Impaired Resolution of Inflammation in Alzheimer's Disease: A Review

Abstract

Alzheimer's disease (AD) remains the leading cause of dementia worldwide, and over the last several decades, the role of inflammation in the pathogenesis of this neurodegenerative disorder has been increasingly elucidated. The initiation of the acute inflammatory response is counterbalanced by an active process termed resolution. This process is designed to restore homeostasis and promote tissue healing by the activation of neutrophilic apoptosis, promotion of neutrophil clearance by macrophages, and increasing anti-inflammatory cytokine levels, while concurrently leading to a diminution in pro-inflammatory mediators. The switch from the initiation to the resolution phase of inflammation is initially characterized by increased production of arachidonic acid-derived pro-resolving lipoxins and decreases in pro-inflammatory prostaglandin and leukotriene levels, subsequently followed by increases in specialized pro-resolving lipid mediators derived from omega-3 fatty acids (ω-3 FAs). There is mounting evidence that in AD, the resolution of inflammation is impaired, resulting in chronic inflammation and the exacerbation of the AD-related pathology. In this review, we examine preclinical and clinical evidence supporting the hypothesis that AD is a neurodegenerative disorder where the impairment or failure of resolution contributes to the disease process. Moreover, we review the literature supporting the potential therapeutic role of ω-3 FAs and specialized pro-resolving lipid mediators in the management of the disease. Lastly, we highlight areas that could strengthen the association of failed resolution to AD and should, therefore, be the focus of future scientific investigations in this research field.

Keywords: Alzheimer’s disease; beta-amyloid; inflammation; omega-3 fatty acids; resolution; resolvins; specialized pro-resolving lipid mediators; tau.

Figure 1

(A) The initiation phase of acute inflammation is characterized by an increase in the arachidonic acid-derived pro-inflammatory eicosanoids including prostaglandins, leukotrienes, and thromboxanes. Increases in prostaglandins eventually lead to a change in the biosynthesis of eicosanoids derived from arachidonic acid resulting in the formation of pro-resolution lipoxins via lipoxygenase-associated pathways. In the presence of aspirin, cyclooxygenase-2 is acetylated leading to the formation of the 15-epi-lipoxins (aspirin-triggered lipoxins). The aspirin-triggered isoforms are more resistant to degradation and hence more bioactive than native specialized pro-resolving mediators (SPMs). (B) Resolution is further propagated by the synthesis of SPMs derived from the omega-3 polyunsaturated fatty acids, docosahexaenoic acid (DHA), and eicosapentaenoic acid (EPA). SPMs derived from DHA include the resolvin D series, protectins, and maresins, as well as the aspirin-triggered epimeric (17R) forms of the resolvin D series and protectins. EPA derived SPMs include the resolvin E series.

Figure 2

Molecular features of Alzheimer’s disease (AD) pathophysiology and key targets of resolution agonists in neurodegeneration. Clockwise from 12 o’clock (1) neurotoxicity, including dysregulated glutamate and calcium signaling, and neurotransmission imbalance contribute to synaptic dysfunction and neuronal loss; (2) glia activation, including microglia and astrocytes, interfere with immunological processes in the brain further promoting non-resolving inflammation and neurodegeneration; (3) tau phosphorylation and neurofibrillary tangle formation; (4) Aβ plaque formation are key hallmarks of the AD brain. Specialized pro-resolving mediators and strategies aimed at boosting resolution such as using omega-3 polyunsaturated fatty acid exert differential effects on these targets and provide anti-inflammatory and pro-cognitive effects in neuroinflammation/degeneration; and (5) The accumulation of Aβ may lead to the microglial accumulation and activation resulting in increases in pro-inflammatory cytokines such as interleukin-1 beta, interleukin-6, and tumor necrosis factor-alpha. These cytokine increases in the brain can subsequently lead to tau hyperphosphorylation and a pathological cycle of increased Aβ deposition and persistent microglial activation, ultimately resulting in chronic neuroinflammation and neurodegeneration.