A high-fat diet exacerbates the Alzheimer's disease pathology in the hippocampus of the AppNL-F/NL-F knock-in mouse model

Insulin resistance and diabetes mellitus are major risk factors for Alzheimer's disease (AD), and studies with transgenic mouse models of AD have provided supportive evidence with some controversies. To overcome potential artifacts derived from , transgenes, we used a knock-in mouse model, App(NL-F/NL-F), which accumulates All plaques from 6 months of age and shows mild cognitive impairment at 18 months of age, without the overproduction of APP. In the present study, 6-month-old male App(NL-F/NL-F) and wild-type mice were fed a regular or high-fat diet (HFD) for 12 months. HFD treatment caused obesity and impaired glucose tolerance (i.e., T2DM conditions) in both wild-type and App(NL-F/NL-F) mice, but only the latter animals exhibited an impaired cognitive function accompanied by marked increases in both A beta deposition and microgliosis as well as insulin resistance in the hippocampus. Furthermore, HFD-fed App(NL-F/NL-F) mice exhibited a significant decrease in volume of the granule cell layer in the dentate gyrus and an increased accumulation of 8-oxoguanine, an oxidized guanine base, in the nuclei of granule cells. Gene expression profiling by microarrays revealed that the populations of the cell types in hippocampus were not significantly different between the two mouse lines, regardless of the diet. In addition, HFD treatment decreased the expression of the A beta binding protein transthyretin (TTR) in App(NL-F/NL-F) mice, suggesting that the depletion of TTR underlies the increased A beta deposition in the hippocampus of HFD-fed App(NL-F/NL-F) mice.

Automated summary

The study found that high-fat diet caused cognitive impairment, increased A beta deposition, and microgliosis in transgenic mouse models of Alzheimer's disease, accompanied by insulin resistance in the hippocampus.