(PTFS07-04-24) Transcriptomic Analyses of Eicosapentaenoic Acid Effects in Adipose Tissue and Cortex From High Fat Diet-Induced Obese Amyloidogenic Alzheimer Disease Mice

Objectives: Alzheimer’s disease (AD) is specified by amyloid-beta (Aβ) plaques and neuroinflammation. Obesity, marked by excessive white adipose tissue (WAT), leads to metabolic dysfunctions, systemic inflammation and enhances risk for AD. We previously reported that eicosapentaenoic acid (EPA), an omega-3 polyunsaturated fatty acids, improved metabolic profiles and reduced serum amyloid β (Aβ40) in diet-induced obese transgenic (TG) amyloidogenic AD mice. Here, we studied the links among obesity, WAT inflammation and neuroinflammation in this AD model.

Methods: To gain mechanistic insights into the metabolic and anti-inflammatory effects of EPA in obese AD mice, male and female APPswePS1E9 TG and non-TG wild-type (WT) littermates were fed HF diets without or with 36g EPA/kg diet (EPA). Metabolic phenotypes were assessed during a 32-week intervention, then blood, WAT (gonadal) and brain (cortex) were collected for further analyses, including fatty acid profiling, and gene expression analyses using RNA-sequencing (RNA Seq) and qRT-PCR. Ingenuity pathway analysis (IPA®) was used to analyze differentially expressed pathways and genes. Data were statistically analyzed by t-test and three-way ANOVA, using GraphPad Prism version 9.

Results: As expected, EPA groups had higher EPA in red blood cells than HF groups (p < 0.001). Compared to HF group, EPA reduced NLRP3 gene expression in TG male and female cortex (p = 0.0205 and < 0.0001) and in WAT of TG female mice (p = 0.02), as assessed by qPCR. RNA Seq analyses using IPA® showed that EPA inhibited oxidative stress (p <0.05) and TNF-a pathways (p <0.05) compared to HF in TG and WT female mice cortex, respectively. Similar analyses in WAT showed that EPA inhibited melatonin degradation 1 (z = -3.35, -log p = 5.66) and netrin1(z = -2.82, -log p = 3.84) pathways in TG males and females, respectively, compared to HF. Moreover, EPA inhibited amyloid fiber formation (z = -2, -log p = 1.40) and leukocyte extravasation pathways (z = -2.64, -log p = 1.56) in WT males, compared to HF.

Conclusions: EPA protective effects in obese AD mice maybe mediated by inhibition of inflammation/neuroinflammation pathways. Further analyses are required to identify regulatory genes/pathways influencing the links between obesity-induced inflammation and neuroinflammation in AD.

Funding Sources: National Center for Complementary and Integrated Health (NCCIH)