The Novel Omega-6 Fatty Acid Docosapentaenoic Acid Positively Modulates Brain Innate Immune Response for Resolving Neuroinflammation at Early and Late Stages of Humanized APOE-Based Alzheimer's Disease Models.

Qiu-Lan Ma,Matteo Pelligrini,Sally A Frautschy,Daniel Castro,Cansheng Zhu,Marco Morselli,Mychica Jones,Zhengqi Lu,Xuelin Gu,Frances Relampagos,Trent Su,Gregory M Cole,Paul Denver,Bruce Teter,Kaitlin Caoili

doi:10.3389/fimmu.2020.558036

Abstract

Neuroinflammation plays a crucial role in the development and progression of Alzheimer's disease (AD), in which activated microglia are found to be associated with neurodegeneration. However, there is limited evidence showing how neuroinflammation and activated microglia are directly linked to neurodegeneration in vivo. Besides, there are currently no effective anti-inflammatory drugs for AD. In this study, we report on an effective anti-inflammatory lipid, linoleic acid (LA) metabolite docosapentaenoic acid (DPAn-6) treatment of aged humanized EFAD mice with advanced AD pathology. We also report the associations of neuroinflammatory and/or activated microglial markers with neurodegeneration in vivo. First, we found that dietary LA reduced proinflammatory cytokines of IL1-β, IL-6, as well as mRNA expression of COX2 toward resolving neuroinflammation with an increase of IL-10 in adult AD models E3FAD and E4FAD mice. Brain fatty acid assays showed a five to six-fold increase in DPAn-6 by dietary LA, especially more in E4FAD mice, when compared to standard diet. Thus, we tested DPAn-6 in aged E4FAD mice. After DPAn-6 was administered to the E4FAD mice by oral gavage for three weeks, we found that DPAn-6 reduced microgliosis and mRNA expressions of inflammatory, microglial, and caspase markers. Further, DPAn-6 increased mRNA expressions of ADCYAP1, VGF, and neuronal pentraxin 2 in parallel, all of which were inversely correlated with inflammatory and microglial markers. Finally, both LA and DPAn-6 directly reduced mRNA expression of COX2 in amyloid-beta42 oligomer-challenged BV2 microglial cells. Together, these data indicated that DPAn-6 modulated neuroinflammatory responses toward resolution and improvement of neurodegeneration in the late stages of AD models.

Highlights

Neuroinflammation, derived from innate immune responses, is commonly characterized by the release of inflammatory cytokines from activated microglia
One series is omega-3 (n-3) that begins with alpha linolenic acid (ALA, 18:3) which is used for the synthesis of long-chain n-3 polyunsaturated fatty acids (PUFAs) such as docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), which can be metabolized to anti-inflammatory eicosanoids to reduce the risks for Alzheimer’s disease (AD), cardiovascular diseases and other chronic inflammatory diseases [32,33,34]
To begin to understand whether a high linoleic acid (LA) diet had an impact on neuroinflammation locally in the brain, we evaluated whether high LA diet altered brain fatty acid composition

Summary

Introduction

Neuroinflammation, derived from innate immune responses, is commonly characterized by the release of inflammatory cytokines from activated microglia. The important role of neuroinflammation in AD is underscored by findings in recent years from human genomewide association studies, whole-genome sequencing, and gene expression network analysis, which have uncovered common and rare genetic variants that are associated with AD. These genes are involved in innate immunity, implicating microglial genes in the development and progression of AD such as TREM2, CD33, TYROBP, and other disease-associated microglia genes [2,3,4,5,6].

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Results

Conclusion