Abstract
High-fat diet (HFD) has been shown to accelerate Alzheimer’s disease (AD) pathology, but the exact molecular and cellular mechanisms remain incompletely understood. Moreover, it is unknown whether AD mice are more susceptible to HFD-induced metabolic dysfunctions. To address these questions, we used 5xFAD mice as an Alzheimer’s disease model to study the physiological and molecular underpinning between HFD-induced metabolic defects and AD pathology. We systematically profiled the metabolic parameters, the gut microbiome composition, and hippocampal gene expression in 5xFAD and wild type (WT) mice fed normal chow diet and HFD. HFD feeding impaired energy metabolism in male 5xFAD mice, leading to increased locomotor activity, energy expenditure, and food intake. 5xFAD mice on HFD had elevated circulating lipids and worsened glucose intolerance. HFD caused profound changes in gut microbiome compositions, though no difference between genotype was detected. We measured hippocampal mRNAs related to AD neuropathology and neuroinflammation and showed that HFD elevated the expression of apoptotic, microglial, and amyloidogenic genes in 5xFAD mice. Pathway analysis revealed that differentially regulated genes were involved in insulin signaling, cytokine signaling, cellular stress, and neurotransmission. Collectively, our results showed that 5xFAD mice were more susceptible to HFD-induced metabolic dysregulation and suggest that targeting metabolic dysfunctions can ameliorate AD symptoms via effects on insulin signaling and neuroinflammation in the hippocampus.
Highlights
Alzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly
In order to evaluate baseline energy homeostasis in 5xFAD mice compared to wild type (WT) mice, we used indirect calorimetry for metabolic profiling and measured locomotor activity, energy expenditure, oxygen consumption, nutrient utilization, and food intake in WT and 5xFAD animals fed normal chow diet (NCD)
We determined that WT and 5xFAD mice had comparable body weight and body composition (Figure 1A–C)
Summary
Alzheimer’s disease (AD) is the most prevalent cause of dementia in the elderly. AD is a progressive and devastating neurological disease, which begins with mild memory loss and eventually can seriously compromise a person’s ability to carry out daily activities. Brain insulin resistance causes metabolic and bioenergetic defects, which is a potential contributing factor to cognitive impairment and AD pathogenesis [9,15,16,17]. Previous studies showed that HFD feeding in a transgenic mouse model harboring five familial AD mutations (5xFAD) had increased amyloid deposition and impaired performance in memory and learning tasks [24,25]. 5xFAD is an early onset mouse model of Alzheimer’s disease harboring five AD-associated mutations in human APP and PS1 which causes rapid progression of amyloid pathology due to the increased generation of insoluble. The mechanisms linking high-fat diet to AD progression are still under investigation, and it remains unknown whether transgenic AD mouse models are more susceptible to HFD-induced metabolic derangements. We revealed the specific effects of HFD on the hippocampi of the transgenic AD mice in terms of individual gene transcription and the collective changes in the neuropathology and neuroinflammatory pathways, thereby providing potential targets for AD therapy
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