Myeloid Cell Deficiency of the Inflammatory Transcription Factor Stat4 Protects Long-Term Synaptic Plasticity From the Effects of a High-Fat, High-Cholesterol Diet
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Cell Biology and Anatomy
Neuroinflammation is associated with neurodegenerative diseases, including Alzheimer's and Parkinson's. The cytokine interleukin-12 activates signal transducer and activator of transcription 4 (Stat4), and consumption of a high-fat, high-cholesterol diet (HFD-C) and Stat4 activity are associated with inflammation, atherosclerosis, and a diabetic metabolic phenotype. In studies of in vitro hippocampal slices from control Stat4Ldlr mice fed a HFD-C diabetogenic diet, we show that Schaffer collateral-CA1 synapses exhibited larger reductions in activity-dependent, long-term potentiation (LTP) of synaptic transmission, compared to mice fed a standard diet. Glucose tolerance and insulin sensitivity shifts produced by HFD-C diet were reduced in Stat4Ldlr mice compared to Stat4Ldlr controls. Stat4Ldlr mice, which lack Stat4 under control of the LysM promoter, were resistant to HFD-C induced impairments in LTP. In contrast, Schaffer collateral-CA1 synapses in Stat4Ldlr mice fed the HFD-C diet showed larger LTP than control Stat4Ldlr mice. Expression of a number of neuroinflammatory and synaptic plasticity genes was reduced by HFD-C diet in control mice, and less affected by HFD-C diet in Stat4Ldlr mice. These data suggest that suppression of Stat4 activation may protect against effects of Western diet on cognition, type 2 diabetes, and reduce risk of Alzheimer's disease and other neurodegenerative disorders associated with neuroinflammation.
Zhang, X., Hollander, C. M., Khan, M. Y., D'silva, M., Ma, H., Yang, X., Bai, R., Keeter, C. K., Galkina, E. V., Nadler, J. L., & Stanton, P. K. (2023). Myeloid Cell Deficiency of the Inflammatory Transcription Factor Stat4 Protects Long-Term Synaptic Plasticity From the Effects of a High-Fat, High-Cholesterol Diet. https://doi.org/10.1038/s42003-023-05304-0