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

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 Ma et al. Resolving Neuroinflammation With DPAn-6 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.

The Impact of Obesity on Microglial Function: Immune, Metabolic and Endocrine Perspectives

“…Docosahexaenoic acid reduces surface presentation of TLR4 and CD14, thereby inhibiting LPS-induced downstream signaling and associated proinflammatory responses [ 219 , 220 ]. Additionally, dietary docosapentaenoic acid restrains microglia-mediated neuroinflammation and promotes neuronal survival in AD mouse models [ 368 ]. In accordance, omega-3 PUFA supplementation reduces microglial inflammatory activation and mitigates neural tissue destruction after traumatic brain injury [ 369 , 370 ].…”

Hawthorn flavonoid ameliorates cognitive deficit in mice with Alzheimer's disease by increasing the levels of Bifidobacteriales in gut microbiota and docosapentaenoic acid in serum metabolites

“…As a member of the long-chain polyunsaturated fatty acid family, DPA could decrease the mRNA expression of inflammatory factor and microglial markers. 43,44 Previous research demonstrated that DPA could improve the damage caused by Aβ and tau in 3xTg-AD mice by the PS1 presenilin pathway, 45 and correlation analysis showed that DPA is positively correlated with Firmicutes, Bifidobacterium , and Aerococcus. These findings reveal that HF-M might increase the DPA level by increasing the proportions of the Firmicutes and Bifidobacterium , thus improving cognitive disorders and reducing Aβ deposition in AD mice.…”

“…As a member of the long-chain polyunsaturated fatty acid family, DPA could decrease the mRNA expression of inflammatory factor and microglial markers. 43,44 Previous research demonstrated that DPA could improve the damage caused by Aβ and tau in 3xTg-AD mice by the PS1 presenilin pathway, 45 and correlation analysis showed that DPA is positively correlated with Firmicutes, Bifidobacterium, and…”

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“…Mushrooms contain about 4% to 9% of soluble fibers as well as 22% to 30% of insoluble fibers. Previous studies have revealed that 100 grams of P. ostreatus mushroom contain 4.1 grams of dietary fibers [ 43 ].…”