive flexibility. We found metformin enhanced attention, inhibitory control, and associative learning in younger NT mice (≤16 months). However, chronic treatment led to impairments in memory retention and discrimination learning at older age. Furthermore, metformin caused learning and memory impairment and increased levels of AMPKα1-subunit, β-amyloid oligomers, plaques, phosphorylated tau, and GSK3β expression in AD mice. No changes in potential confounding factors on cognition, including levels of motivation, locomotion, appetite, body weight, blood glucose, and serum vitamin B12, were observed in metformin-treated AD mice. We also identified an enhanced amyloidogenic pathway in db/db mice, as well as in Neuro2a-APP695 cells and a decrease in synaptic markers, such as PSD-95 and synaptophysin in primary neurons, upon metformin treatment. Our findings collectively suggest that the repurposing of metformin should be carefully reconsidered when this drug is used for individuals with AD

Structural connectome alterations between individuals with autism and neurotypical controls using feature representation learning

Abstract Autism spectrum disorder is one of the most common neurodevelopmental conditions associated with sensory and social communication impairments. Previous neuroimaging studies reported that atypical nodal- or network-level functional brain organization in individuals with autism was associated with autistic behaviors. Although dimensionality reduction techniques have the potential to uncover new biomarkers, the analysis of whole-brain structural connectome abnormalities in a low-dimensional latent space is underinvestigated. In this study, we utilized autoencoder-based feature representation learning for diffusion magnetic resonance imaging-based structural connectivity in 80 individuals with autism and 61 neurotypical controls that passed strict quality controls. We generated low-dimensional latent features using the autoencoder model for each group and adopted an integrated gradient approach to assess the contribution of the input data for predicting latent features during the encoding process. Subsequently, we compared the integrated gradient values between individuals with autism and neurotypical controls and observed differences within the transmodal regions and between the sensory and limbic systems. Finally, we identified significant associations between integrated gradient values and communication abilities in individuals with autism. Our findings provide insights into the whole-brain structural connectome in autism and may help identify potential biomarkers for autistic connectopathy

Improvement of hull form for an 1,800 TEU containership toward reduced fuel consumption under in-service conditions

In the present study, the hull form of an 1,800 TEU containership was developed to reduce fuel consumption under real operation conditions. Contrary to the conventional hull form design practice in terms of the calm-sea performance, the hull form design in this study was aimed at improving the performance of a ship under in-service condition, which is closely associated with the added resistance due to waves. In order to reduce the added resistance due to waves, the bow hull form was modified to have sharper entrance with increased length between perpendicular. This enabled the waves to follow the bow part more smoothly. The added resistance of the developed hull was predicted by means of a series of CFD simulations in regular waves with wavelengths λ/Lpp=0.5∼2.0. The added resistance at irregular waves was calculated by frequency integration. The Daily Fuel Oil Consumption (DFOC) was subsequently calculated based on the wave statistics on the operating route. The significance of the present study lies in the point that the performance evaluation was carried out by means of the free-surface CFD simulation in the presence of regular waves. Final performance verification was made through a series of model tests. The resulting DFOC and daily CO2 emission for the optimal hull form under the in-service conditions was found to be reduced by 7.65%. Furthermore, the calm-sea DFOC and CO2 emission were also improved by 3.43%

Whole-brain structural connectome asymmetry in autism

Autism spectrum disorder is a common neurodevelopmental condition that manifests as a disruption in sensory and social skills. Although it has been shown that the brain morphology of individuals with autism is asymmetric, how this differentially affects the structural connectome organization of each hemisphere remains under-investigated. We studied whole-brain structural connectivity-based brain asymmetry in individuals with autism using diffusion magnetic resonance imaging obtained from the Autism Brain Imaging Data Exchange initiative. By leveraging dimensionality reduction techniques, we constructed low-dimensional representations of structural connectivity and calculated their asymmetry index. Comparing the asymmetry index between individuals with autism and neurotypical controls, we found atypical structural connectome asymmetry in the sensory and default-mode regions, particularly showing weaker asymmetry towards the right hemisphere in autism. Network communication provided topological underpinnings by demonstrating that the inferior temporal cortex and limbic and frontoparietal regions showed reduced global network communication efficiency and decreased send-receive network navigation in the inferior temporal and lateral visual cortices in individuals with autism. Finally, supervised machine learning revealed that structural connectome asymmetry could be used as a measure for predicting communication-related autistic symptoms and nonverbal intelligence. Our findings provide insights into macroscale structural connectome alterations in autism and their topological underpinnings

