Interplay Between Mitochondrial Oxidative Disorders and Proteostasis in Alzheimer’s Disease

Abstract

Although the basis of Alzheimer's disease (AD) etiology remains unknown, oxidative stress (OS) has been recognized as a prodromal factor associated to its progression. OS refers to an imbalance between oxidant and antioxidant systems, which usually consist in an overproduction of reactive oxygen species (ROS) and reactive nitrogen species (RNS) which overwhelms the intrinsic antioxidant defenses. Due to this increased production of ROS and RNS, several biological functions such as glucose metabolism or synaptic activity are impaired. In AD, growing evidence links the ROS-mediated damages with molecular targets including mitochondrial dynamics and function, protein quality control system, and autophagic pathways, affecting the proteostasis balance. In this scenario, OS should be considered as not only a major feature in the pathophysiology of AD but also a potential target to combat the progression of the disease. In this review, we will discuss the role of OS in mitochondrial dysfunction, protein quality control systems, and autophagy associated to AD and suggest innovative therapeutic strategies based on a better understanding of the role of OS and proteostasis.

The biological pathways of Alzheimer disease: a review

“…Oxidative stress (OS) has been widely recognized as a prodromal factor associated to AD [186] . Cell control on OS is particularly important to maintain the balanced microenvironment needed for multiple biological processes, from bioenergetics to other essential functions such as vesicle transport or post-transcriptional modulations [187] .…”

Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review

“…From the perspective of the classic “mitochondrial cascade hypothesis” ( 245 ) for the LOAD form, mitochondrial malfunction acts as a proximal event that causes Aβ deposition, synaptic degeneration, and intracellular NFT formation. Indeed, there are a wealth of studies showing that mitochondrial dysfunction is a frequent and decisive event in AD ( 246 ). The primary pathogenic role of mitochondria has been further nurtured in recent years.…”

Novel insights into potential therapeutic targets and biomarkers using integrated multi-omicsapproaches for dilated and ischemic cardiomyopathies

“…Another candidate gene and potential biomarker of note, TMEM259, has some associations with ischemic conditions as well as ER protein degradation pathways 65 . A number of other genes: FOC, REC8, FHOD1 as well as TAOK1 and MINDY2, are involved in the modulation of cell proliferation, immune signalling and protein turnover 69,117 . These findings provided the first hints of potential exacerbation of the ER stress as well as inflammation induced fibrotic tissue damage propagating the ischemia cycle.…”

“…12, Table 1) and this population under myocardial stress conditions can change its proportions further by propagating proinflammatory and pro-fibrotic environment. Moreover, normal subpopulations of immune cells identified in the heart, such as monocytes, macrophages, mast cells, eosinophils, neutrophils B cells and T cells, can also be activated and lead to a pro-inflammatory state 56,61,117,123 . These considerations need to be taken into account when analysing data at different resolution levels where different types of cells can show a varying degree of contribution in the bulk transcriptome.…”