High‐Fat‐Diet Intake Enhances Cerebral Amyloid Angiopathy and Cognitive Impairment in a Mouse Model of Alzheimer's Disease, Independently of Metabolic Disorders

Abstract

BackgroundThe high‐fat Western diet is postulated to be associated with the onset and progression of Alzheimer's disease (AD). However, the role of high‐fat‐diet consumption in AD pathology is unknown. This study was undertaken to examine the role of high‐fat‐diet intake in AD.Methods and Results5XFAD mice, a useful mouse model of AD, and control wild‐type mice were fed (1) high‐fat diet or (2) control diet for 10 weeks. The effects on cerebral AD pathology, cognitive function, and metabolic parameters were compared between each group of mice. High‐fat diet significantly enhanced cerebrovascular β‐amyloid (Aβ) deposition (P<0.05) and impaired cognitive function (P<0.05) in 5XFAD mice, but not in wild‐type mice. High‐fat diet enhanced hippocampal oxidative stress (P<0.05) and NADPH oxidase subunits, gp91phox (P<0.01) and p22phox (P<0.01) in 5XFAD mice, but not in wild‐type mice. Furthermore, high‐fat diet reduced cerebral occludin (P<0.05) in 5XFAD mice, but not in wild‐type mice. Thus, 5XFAD mice exhibited greater susceptibility to high‐fat diet than wild‐type mice regarding cerebrovascular injury and cognitive impairment. On the other hand, 5XFAD mice fed high‐fat diet exhibited much less increase in body weight, white adipose tissue weight, and adipocyte size than their wild‐type counterparts. High‐fat diet significantly impaired glucose tolerance in wild‐type mice but not in 5XFAD mice. Thus, 5XFAD mice had much less susceptibility to high‐fat‐diet‐induced metabolic disorders than wild‐type mice.ConclusionsHigh‐fat diet, independently of metabolic disorders, significantly promotes the progression of AD‐like pathology through enhancement of cerebral amyloid angiopathy and oxidative stress.

Detrimental Effects of Centrally Administered Angiotensin II are Enhanced in a Mouse Model of Alzheimer Disease Independently of Blood Pressure

“…In the present study, we used 5XFAD mice because 5XFAD mice recapitulate major features of AD pathology and are regarded as 1 of the popular models of AD. [18][19][20]27 To examine spatial learning and memory function of 5XFAD mice, we used the Morris water maze test because it is the most popular behavioral assay for detecting AD-relevant cognitive impairments across species. 36,37 We found that 5XFAD mice were more prone to angiotensin II-induced cognitive impairment than control mice, as evidenced by the findings of the water maze test.…”

“…To assess spatial learning and memory function, from 21 to 25 days after the start of ICV infusion, the Morris water maze test was performed according to our previous protocol. 27 Briefly, swimming paths were video-tracked with a camera fixed on the ceiling of the room and analyzed by the software (Muromachi Kikai, Tokyo, Japan). On the hidden test, the mice had 4 sessions per day on the following 4 consecutive days (days 1 to 4).…”

In vivoimaging of prodromal hippocampus CA1 subfield oxidative stress in models of Alzheimer disease and Angelman syndrome

“…Aldehyde dehydrogenase 2 mice are also called HNE mice because they exhibit a greater‐than‐normal hippocampus concentration of the peroxidation product HNE (the earliest evidence for oxidative stress in patients with prodromal AD (30), together with spatial learning and memory impairments and age‐dependent spontaneous AD‐like histopathology (17). 5xFAD mice are a common β‐amyloidogenic model of familial AD that demonstrates hippocampus oxidative stress (including HNE accumulation) and spatial cognitive defects (26, 28). UBE3A ‐knockout mice are a model of AS, a genetic neurodevelopmental disorder characterized by hippocampus oxidative stress and impaired goal location based on external cues and other endophenotypes consistent with that in patients with AS (2, 31).…”

“…We evaluated Quest MRI during sustained superoxide production from the xanthine/xanthine oxidase reaction (23, 24). We provide proof-of-concept data that Quest MRI can be applied to evaluate hippocampus subfields in vivo in 3 disease models: aldehyde dehydrogenase 2-knockout mice, 5xFAD mice, and UBE3A-knockout mice (25)(26)(27)(28)(29). Aldehyde dehydrogenase 2 mice are also called HNE mice because they exhibit a greater-than-normal hippocampus concentration of the peroxidation product HNE (the earliest evidence for oxidative stress in patients with prodromal AD (30), together with spatial learning and memory impairments and age-dependent spontaneous AD-like histopathology (17).…”

Enhanced oxidative stress contributes to worse prognosis and delayed neurofunctional recovery after striatal intracerebral hemorrhage in 5XFAD mice

“…Currently, there are many preclinical animal models with AD‐like pathology. Among them, 5XFAD (5X) mice exhibit overexpression of the human amyloid precursor protein (APP695) with the Swedish (K670N, M671L), Florida (I716V), and London (V717I) familial AD mutations, together with mutant human presenilin‐1 (M146L, L286V) under control of the murine Thy‐1 promoter (Lin et al, ; Oakley et al, ). These mice display significantly accumulated Aβ 1‐42 deposition in their brain parenchyma and develop progressive cognitive impairment with age (Oakley et al, ; Webster, Bachstetter, Nelson, Schmitt, & Eldik, ).…”