High fat diet worsens Alzheimer’s disease-related behavioral abnormalities and neuropathology in APP/PS1 mice, 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 recently showed that non-flowing capillaries, caused by adhered neutrophils, contribute to 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 sensory-motor 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 on 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 that 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.

Assessment of Neurovascular Coupling & Cortical Spreading Depression in Mixed Models of Atherosclerosis & Alzheimer’s Disease

“…However, the number of cortical plaques were not significantly increased between J20-AD and J20-PCSK9-MIX mice, again confirming findings from the previously discussed study (31). Furthermore, other research has found that high-fat diet in APP/PS1 double transgenic mouse model of AD is able to increase neuropathological changes as well as worsen behavioural abnormalities, however, without any further alterations to CBF (32), as seen in our study.…”

Animal Models of Metabolic Disorders in the Study of Neurodegenerative Diseases: An Overview

“…It was recently demonstrated that HFD feeding induced the higher entry of 14C-sucrose and 99mTc-albumin into the brains of mice, which indicates BBB disruption ( Salameh et al, 2019 ). It is also important to note that a HFD also caused an increased neuroinflammatory response, increased brain concentration of Aβ species, and exacerbated behavioral deficits in APP/PS1 mice ( Bracko et al, 2020 ).…”

Role of sex and high-fat diet in metabolic and hypothalamic disturbances in the 3xTg-AD mouse model of Alzheimer’s disease

“…Brains of AD patients commonly exhibit defective insulin signaling [ 38 , 39 ], leading some to argue that AD is actually “Type 3 diabetes” [ 40 ]. Consumption of a hypercaloric diet (e.g., high fat, Western) and metabolic disease have been shown to exacerbate AD pathology and related behaviors in rodent models [ 41 – 45 ]. Mechanistically, metabolic disease also causes dysregulation of hormones involved in energy balance, as well as increased inflammation and amyloidosis, which is common to AD [ 46 – 48 ].…”