Abstract
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, AppNL−F/NL−F , which accumulates Aβ 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 AppNL−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 AppNL−F/NL−F mice, but only the latter animals exhibited an impaired cognitive function accompanied by marked increases in both Aβ deposition and microgliosis as well as insulin resistance in the hippocampus. Furthermore, HFD‐fed AppNL−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 Aβ binding protein transthyretin (TTR) in AppNL−F/NL−F mice, suggesting that the depletion of TTR underlies the increased Aβ deposition in the hippocampus of HFD‐fed AppNL−F/NL−F mice.
Highlights
Dementia is a syndrome that affects memory, thinking, behavior, and the ability to perform everyday activities (Ninomiya, 2019)
The major conclusion of the present study is that chronic high-fat diet (HFD) treatment caused obesity and impaired glucose tolerance in both wild-type and AppNL−F/NL−F mice, with only the latter exhibiting an impaired cognitive function accompanied by marked increases in both a humanized β-amyloid (Aβ) deposition and microgliosis as well as insulin resistance in the hippocampus
HFD treatment decreased the expression of TTR, a known Aβ-binding protein, in AppNL−F/NL−F mice but not wild-type mice, suggesting that decreased levels of TTR may be a cause of the increased Aβ deposition in the hippocampus of HFD-fed AppNL−F/NL−F mice
Summary
Dementia is a syndrome that affects memory, thinking, behavior, and the ability to perform everyday activities (Ninomiya, 2019). Some studies with 3xTg-AD mice carrying mutant APP and MAPT transgenes together with a Psen knock-in mutation have shown that HFD treatment increases brain Aβ levels with an exacerbated cognitive decline (Barron et al, 2013; Vandal et al, 2014). It is reasonable to assume that T2DM has an impact on amyloidosis since Aβ deposition starts at 10–20 years before the clinical onset of AD (Bateman et al, 2012), and T2DM increases the risk of AD development during this early stage without clinical symptoms of AD (Ninomiya, 2014) To test this hypothesis, we applied HFD treatment to an AppNL−F/NL−F knock-in mouse model of AD, which carries a humanized β-amyloid (Aβ) sequence with two pathogenic mutations: Swedish “NL” and Iberian “F” at the authentic mouse App locus, thereby increasing the production of the pathogenic Aβ without the overproduction of APP. The results in (d–f) were statistically analyzed by a two-way ANOVA (p values for each analysis shown) followed by post hoc Tukey's HSD test, *p < 0.05, **p < 0.01 and ***p < 0.001
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