Restoration of Lipoxin A4 Signaling Reduces Alzheimer's Disease-Like Pathology in the 3xTg-AD Mouse Model

Abstract

The initiation of an inflammatory response is critical to the survival of an organism. However, when inflammation fails to reach resolution, a chronic inflammatory state may occur, potentially leading to bystander tissue damage. Accumulating evidence suggests that chronic inflammation contributes to the progression of Alzheimer’s disease (AD), and identifying mechanisms to resolve the pro-inflammatory environment stimulated by AD pathology remains an area of active investigation. Previously, we found that treatment with the pro-resolving mediator aspirin-triggered lipoxin A4 (ATL), improved cognition, reduced Aβ levels, and enhanced microglia phagocytic activity in Tg2576 transgenic AD mice. Here, we evaluated the effect of aging on brain lipoxin A4 (LXA4) levels using non-transgenic and 3xTg-AD mice. Additionally, we investigated the effect of ATL treatment on tau pathology in 3xTg-AD mice. We found that LXA4 levels are reduced with age, a pattern significantly more impacted in 3xTg-AD mice. Moreover, ATL delivery enhanced the cognitive performance of 3xTg-AD mice, reduced Aβ levels, as well as decreased the levels of phosphorylated-tau (p-tau). The decrease in p-tau was due in part to an inhibition of the tau kinases GSK-3β and p38 MAPK. In addition, microglial and astrocyte reactivity was inhibited by ATL treatment. Our results suggest that the inability to resolve the immune response during aging might be an important feature that contributes to AD pathology and cognitive deficits. Furthermore, we demonstrate that activation of LXA4 signaling could serve as a potential therapeutic target for AD related inflammation and cognitive dysfunction.

Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells: the OmegAD study

“…There is ample evidence that TTR counteracts the toxic effects of A ␤ in various AD-related models (50)(51)(52)(53)(54). LXA 4 , and its analog aspirin-triggered LXA 4 , have also been shown to ameliorate the detrimental effects of A ␤ in vitro and in vivo ( 17,18,55 ), probably by increasing phagocytosis, downregulating proinfl ammatory signaling, and upregulating antiinflammatory cytokine production ( 11 ). RvD1 was also reported to enhance phagocytosis by macrophages ( 56 ).…”

“…Recent studies have indicated that resolution of infl ammation is disturbed in AD ( 12,13 ) and AD-related models (14)(15)(16). Treatment with one of the SPMs, lipoxin A 4 (LXA 4 ), has been demonstrated to rescue synaptic loss and reduce AD-like pathologies in transgenic AD mouse models ( 17,18 ). These studies suggest that stimulating resolution of infl am mation with SPMs is a promising new strategy for AD therapy.…”

Astrocyte-derived lipoxins A4 and B4 promote neuroprotection from acute and chronic injury

“…The delivery and dosage of LXB 4 were based on previous publications (78)(79)(80). Briefly, LXB 4 or PBS vehicle was administered 3 times a week starting from week 8.…”

N-3 PUFAs and neuroinflammatory processes in cognitive disorders

“…Importantly, dietary supplementation of DHA prevented this reduction (Wang et al, 2015a), suggesting that long chain n-3 PUFAs protect from the Alzheimer-associated inflammation through the promotion of pro-resolving signaling. Interestingly, LOX and LTB4 expression increases while LXA4 decreases in the brain of aged and AD mice models (Dunn et al, 2015).…”