Myeloid cell deficiency of the inflammatory transcript factor STAT4 protects long-term synaptic plasticity from the effects of a high-fat, high-cholesterol diet

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), 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 Stat4fl/flLdlr-/- mice fed a HFD-C diabetogenic diet, we found 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 Stat4ΔLysMLdlr-/- mice compared to Stat4fl/flLdlr-/- controls. Stat4ΔLysMLdlr-/- mice, which lack Stat4 under control of the LysMCre promoter, were resistant to HFD-C induced impairments in LTP. In contrast, Schaffer collateral-CA1 synapses in Stat4ΔLysMLdlr-/- mice fed the HFD-C diet showed larger LTP than control Stat4fl/flLdlr-/- 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 Stat4ΔLysMLdlr-/- mice. Suppression of Stat4 activation has potential for protecting against effects of western diet on cognition, type 2 diabetes, and reduce risk of Alzheimer’s disease and other neurodegenerative disorders associated with neuroinflammation. We collected the gene expression profile in a Host Response Panel, a custom Code Set which profiled 785 genes in mouse across 50+ pathways. Tissue was extracted and analyzed from the hippocampus of the following groups of animals at 24 weeks old: Stat4ΔLysMLdlr-/- mice on normal chow diet, Stat4ΔLysMLdlr-/- on HFD-C diet for 16 weeks, Stat4fl/flLdlr-/- mice on normal chow diet, and Stat4fl/flLdlr-/- mice on HFD-C diet for 16 weeks.