Reconsidering repurposing: long-term metformin treatment impairs cognition in Alzheimer’s model mice

Acknowledgements: This study was supported by grants from Research Driven Hospitals Development R&D Project (HR22C141102; Ministry of Health and Welfare, Republic of Korea), the Source Technology Development Project (2022M3E5E8030792; NRF of Korea, the Ministry of Science and ICT), Basic Science Research Program (NRF-2021R1I1A1A01047462; NRF of Korea funded by the Ministry of Education). BUP is currently an employee of AstraZeneca PLC.AbstractMetformin, a primary anti-diabetic medication, has been anticipated to provide benefits for Alzheimer’s disease (AD), also known as “type 3 diabetes”. Nevertheless, some studies have demonstrated that metformin may trigger AD pathology and even elevate AD risk in humans. Despite this, limited research has elucidated the behavioral outcomes of metformin treatment, which would hold significant translational value. Thus, we aimed to perform thorough behavioral research on the prolonged administration of metformin to mice: We administered metformin (300 mg/kg/day) to transgenic 3xTg-AD and non-transgenic (NT) C57BL/6 mice over 1 and 2 years, respectively, and evaluated their behaviors across multiple domains via touchscreen operant chambers, including motivation, attention, memory, visual discrimination, and cognitive flexibility. We found metformin enhanced attention, inhibitory control, and associative learning in younger NT mice (≤16 months). However, chronic treatment led to impairments in memory retention and discrimination learning at older age. Furthermore, metformin caused learning and memory impairment and increased levels of AMPKα1-subunit, β-amyloid oligomers, plaques, phosphorylated tau, and GSK3β expression in AD mice. No changes in potential confounding factors on cognition, including levels of motivation, locomotion, appetite, body weight, blood glucose, and serum vitamin B12, were observed in metformin-treated AD mice. We also identified an enhanced amyloidogenic pathway in db/db mice, as well as in Neuro2a-APP695 cells and a decrease in synaptic markers, such as PSD-95 and synaptophysin in primary neurons, upon metformin treatment. Our findings collectively suggest that the repurposing of metformin should be carefully reconsidered when this drug is used for individuals with AD.</jats:p

Peroxiredoxin5 controls vertebrate ciliogenesis by modulating mitochondrial ROS

Aims: Peroxiredoxin5 (Prdx5) - a thioredoxin peroxidase is an antioxidant enzyme that is widely studied for its antioxidant properties and protective roles in neurological and cardiovascular disorders. The present study is aimed to investigate the functional significance of Prdx5 in mitochondria and to analyze its roles in ciliogenesis during the process of vertebrate development. Results: We found that several Prdx genes were strongly expressed in multiciliated cells in developing Xenopus embryos, and their peroxidatic functions were crucial for normal cilia development. Depletion of Prdx5 increased levels of cellular ROS, consequently leading to mitochondrial dysfunction and abnormal cilia formation. Proteomic and transcriptomic approaches revealed that excessive ROS accumulation upon Prdx5 depletion subsequently reduced the expression level of pyruvate kinase (PK), a key metabolic enzyme in energy production. We further confirmed that the promotor activity of PK was significantly reduced upon Prdx5 depletion and that the reduction in PK expression and its promoter activity led to ciliary defects observed in Prdx5-depleted cells. Innovation: Our data revealed the novel relationship between ROS and Prdx5 and the consequent effects of this interaction on vertebrate ciliogenesis. The normal process of ciliogenesis is interrupted by the Prdx5 depletion resulting in excessive ROS levels suggesting cilia as vulnerable targets of ROS. Conclusion: Prdx5 play protective roles in mitochondria and is critical for normal cilia development by regulating the levels of ROS. The loss of Prdx5 is associated with excessive production of ROS resulting in mitochondrial dysfunction and aberrant ciliogenesis