A high‐fat diet exacerbates the Alzheimer's disease pathology in the hippocampus of the App^{NL−F/NL−F} knock‐in mouse model

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.

MUTYH Actively Contributes to Microglial Activation and Impaired Neurogenesis in the Pathogenesis of Alzheimer’s Disease

“…We recently demonstrated that type 2 diabetes mellitus (T2DM) induced by a high-fat diet causes an impaired cognitive function in a mild preclinical AD model of App NL-F/NL-F mice accompanied by marked increases in both microgliosis and 8-oxoG accumulation as well as insulin resistance in the hippocampus [ 78 ]. The AD brain exhibits insulin resistance, and T2DM is a major risk factor for AD [ 1 – 3 , 31 ]; therefore, insulin secretagogues which can induce MUTYH degradation are promising therapeutic agents for the prevention of the AD pathogenesis.…”

The effect of dietary fat consumption on Alzheimer’s disease pathogenesis in mouse models

“…In a separate study, it was hypothesized that Aβ deposition prior to the onset of HFD consumption may be a prerequisite for exacerbated development or progression of AD-related pathologies in APP knock-in mouse models of AD [ 43 ]. Mazzei et al used the APP NL-F/NL-F knock-in AD mouse model, which expresses APP with a humanized Aβ region under the control of the endogenous APP mouse promoter.…”

“…APP NL-F/NL-F knock-in mice start accumulating Aβ as early as at 6 months-of-age and show mild cognitive deficits by 18 months [ 39 ]. APP NL-F/NL-F male mice were fed a 40% HFD or a regular diet starting at 6 months-of-age for 12 consecutive weeks [ 43 ]. The authors found that HFD increases body weight, fasting glucose levels, and glucose tolerance in both APP NL-F/NL-F mice and their WT littermates.…”

“…Several studies included in this review reported enhanced brain oxidative stress in response to HFD intake in different AD mouse lines (Fig. 2 ) [ 35 , 43 , 62 ]. Lin et al attributed cognitive impairment in HFD-fed 5XFAD mice to enhanced oxidative stress in the hippocampus in combination with exacerbated CAA [ 35 ].…”

“…HFD-fed APP NL-F/NL-F mice also show a reduced GCL volume. Thus, HFD-induced oxidative stress exacerbated by either Aβ accumulation of microgliosis may drive hippocampal atrophy by affecting dendrite stability and architecture [ 43 ]. Mazzei et al also hypothesized that HFD-induced increase in Aβ deposition in APP NL-F/NL-F mice might be due to decreased levels of transthyretin [ 43 ], a known Aβ-binding protein that can suppress Aβ aggregation [ 71 ].…”