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

Article type: Research Article

Authors: Dunn, Haley C.^{a; b} | Ager, Rahasson R.^a | Baglietto-Vargas, David^{a; b} | Cheng, David^{a; b} | Kitazawa, Masashi^d | Cribbs, David H.^{a; c} | Medeiros, Rodrigo^{a; b; *}

Affiliations: [a] Institute for Memory Impairments and Neurological Disorders, University of California, Irvine, CA, USA | [b] Department of Neurobiology and Behavior, University of California, Irvine, CA, USA | [c] Department of Neurology, University of California, Irvine, CA, USA | [d] Department of Molecular and Cell Biology, University of California, Merced, CA, USA

Correspondence: [*] Correspondence to: Rodrigo Medeiros, PhD, Institute for Memory Impairments and Neurological Disorders (UCI MIND), Department of Neurobiology and Behavior, University of California, Irvine, 3400A Biological Sciences III, Irvine, CA 92697-4545, USA. E-mails: rodrigo.medeiros@uci.edu; rodrigo.medeiros@neurula.org.

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 and 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.

Keywords: Aging, Alzheimer's disease, aspirin-triggered lipoxin A₄, inflammation, lipoxin, lipoxygenase, resolution, 3xTg-AD

DOI: 10.3233/JAD-141335

Journal: Journal of Alzheimer's Disease, vol. 43, no. 3, pp. 893-903, 2015