Mitochondrial Dysfunction and Alzheimer's Disease: Role of Microglia

Abstract

In 1907, Alois Alzheimer observed, as he quoted, development of "numerous fibers" and "adipose saccules" in the brain of his diseased patient Auguste Deter. The neurodegenerative disease became known as Alzheimer's disease (AD) and is the most common cause of dementia worldwide. AD normally develops with aging and is mostly initiated because of the imbalance between the formation and clearance of amyloid-β (Aβ). Formation of neurofibrillary tangles (NFTs) of hyperphosphorylated tau is another hallmark of AD. Neuroinflammation plays a significant role in the development and pathology of AD. This chapter explores the role of mitochondrial dysfunction in microglia in case of AD. Mitochondrial oxidative stress in microglia has been linked to the development of AD. Elevated generation of reactive oxygen species (ROS) and loss of mitochondrial membrane potential through various mechanisms have been observed in AD. Aβ interacts with microglial receptors, such as triggering receptor expressed in myeloid cells 2 (TREM2), activating downstream pathways causing mitochondrial damage and aggravating inflammation and cytotoxicity. Fibrillar Aβ activates nicotinamide adenine dinucleotide phosphate (NADPH) oxidase in microglia leading to elevated induction of mitochondrial ROS which further causes neurotoxicity. Elevated ROS in microglia causes activation of inflammatory and cell death pathways. Production of ATP, regulation of mitochondrial health, autophagy, and mitophagy in microglia play significant roles in the AD pathology. Understanding microglial physiology and mitochondrial dysfunction will enable better therapeutic interventions.

Keywords: ROS; amyloid-β; microglia; mitochondria; neurodegeneration.

Figure 1

Mitochondrial dysfunction in microglia. Amyloid-β (Aβ) interacts with different receptors present on microglia. Impaired triggering receptor expressed in myeloid cells 2 (TREM2) leads to impaired mammalian target of rapamycin (mTOR) pathway. Impaired mTOR pathway increases autophagy and decreases population of mitochondria which further decrease the production of ATP. Aβ interaction with P2X₇ activates NF-κB and leads to activation of NLRP3 and release of cytochrome c (cytc) from mitochondria (mechanism not clear) and apoptosis. Aβ gets phagocytosed through different receptors such as TREM2, toll-like receptors (TLRs), receptor for advanced glycosylation end products (RAGE), and CD36, and internalized Aβ interacts with mitochondrial calcium uniporter (MCU) on mitochondria leading to cell cytotoxicity. Through unknown receptors (?), Aβ decreases mitophagy and also increases reactive oxygen species (ROS) production. All these mechanisms contribute to Alzheimer’s Disease (AD) pathogenesis through inflammation or other mechanisms which are still under investigation.

Figure 2

Role of different drugs in improving AD pathology. mdivi-1 inhibits mitochondrial fission and inhibits the release of cytc, which in turn increases cell viability. Ru-360 decreases excessive calcium uptake by mitochondria and reduces the expression of C/-EBP homologous protein (CHOP) on the endoplasmic reticulum. This inhibits ROS production. Urolithin A (UA) and actinonin (AC) increases phagocytosis of Aβ and increases mitophagy which reduces the number of damaged mitochondria inside cells. UA and AC also increase the expression of IL-10 and inhibit IL-6 and TNF-α. Mitochonic acid 5 (MA-5) also increases mitophagy and decreases the production of ROS. These drug effects enhanced cell viability, and reduced inflammation and AD pathology.