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.
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http://dx.doi.org/10.1038/s42003-023-05304-0 | DOI Listing |
J Immunol
November 2017
Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA 23501;
The metabolic syndrome and diabetic conditions support atherosclerosis, but the exact mechanisms for accelerated atherogenesis remain unclear. Although the proinflammatory role of STAT4 in atherosclerosis and diet-induced insulin resistance (IR) was recently established, the impact of STAT4 on atherogenesis in conditions of IR is not known. In this study, we generated mice that were fed a diabetogenic diet with added cholesterol (DDC).
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