Mitochondrial Dysfunction and Alzheimer's Disease: Role of Microglia.

Ishan Agrawal,Sushmita Jha

doi:10.3389/fnagi.2020.00252

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.

Highlights

In 1907 at the state asylum in Frankfurt, Germany, Aloysius ‘‘Alöis’’ Alzheimer meticulously described the symptoms of his 51-year-old patient Auguste Deter which included memory loss and other cognitive impairment
Microglial receptors like triggering receptor expressed in myeloid cells 2 (TREM2), Fc receptors, formyl peptide receptors, complement receptors, scavenger receptors, receptor for advanced glycosylation end products (RAGE), toll-like receptors (TLRs), NLRP3 inflammasome, and others play a significant role in Aβ-induced inflammation (Doens and Fernández, 2014)
The effects of metal ions, such as zinc and iron, on neurons have been studied in Alzheimer’s disease (AD), the relationship between mitochondrial dysfunction in microglia and metal ions remains largely underexplored (Scott and Orvig, 2009; Sensi et al, 2011; Liu et al, 2019)

Summary

Introduction

In 1907 at the state asylum in Frankfurt, Germany, Aloysius ‘‘Alöis’’ Alzheimer meticulously described the symptoms of his 51-year-old patient Auguste Deter which included memory loss and other cognitive impairment. Mitochondrial dysfunction in microglia has been reported to play a significant role in the pathogenesis of AD and other neurological disorders (Picone et al, 2014; Cenini and Voos, 2019; Flannery and Trushina, 2019). The authors reported that TREM2 deficiency leads to impaired mammalian target of rapamycin (mTOR) signaling pathway, which plays a major role in regulation of autophagy and increases autophagy.

Results

Conclusion