High fat diet worsens pathology and impairment in an Alzheimer’s mouse model, but not by synergistically decreasing cerebral blood flow

Abstract

Obesity is linked to increased risk for and severity of Alzheimer's disease (AD). Cerebral blood flow (CBF) reductions are an early feature of AD and are also linked to obesity. We showed that non-flowing capillaries, caused by adhered neutrophils, underlie the CBF reduction in mouse models of AD. Because obesity could exacerbate the vascular inflammation likely underlying this neutrophil adhesion, we tested links between obesity and AD by feeding APP/PS1 mice a high fat diet (Hfd) and evaluating behavioral, physiological, and pathological changes. We found trends toward poorer memory performance in APP/PS1 mice fed a Hfd, impaired social interactions with either APP/PS1 genotype or a Hfd, and synergistic impairment of sensorymotor function in APP/PS1 mice fed a Hfd. The Hfd led to increases in amyloid-beta monomers and plaques in APP/PS1 mice, as well as increased brain inflammation. These results agree with previous reports showing obesity exacerbates AD-related pathology and symptoms in mice. We used a crowd-sourced, citizen science approach to analyze imaging data to determine the impact of the APP/PS1 genotype and a Hfd capillary stalling and CBF. Surprisingly, we did not see an increase in the number of non-flowing capillaries or a worsening of the CBF deficit in APP/PS1 mice fed a Hfd as compared to controls, suggesting capillary stalling is not a mechanistic link between a Hfd and increased severity of AD in mice. Reducing capillary stalling by blocking neutrophil adhesion improved CBF and short-term memory function in APP/PS1 mice, even when fed a Hfd. Keywords: animal behavior; nonlinear microscopy; brain blood flow; western high fat diet Significance statement:Obesity, especially in mid-life, has been linked to increased risk for and severity of Alzheimer's disease. Here, we show that blocking adhesion of white blood cells leads to increases in brain blood flow that improve cognitive function, regardless of whether mice are obese or not.

High-Fat Diet-Induced Obesity Increases Brain Mitochondrial Complex I and Lipoxidation-Derived Protein Damage

“…Our results demonstrate that a Western-type diet applied to female pigs increases brain lipoxidative damage, an effect that can be reversed by applying a probiotic n3supplemented diet. Numerous studies have indicated a correlation between obesity and the risk of developing AD [1,4,32,33]. This risk represents a modifiable factor in neurodegenerative processes [1,4], suggesting that dietary components could serve as preventive measures.…”

Effects of menopause and high fat diet on metabolic outcomes in a mouse model of Alzheimer’s disease

“…Animal studies, including our own, are in line with these clinical observations. Inducing metabolic disease via consumption of a high fat (HF) diet has been shown to worsen AD pathology and cognitive deficits in animal models (5,(15)(16)(17)(18)(19). Previously, we reported that consumption of a HF diet from ~3-7 months of age in 3xTg-AD mice resulted in a wider array of cognitive deficits (20) as well as more severe weight gain, glucose intolerance, and hypothalamic inflammation in females compared to males (5).…”