Mechanisms Mediating the Protective Effects of Eicosapentaenoic Acid in Brain of the APPswePS1dE9 Alzheimer’s Mouse Model

Abstract

ObjectivesAlzheimer's disease (AD) is the leading cause of dementia and is characterized by accumulation of amyloid-beta (Aβ) and phosphorylated tau tangles. Obesity is a complex disease, associated with inflammation, metabolic dysfunctions, and a risk factor for AD. Marine eicosapentaenoic acid (EPA), exerts beneficial effects on obesity and inflammation in rodents. Our objective is to determine in diet-induced obese amyloidogenic mice, whether EPA reduces Aβ levels and if so, through which transcriptional mechanisms.MethodsMale and female APPswePS1E9 transgenic (TG) and non-TG wild type (WT) littermates were fed low fat (LF), high fat (HF), or HF diets supplemented with 36g EPA/kg (HF-EPA) for 8 months. We conducted metabolic phenotyping during feeding period, and harvested brain and blood at termination. Fatty acid (FA) composition was analyzed in cortex and red blood cells (RBC) using GC-MS. Cortex gene expression was analyzed using RNA-seq and qRT-PCR. RNA-seq data was processed using CLC Genomics Workbench 20 (Qiagen) and analyzed using IPA software. Data were analyzed by 3-way ANOVA using GraphPad Prism.ResultsHF groups weighted more and were fatter than LF groups (p < 0.001), and males gained more weight and adiposity than females (p < 0.001). EPA groups had higher amount of EPA and lower amount of arachidonic acid in RBC than HF groups (p < 0.001), while EPA groups have higher amount of DHA than HF and LF (p < 0.001) in the brain. TG mice had higher serum Aβ-40 levels (p = 0.004) and human APP mRNA levels in cortex (p = 0.0204) compared to WT mice. EPA decreased serum Aβ-40 level only in WT males (p = 0.0182) but reduced APP mRNA level in the cortex of both sex in TG mice (p = 0.0168 and 0.0030), compared to HF mice. Transcriptomic profiles revelated that cAMP response element-binding protein and wound healing/cell repair pathways were downregulated by HF (p < 0.001), compared to LF, but rescued by EPA (p < 0.001). Similarly, compared to LF, neuronal repair genes, such as Pcdha10 and Ccl21 were increased by HF (p < 0.05), but downregulated by EPA (p < 0.05).ConclusionsOverall, our results demonstrate protective effects of EPA in AD, in part through amyloid reduction and induction of brain neuroprotective signaling pathways. These findings merit further mechanistic studies as well as exploring potential translation into humans.Funding SourcesNIH R15 AT008879‐01A1S1 (NCCIH and NIA)