Abstract
Brain aging is characterized by a chronic low-grade inflammation, which significantly impairs cognitive function. Microglial cells, the immunocompetent cells of the brain, present a different phenotype, switching from a homeostatic signature (M0) to a more reactive phenotype called “MGnD” (microglial neurodegenerative phenotype), leading to a high production of pro-inflammatory cytokines. Furthermore, microglial cells can be activated by age-induced gut dysbiosis through the vagus nerve or the modulation of the peripheral immune system. Nutrients, in particular n-3 long chain polyunsaturated fatty acids (LC-PUFAs) and low molecular weight peptides, display powerful immunomodulatory properties, and can thus prevent age-related cognitive decline. The objective of this study was to investigate the effects of n-3 LC-PUFAs and low molecular weight peptides contained in a marine by-product-derived hydrolysate on microglial phenotypes and intestinal permeability and their consequences on cognition in mice. We demonstrated that the hydrolysate supplementation for 8 weeks prevented short- and long-term memory decline during aging. These observations were linked to the modulation of microglial signature. Indeed, the hydrolysate supplementation promoted homeostatic microglial phenotype by increasing TGF-β1 expression and stimulated phagocytosis by increasing Clec7a expression. Moreover, the hydrolysate supplementation promoted anti-inflammatory intestinal pathway and tended to prevent intestinal permeability alteration occurring during aging. Therefore, the fish hydrolysate appears as an interesting candidate to prevent cognitive decline during aging.
Highlights
Brain aging has been associated with a chronic low-grade inflammation, in humans [1,2,3] and rodents [4,5,6]
In this study we investigated the effects of n-3 LC-PUFAs and low molecular weight peptides contained in a marine byproduct-derived hydrolysate on microglial signature, intestinal permeability, and cognition in mice
We focused on IL-6 (Mm00446190_m1), IL-1β (Mm00434228_m1), tumor necrosis factor α (TNF-α) (Mm00443258_m1), TGF-β1 (Mm01178820_m1), transforming growth factor β receptor 2 (TGF-βr2; Mm03024091_m1), αM integrin (Itgam; Mm00434455_m1); transmembrane protein 119 (Tmem119; Mm00525305_m1), P2Y purinoceptor 12 (P2y12; Mm00446026_m1), colony-stimulating factor 1 receptor (CSF1r; Mm01266652_m1), major histocompatibility complex class II (MHCII) (Mm00439216_m1), triggering receptor expressed on myeloid cells 2 (Trem2; Mm04209424_g1), Apolipoprotein E (ApoE; Mm01307193_g1), Lgals3 (Mm00802901_m1), AXL receptor tyrosine kinase (Axl) (Mm00437221_m1), c-type lectin domain family 7-member A (Clec7a) (Mm01183349_m1), Itgax (Mm00498708_g1), IL10 (Mm01288386_m1), Ocln (Mm00500912_m1), zonula occludens 1 (ZO-1) (Mm00493699_m1), claudin 5 (Cldn5; Mm00727012_s1), and myosin light chain kinase (MLCK) (Mm00653039_m1)
Summary
Brain aging has been associated with a chronic low-grade inflammation, in humans [1,2,3] and rodents [4,5,6]. Microglial cells exhibit a unique molecular homeostatic signature (M0) but with aging, these cells can display a novel. Fish Hydrolysate Improves Memory Performance non-homeostatic signature called “MGnD” (microglial neurodegenerative phenotype) and become sensitized to inflammation and highly reactive, leading to an imbalance between pro- and anti-inflammatory cytokine production [7, 8]. Transforming growth factor β (TGF-β), an important molecule in the maintaining of the M0 phenotype, is decreased in microglial cells of aged mice, contributing to the shift toward MGnD signature [7, 10]. Aging has been linked to a decrease of gut microbiota diversity and an increase of intestinal permeability and inflammation, contributing to microglia activation via the vagus nerve or by direct modulation of the peripheral immune system [12,13,14,15]
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