The effect of altered nitric oxide bioavailability on the interaction of obesity and Alzheimer’s disease. Exploration of whether a high fat diet produces early cognitive decline in an Alzheimer’s mouse model.

Abstract

AbstractBackgroundAlzheimer’s disease (AD) can be predicted by obesity and vascular risk factors. Obesity and AD are associated with vascular dysfunction, resulting in reduced peripheral and cerebral blood flow. Obesity is associated with reduced nitric oxide (NO) bioavailability, which contributes to reduced blood flow, the accumulation of β‐amyloid (Aβ), and eventual cognitive decline in AD. In animal models of AD, obesity or high fat diet exacerbates cognitive decline. The APPswe/PS1dE9 (APP/PS1) mouse, a model of beta amyloid neuropathology, demonstrates significant NO substrate dysfunction. NO substrate dysfunction and obesity potentially initiates metabolic and vascular dysfunction that can accelerate cognitive function decline. We investigated the impact of a high‐fat diet (HFD) on cognitive performance (discrimination reversal) in transgenic (Tg) and non‐transgenic (Non‐Tg) APP/PS1 mice prior to evaluating the role of NO in AD and obesity.MethodFemale APP/PS1 mice were split into four groups: Non‐Tg Chow (n = 9), Non‐Tg HFD (n = 5), Tg Chow (n = 9), and Tg HFD (n = 14). Mouse operant chambers with two nose poke ports and a dipper for delivering sucrose solution (15%) were used. Discrimination reversal procedure involved nose pokes in the left or right nose poke port produced access to 15% sucrose under a fixed ratio (FR) 1 schedule of reinforcement. Once the performance met criteria, the “correct” nose poke port was switched.ResultTg mice averaged fewer sessions to meet criteria in training. Non‐Tg and Tg mice on HFD failed to learn the discrimination to criteria and never experienced reversals. Non‐Tg mice on chow learned the discrimination multiple times. Only one Tg mice fed chow learned. Mice fed the chow diet received more sucrose reinforcers compared to mice fed the HFD.ConclusionAlthough HFD‐fed mice responded at lower rates, on average, they still made substantial numbers of responses suggesting that the failure to obtain the discrimination was not simply a result of a motivational deficit. Non‐Tg chow‐fed subjects made fewer errors than Tg chow‐fed subjects. Tg HFD‐fed mice originally made as many errors as their chow‐fed littermates but made more errors over the course of the study. Future research will investigate the impacts of decreased NO bioavailability.