Intermittent fasting promotes adult hippocampal neuronal differentiation by activating GSK-3ß in 3xTg-AD mice.

Moderate dietary restriction can ameliorate age-related chronic diseases such as Alzheimer's disease (AD) by increasing the expression of neurotrophic factors and promoting neurogenesis in the brain. Glycogen synthase kinase-3ß (GSK-3ß) signaling is essential for the coordination of progenitor cell proliferation and differentiation during brain development. The mechanisms by which GSK-3ß is involved in dietary restriction-induced neurogenesis and cognitive improvement remain unclear. Six-month-old male 3xTg-AD and wild-type mice were fed on alternate days (intermittent fasting, IF) or ad libitum (AL) for 3 months. GSK-3ß activity was regulated by bilaterally infusing lentiviral vectors carrying siRNA targeting GSK-3ß into the dentate gyrus region of the hippocampus. Intermittent fasting promoted neuronal differentiation and maturation in the dentate gyrus and ameliorated recognized dysfunction in 3xTg-AD mice. These effects were reversed by siRNA targeting GSK-3ß. After intermittent fasting, the insulin and protein kinase A signaling pathways were inhibited, while the adenosine monophosphate-activated protein kinase and brain-derived neurotrophic factor pathways were activated. These findings suggest that intermittent fasting can promote neuronal differentiation and maturation in the hippocampus by activating GSK-3ß, thus improving learning and memory.

Inhibition of mGluR5/PI3K-AKT Pathway Alleviates Alzheimer's Disease-Like Pathology Through the Activation of Autophagy in 5XFAD Mice.

BACKGROUND: The metabotropic glutamate receptor 5 (mGluR5) is widely expressed in postsynaptic neurons and plays a vital role in the synaptic plasticity of the central nervous system. mGluR5 is a coreceptor for amyloid-ß (Aß) oligomer, and downregulation or pharmacological blockade of mGluR5 presents the therapeutic potential of Alzheimer's disease (AD). However, the abnormality of mGluR5 in the pathogenesis of AD and its mechanism of pathology is not clear. OBJECTIVE: In this study, we would like to investigate the expression of mGluR5 in the process of AD and explore the effects and the underlying mechanisms of antagonizing mGluR5 on cognitive function, synaptic structure, and inflammation in 5xFAD mice. METHODS: mGluR5 expression and interactions with PrPc in 5XFAD mice were detected using western blot and co-immunoprecipitation. The selective mGluR5 antagonist MPEP was infused into 4-month-old 5XFAD mice for 60 consecutive days. Then, cognitive function, AD-like pathology and synaptic structure were measured. Further observations were made in mGluR5 knockdown 5XFAD mice. RESULTS: mGluR5 expression was increased with Aß levels at 6 months in 5XFAD mice. mGluR5 antagonist rescued cognitive disorders, promoted synaptic recovery, and alleviated both the Aß plaque load and abnormal hyperphosphorylation in 6-month-old 5XFAD mice. Meanwhile, the results were validated in mGluR5 knockdown mice. Blockade of mGluR5 efficiently alleviates AD-like pathologies by inhibiting the PI3K/AKT/mTOR pathway and activates autophagy in 5XFAD mice. Furthermore, antagonism of mGluR5 attenuated neuroinflammation by inactivating the IKK/NF-κB pathway. CONCLUSION: These findings suggest that mGluR5 may be an effective drug target for AD treatment, and inhibition of the mGluR5/PI3K-AKT pathway alleviates AD-like pathology by activating autophagy and anti-neuroinflammation in 5XFAD mice.

CEP192 is a novel prognostic marker and correlates with the immune microenvironment in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) responds poorly to standard chemotherapy or targeted therapy; hence, exploration for novel therapeutic targets is urgently needed. CEP192 protein is indispensable for centrosome amplification, which has been extensively characterized in both hematological malignancies and solid tumors. Here, we combined bioinformatics and experimental approaches to assess the potential of CEP192 as a prognostic and therapeutic target in HCC. CEP192 expression increased with tumor stage and was associated with poor clinicopathologic features, frequent recurrence, and higher mortality. Upon single-cell RNA sequencing, CEP192 was found to be involved in the proliferation and self-renewal of hepatic progenitor-like cells. This observation was further evidenced using CEP192 silencing, which prevented tumor cell proliferation and self-renewal by arresting cells in the G0/G1 phase of the cell cycle. Notably, CEP192 was highly correlated with multiple tumor-associated cytokine ligand-receptor axes, including IL11-IL11RA, IL6-IL6R, and IL13-IL13RA1, which could promote interactions between hepatic progenitor-like cells, PLVAP+ endothelial cells, tumor-associated macrophages, and CD4+ T cells. Consequently, CEP192 expression was closely associated with an immunosuppressive tumor microenvironment and low immunophenoscores, making it a potential predictor of response to immune checkpoint inhibitors. Taken together, our results unravel a novel onco-immunological role of CEP192 in establishing the immunosuppressive tumor microenvironment and provide a novel biomarker, as well as a potential target for therapeutic intervention of HCC.