Contributions of a high-fat diet to Alzheimer's disease-related decline: A longitudinal behavioural and structural neuroimaging study in mouse models

Abstract

Obesity is recognized as a significant risk factor for Alzheimer's disease (AD). Studies have supported that obesity accelerates AD-related pathophysiology and memory impairment in mouse models of AD. However, the nature of the brain structure-behaviour relationship mediating this acceleration remains unclear. In this manuscript we evaluated the impact of adolescent obesity on the brain morphology of the triple transgenic mouse model of AD (3xTg) and a non-transgenic control model of the same background strain (B6129s) using longitudinally acquired structural magnetic resonance imaging (MRI). At 8 weeks of age, animals were placed on a high-fat diet (HFD) or an ingredient-equivalent control diet (CD). Structural images were acquired at 8, 16, and 24 weeks. At 25 weeks, animals underwent the novel object recognition (NOR) task and the Morris water maze (MWM) to assess short-term non-associative memory and spatial memory, respectively. All analyses were carried out across four groups: B6129s-CD and -HFD and 3xTg-CD and -HFD. Neuroanatomical changes in MRI-derived brain morphology were assessed using volumetric and deformation-based analyses. HFD-induced obesity during adolescence exacerbated brain volume alterations by adult life in the 3xTg mouse model in comparison to control-fed mice and mediated volumetric alterations of select brain regions, such as the hippocampus. Further, HFD-induced obesity aggravated memory in all mice, lowering certain memory measures of B6129s control mice to the level of 3xTg mice maintained on a CD. Moreover, decline in the volumetric trajectories of hippocampal regions for all mice were associated with the degree of spatial memory impairments on the MWM. Our results suggest that obesity may interact with the brain changes associated with AD-related pathology in the 3xTg mouse model to aggravate brain atrophy and memory impairments and similarly impair brain structural integrity and memory capacity of non-transgenic mice. Further insight into this process may have significant implications in the development of lifestyle interventions for treatment of AD.

High Fat Diet Suppresses Peroxisome Proliferator-Activated Receptors and Reduces Dopaminergic Neurons in the Substantia Nigra

“…Similar to our results, prolonged HFD consumption caused mice to be hypoactive, but more anxious in another study [17]. In mice, HFD intake increases the risk of neurological disorders that are characterized by cognitive impairments, most notably AD [18]. The peripubertal period is a critical maturational window that is highly sensitive to external influences, such as that of diet on brain function [19].…”

Exposure to maternal high-fat diet induces extensive changes in the brain of adult offspring

“…We also found maternal brain anatomy was not substantially impacted by the high-fat diet given over the course of approximately 12 weeks. Our results, conducted on C57Bl6/J mice, were consistent with results from Rollins et al, who found that 16 weeks of high-fat diet (60% calories from fat) were needed before adult mice (C57Bl6/J x 129S1/SvImJ strain) had a neuroanatomical phenotype detectable by MR imaging [30].…”

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

“…On the whole, the behavioral, histopathological, and molecular data above suggest that the APP/PS1 mice on the high fat diet in this study showed a similar exacerbation of Alzheimer'srelated effects as in previous studies [16,17,22]. We next sought to determine the role of capillary stalling and CBF deficits in this Hfd-linked exacerbation of Alzheimer's related symptoms.…”

“…Several studies have reported that feeding mouse models of APP overexpression a high fat diet leads to more severe short-term memory deficits [17,22,44]. In our work, we did not observe poorer short term memory function in APP/PS1 mice on a Hfd, as compared to normal chow, perhaps reflecting the sensitivity of the memory tests used here or reflecting differences in the composition, time of onset, duration of administration of the Hfd, or the control diet, as compared to other studies.…”

“…The emerging picture from this body of work is that a Hfd leads to increased deposition of amyloid-beta (Aβ) as plaques in the brain, as well as to increased brain inflammation, likely driving more Aβ-and inflammation-induced neural dysfunction. However, there have been variable findings on the impact of Hfd on the number and composition of amyloid-beta (Aβ) aggregates, the amount of hyperphosphorylated tau, and the degree of brain inflammation [18,22,23], again likely due to differences in diet parameters and AD mouse models. More recently, other mechanisms that may link obesity and consumption of a Hfd to dementia have been explored.…”