Molecular Mechanisms and Genetics of Oxidative Stress in Alzheimer’s Disease

Abstract

Alzheimer's disease is the most common neurodegenerative disorder that can cause dementia in elderly over 60 years of age. One of the disease hallmarks is oxidative stress which interconnects with other processes such as amyloid-␤ deposition, tau hyperphosphorylation, and tangle formation. This review discusses current thoughts on molecular mechanisms that may relate oxidative stress to Alzheimer's disease and identifies genetic factors observed from in vitro, in vivo, and clinical studies that may be associated with Alzheimer's disease-related oxidative stress.

Klotho Pathways, Myelination Disorders, Neurodegenerative Diseases, and Epigenetic Drugs

“…61,70,71,74,[77][78][79][80] Manifestations of OS are hallmark symptoms in neurological disease, including cognitive deficits. 52,54,65,76,79,[81][82][83][84][85][86][87][88] In concert with the above, a correlation was found between OS in the CNS and demyelination, which results in the loss of integrity and proper maintenance of oligodendrocytes and their myelin sheaths, the latter being crucial for cognitive performance and higher brain function. 57,[89][90][91] Thus, inclusion of strategies for enhancing mitochondrial biogenesis, function, and protection 68,80,[92][93][94][95][96] that may also rely on pathways epigenetically induced by diet [97][98][99][100][101][102][103][104][105][106][107][108] and/or exercise 99,100,…”

“…[50][51][52] Beyond AD and PD, age-related declines in Klotho 8,13,17,24,53 are associated with a range of other deteriorating central nervous system (CNS) processes. 17,24 For example, mounting evidence implicates dysregulation of Klotho in shared mechanistic pathological relationships linking iron and myelin in various common and rare brain diseases, [54][55][56] including abnormalities in myelination and the maturation of oligodendrocytes that are central to the pathogenicity of diseases such as multiple sclerosis (MS) 26,56,57 and amyotrophic lateral sclerosis (ALS). 56,58 OS Demyelination and Mitochondrial Dysfunction Mitochondrial dysfunction is a well-documented enabling factor in the pathophysiology of neurological conditions and disorders ( Fig.…”

Harnessing endophenotypes and network medicine for Alzheimer's drug repurposing

“…We have identified six endophenotype hypotheses in AD: (i) amyloidosis, (ii) tauopathy, (iii) neuroinflammation, (iv) mitochondrial dysfunction, (v) vascular dysfunction, and (vi) lysosomal dysfunction ( Figure 5). We acknowledged the existence of additional endophenotypes in AD, including oxidative stress, 55 proteostasis 56,57 and synaptic dysfunction 58 that are also worthy of consideration, and which will be the subject of future investigation. In addition, we highlight new opportunities for endophenotype networkinformed, in silico drug repurposing in AD.…”

“…In addition to the six endophenotypes discussed, there are several additional endophenotypes in AD, including oxidative stress, 55 proteostasis, 56,57 and synaptic dysfunction. 58 Oxidative stress involves in multiple biological processes in AD, such as Aβ deposition, tau hyperphosphorylation, and tangle formation.…”

“…The detailed molecular mechanisms and genetics of oxidative stress in AD were comprehensive described in a previous Review. 55 Proteostasis refers to the dysfunction in protein homeostasis, leading to the accumulation of protein aggregates. 56 Targeting endoplasmic reticulum acetylation to improve proteostasis in the secretory pathway can rescue AD in a mouse model.…”