The Link between Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation in the Pathophysiology of Alzheimer’s Disease: Therapeutic Implications and Future Perspectives

Abstract

Alzheimer’s disease (AD), the most common form of dementia, has increasing incidence, increasing mortality rates, and poses a huge burden on healthcare. None of the currently approved drugs for the treatment of AD influence disease progression. Many clinical trials aiming at inhibiting amyloid plaque formation, increasing amyloid beta clearance, or inhibiting neurofibrillary tangle pathology yielded inconclusive results or failed. Meanwhile, research has identified many interlinked vicious cascades implicating oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, and has pointed to novel therapeutic targets such as improving mitochondrial bioenergetics and quality control, diminishing oxidative stress, or modulating the neuroinflammatory pathways. Many novel molecules tested in vitro or in animal models have proven efficient, but their translation into clinic needs further research regarding appropriate doses, delivery routes, and possible side effects. Cell-based therapies and extracellular vesicle-mediated delivery of messenger RNAs and microRNAs seem also promising strategies allowing to target specific signaling pathways, but need further research regarding the most appropriate harvesting and culture methods as well as control of the possible tumorigenic side effects. The rapidly developing area of nanotechnology could improve drug delivery and also be used in early diagnosis.

Therapeutic Inhalation of Hydrogen Gas for Alzheimer’s Disease Patients and Subsequent Long-Term Follow-Up as a Disease-Modifying Treatment: An Open Label Pilot Study

“…Therefore, one strategy for AD therapy or drug development is to modulate oxidative stress, inflammation, and energy metabolism [ 29 ].…”

Stem Cell- and Cell-Based Therapies for Ischemic Stroke

“…Takahashi and Yamanaka managed to successfully reprogram adult somatic cells and obtain gene-matched induced pluripotent stem cells (iPSCs) through the retroviral transduction of the sex-determining region Y-box and the octamer-binding transcription factor 4 (2 transcription factors), and C-MYC and the Kruppellike factor 4 (two signaling molecules) [ 35 ]. Further, in the presence of specific proteins and inducers, iPSCs can differentiate into NSCs [ 36 ]. Unfortunately, the obtained iPSCs may have chromosomal aberrations, and they have tumorigenic and immunogenic potential [ 21 , 37 ].…”

“…For the formation of the exosome, the plasma membrane initially bulges inward and forms an intracellular vesicle (the endosome), which subsequently fuses with the plasma membrane and empties its contents into the extracellular space [ 55 ]. Microvesicles bud directly from the plasma membrane, are larger than exosomes, contain cytosolic proteins, lipids, and mRNAs and miRNAs as well, and they are internalized by the recipient cell following ligand–receptor interaction [ 36 , 56 ]. These cell-derived vesicles have the advantages of low immunogenicity, a low risk of vessel thrombosis following transplantation, and they are able to cross the BBB.…”

Ginkgo biloba Extract EGb 761 in the Treatment of Patients with Mild Neurocognitive Impairment: A Systematic Review

“… 26–28 It also showed antioxidant activity and protection of mitochondrial function against various toxicities, 23 , 29 a process that is strongly linked to Alzheimer’s disease pathophysiology. 30 …”

“…[26][27][28] It also showed antioxidant activity and protection of mitochondrial function against various toxicities, 23,29 a process that is strongly linked to Alzheimer's disease pathophysiology. 30 Clinical trials assessing the effects of EGb 761 on cognitive functions were conducted long before internationally or even globally recognized terms, concepts and diagnostic criteria for the condition now called MCI or mild NCD existed. Most of these studies demonstrated improvements in cognitive performance that were comparable to later studies, which enrolled patients with criteria-based diagnoses of MCI or dementia.…”