Mitochondrial Regulation of Microglial Immunometabolism in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is an age-associated terminal neurodegenerative disease with no effective treatments. Dysfunction of innate immunity is implicated in the pathogenesis of AD, with genetic studies supporting a causative role in the disease. Microglia, the effector cells of innate immunity in the brain, are highly plastic and perform a diverse range of specialist functions in AD, including phagocytosing and removing toxic aggregates of beta amyloid and tau that drive neurodegeneration. These immune functions require high energy demand, which is regulated by mitochondria. Reflecting this, microglia have been shown to be highly metabolically flexible, reprogramming their mitochondrial function upon inflammatory activation to meet their energy demands. However, AD-associated genetic risk factors and pathology impair microglial metabolic programming, and metabolic derailment has been shown to cause innate immune dysfunction in AD. These findings suggest that immunity and metabolic function are intricately linked processes, and targeting microglial metabolism offers a window of opportunity for therapeutic treatment of AD. Here, we review evidence for the role of metabolic programming in inflammatory functions in AD, and discuss mitochondrial-targeted immunotherapeutics for treatment of the disease.

Keywords: beta amyloid (Aβ); metabolism; microglia; mitochondria; neurodegeneration; tau.

Figure 1

Microglial metabolic programming and immune functions in AD. Alzheimer’s pathogenic stimuli Aβ and tau induce microglial metabolic alterations. Metabolic alterations are mediated by the mTOR-HIF1a pathway and characterized by decreased OXPHOS, increased glycolysis, impaired ATP production, a “broken” TCA cycle, increased ROS, and lipid droplet accumulation. These alterations in turn effect microglial immune functions including phagocytosis, chemotaxis, cytokine production, membrane biogenesis, and antigen presentation. GLUTs, glucose transporters; PPP, pentose phosphate pathway; TCA, tricarboxylic acid; ROS, reactive oxygen species; OXPHOS, oxidative phosphorylation; TNF-α, tumor necrosis factor- α; IL-6, interleukin-6; IL-1β, interleukin-1β; HIF-1α, hypoxia inducible factor-1α; mTOR, mammalian target of rapamycin.