High-fat diet-induced deregulation of hippocampal insulin signaling and mitochondrial homeostasis deficiences contribute to Alzheimer disease pathology in rodents

Abstract

Global obesity is a pandemic status, estimated to affect over 2 billion people, that has resulted in an enormous strain on healthcare systems worldwide. The situation is compounded by the fact that apart from the direct costs associated with overweight pathology, obesity presents itself with a number of comorbidities, including an increased risk for the development of neurodegenerative disorders. Alzheimer disease (AD), the main cause of senile dementia, is no exception. Spectacular failure of the pharmaceutical industry to come up with effective AD treatment strategies is forcing the broader scientific community to rethink the underlying molecular mechanisms leading to cognitive decline. To this end, the emphasis is once again placed on the experimental animal models of the disease. In the current study, we have focused on the effects of a high-fat diet (HFD) on hippocampal-dependent memory in C57/Bl6 Wild-type (WT) and APPswe/PS1dE9 (APP/PS1) mice, a well-established mouse model of familial AD. Our results indicate that the continuous HFD administration starting at the time of weaning is sufficient to produce β-amyloid-independent, hippocampal-dependent memory deficits measured by a 2-object novel-object recognition test (NOR) in mice as early as 6months of age. Furthermore, the resulting metabolic syndrome appears to have direct effects on brain insulin regulation and mitochondrial function. We have observed pathological changes related to both the proximal and distal insulin signaling pathway in the brains of HFD-fed WT and APP/PS1 mice. These changes are accompanied by a significantly reduced OXPHOS metabolism, suggesting that mitochondria play an important role in hippocampus-dependent memory formation and retention in both the HFD-treated and AD-like rodents at a relatively young age.

Anti-amnesic effect of Dendropanax morbifera via JNK signaling pathway on cognitive dysfunction in high-fat diet-induced diabetic mice

“…6, consumption of EFDM down-regulated expression levels of p-JNK, p-Akt, and p-tau in brain tissue. Previous researchs [38,39] only reported that non-phosphorylated forms of proteins, such as JNK, IRS and tau, were not changed in the HFD-induced diabetic mice brain, and only phosphorylated forms of proteins related with neurodegeneration were increased in the 24 diabetic mice. As these results, non-phosphorylated forms of JNK, IRS, and tau seem to be similarly expressed in the brain tissues.…”

Assessment of Cognitive Impairment in a Mouse Model of High-Fat Diet-Induced Metabolic Stress with Touchscreen-Based Automated Battery System

“…In this regard, numerous studies have shown that people with midlife obesity (measured by body mass index or central adiposity) have an augmented risk of AD [23]. According to previous studies, HFD increases hippocampal oxidative stress, which reduces NF-E2-related factor 2 signaling [24], causes mitochondrial homeostasis deficiency [25], and impairs hippocampus-dependent memory function [26]. Therefore, measuring the impairment of cognitive function due to a HFD in an animal model, especially the hippocampus-dependent memory function, is crucial.…”

The effect of abscisic acid chronic treatment on neuroinflammatory markers and memory in a rat model of high-fat diet induced neuroinflammation

“…Even though the relationship between obesity (excess body fat) and neurodegeneration is highly complex, many sources link obesity and high fat consumption with certain neurodegenerative processes [19]. Growing evidence demonstrates that HFD induces insulin resistance, immunological and synaptic alterations in different brain areas [32, 33], and cognitive impairment [34]. …”