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.

Neuroinflammation in Alzheimer’s Disease

“…]. Microglia exhibit high metabolic flexibility to cope with their high energy demands [ 214 ]. Microglial activity becomes compromised with age as mitochondrial activity declines with age and especially in age-related diseases such as AD [ 215 ] and they have a low mitochondrial turnover [ 213 , 216 ].…”

Mitoprotective Effects of Centella asiatica (L.) Urb.: Anti-Inflammatory and Neuroprotective Opportunities in Neurodegenerative Disease

“…Further, enhancing mitochondrial biogenesis and quality control may be an efficient strategy for preventing mitochondrial disorders ( Smith et al, 2012 ; Suliman and Piantadosi, 2016 ; Murphy and Hartley, 2018 ) and providing neuroprotection in AD and PD mouse models ( Johri and Beal, 2012 ). Several therapeutic approaches that aim to protect against neurodegeneration and inflammation by improving brain bioenergetics, rescuing mitochondrial dysfunction and reducing oxidative damage are being developed ( Cunnane et al, 2020 ; Fairley et al, 2021 ). In this section, we will focus on the mitoprotective and antioxidative effects of CA and its key phytochemicals as potential therapeutic agents that can 1) promote neuronal health and survival, and 2) reduce neuroinflammation.…”

“…Furthermore, microglial activation releases neurotoxic factors, such as mitochondrial-generated ROS, that exacerbate the neuroinflammation, thus resulting in neuronal death and neurodegeneration ( González et al, 2014 ; Simpson and Oliver, 2020 ). Microglia are metabolically plastic and, hence, are potential therapeutic targets for the treatment of AD using metabolic reprogramming strategies ( Fairley et al, 2021 ).…”

Long-term running exercise improves cognitive function and promotes microglial glucose metabolism and morphological plasticity in the hippocampus of APP/PS1 mice

“…However, the effects of microglial glucose metabolism on brain metabolism have only recently been discovered [ 21 ]. Microglial activation depends on high metabolic activity [ 22 ], and this activation has become an important consumer of glucose metabolism in the AD brain [ 23 ]. However, it is unclear whether microglia are involved in the improvement in regional brain glucose metabolism after running exercise.…”