The Link between Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation in the Pathophysiology of Alzheimer’s Disease: Therapeutic Implications and Future Perspectives
Abstract
:1. Introduction
2. Oxidative Stress
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- The brain has high energy demands required to maintain the ionic gradients and support synaptic transmission [19].
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- Low antioxidant defenses (neurons have 50 times less catalase than hepatocytes and 50% lower cytosolic glutathione than other cells) [20].
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- The metabolism or auto-oxidation of neurotransmitters, such as dopamine, serotonin or adrenaline can also generate ROS [17].
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- The brain is enriched in transition metals, such as Cu+ and Fe2+, which act as catalyzers in the hydroxyl-generating Fenton reaction [21].
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- Brain cells have a high membrane surface/cytoplasmic volume ratio and cell membranes are rich in cholesterol, which may undergo auto-oxidation [22], as well as polyunsaturated fatty acids, which are very susceptible to free radical-induced peroxidation.
3. Oxidative Stress and Mitochondrial Dysfunction in Alzheimer’s Disease
3.1. Oxidative Stress and Mitochondrial Dysfunction in Alzheimer’s Disease
3.1.1. Oxidative Stress and Normal Aging
3.1.2. Oxidative Stress and Energetic Failure in Alzheimer’s Disease
3.1.3. Oxidative Stress and Impaired Mitochondrial Quality Control
3.1.4. Oxidative Stress and Mitochondrial Trafficking
3.1.5. Oxidative Stress and Disruption of Calcium Homeostasis
3.1.6. Oxidative Stress and Protein Homeostasis
3.1.7. Oxidative Stress, Transcriptional Dysregulation, and Impaired Signaling
4. Oxidative Stress and Neuroinflammation
4.1. PRR Signaling
4.2. Inflammasome Assembly
4.3. Reactive Oxygen Species
4.4. The Role of TREM2 in Alzheimer’s Disease
5. Novel Therapeutic Strategies in Alzheimer’s Disease
5.1. Targeting Mitochondria and Mitochondrial Bioenergetics
5.2. Targeting Oxidative Stress and the Nrf2/ARE Pathway
5.3. Targeting TNFRs and Neuroinflammation
5.4. Cell-Based Therapies for AD
5.5. Applications of nanotechnology in AD
5.5.1. Organic Nanostructures
- Carbon nanotubes are cylindrical graphene sheets with a diameter of 1 nm and a length varying from 1 to 100 μm that have an impressive drug loading capacity. Depending on the arrangement of their graphene cylinders, they can be single-walled or multi-walled nanotubes [231]. Multi-walled carbon nanotubes have been successfully used to deliver berberine in a rat model of AD [250].
- Liposomes have low toxicity and are non-immunogenic, but are expensive, have poor stability and are rapidly removed by the reticuloendothelial system. To eliminate these drawbacks, solid nanoparticles and nanostructured lipid carriers were created in the 1990s. Phytochemicals such as quercetin [251], curcumin [252], or resveratrol delivered via solid nanoparticles showed increased and sustained levels of the drug in the brain with reduced formation of Aβ [252,253]. Nanostructured lipid carriers have also been successfully employed to deliver resveratrol [254] or curcumin for diminishing Aβ toxicity and improving the symptoms in AD models [255].
- Polymeric nanoparticles use highly biodegradable compounds, such as poly-ethylene glycol, poly-ethylenimine, poly-vinylpyrrolidone, poly-lactic acid, poly-lactic-co-glycolic acid or chitosan, which can modify their surface leading to improved drug delivery across the BBB. They have also been successfully used to deliver curcumin (leading to a six-fold increase of curcumin concentration in the brain compared to conventional delivery methods) [256] or donepezil, galantamine [257], rivastigmine [258], or memantine [259] to the brain, leading to improved efficacy and fewer side effects.
5.5.2. Inorganic Nanoparticles
6. Conclusions and Future Directions
Author Contributions
Funding
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Substrate | Mechanism ROS and RNS-induced damage | Biomarkers |
---|---|---|
Proteins | 1. O2•− + NO• ―> ONOO− (peroxynitrite), which nitrates proteins mainly on tyrosine residues 2. Protein glycation by sugars and oxidation of amino acid side chains by ROS―> carbonyls | 3-nitrotyrosine (3-NT) Protein carbonyls |
Lipids | 1. HO•, peroxy radicals (LOO•), alkoxy radicals (LO•), and alkyl radicals (L•) separate hydrogen atoms from fatty acid chains: L• +O2―> LOO•LOO• + LH ―> LOOH + L•; Subsequently the chain reaction propagates as long as labile H atoms are available | Lipid peroxides |
2. Lipid peroxides react with cell membrane proteins, generating aldehydes, 4-hydroxy-2-nonenal (4-HNE), 2-propene-1-al (acrolein) and malondialdehyde (MDA) | 4-HNE, MDA | |
3. lipid peroxidation of arachidonic acid (F2), eicosapentaenoic acid (F3) or docosahexaenoic acid (F4) generate isoprostanes | F2-, F3-, and F4-isoprostanes | |
DNA | ROS and RNS attack on guanine residues in DNA | 8-hydroxy-deoxyguanosine (8OHdG) |
RNA | ROS and RNS attack on guanine residues in RNA | 8-hydroxyguanine (8OHG) |
Molecule(s) | Natural Source | Targeted Pathway | Outcomes | Reference |
---|---|---|---|---|
Phenolic compounds | ||||
Sulfuretin | Flavonoid from the stem bark of Albizzia julibrissin | Nrf2/heme oxygenase-1; Pi3K/Akt | Decreased ROS, increased heme oxygenase 1; activated PI3K/Akt and Nrf2 pathway | [210] |
Anthocyanins | Korean black beans | PI3K/Akt/nrf2 pathway | Increased phosphorylated PI3K, Akt, decreased hydrogen peroxide, 8-oxoguanine, cleaved caspase-3, inhibited PARP1, activated Nrf2 signaling | [211,212] |
Resveratrol | Polyphenol from grapes and grapeseeds | PI3K/Akt/Nrf2 pathway | Diminished ROS and markers of lipid peroxidation, increased SOD, and GSH, activated PI3K, Akt, and heme oxygenase-1 and Nrf2 | [213] |
Tea polyphenols | Flavonoids from tea | TrkB/CREB/BDNF and KEAP-1/Nrf2 pathways | Decreased hydrogen peroxide, increased phosphorylated TrkB, BDNF, Phosphorylated Akt, SOD, GSH, catalase, activated Nrf2 | [142] |
Curcumin | Curcuma longa (turmeric) | PI3K/Akt and Nrf2 pathways | Scavenges ROS, increases SOD, catalase, GSH, decreases lipid peroxidation | [214,215] |
Quercetin | Citrus fruits, apples, broccoli | Nrf2/ARE | Scavenges ROS, increases HO-1, SOD, catalase, thioredoxins | [216] |
Naringenin and naringin | Citrus fruits, tomatoes, cherries | Nrf2/ARE pathway | Increased SOD, GSH, catalase | [217] |
Non-phenolic compounds | ||||
Acerogenin A | Stem bark of Acer nikoense | PI3K/Akt/Nrf2/HO-1 pathway | Diminished ROS, activated phosphorylated ASkt, Nrf2 and heme oxygenase-1 | [218] |
Brassica phenantrene | Brassica rapa ssp. campestris (turnip) | Nrf2-mediated expression of heme oxygenase-1 mediated by PI3K/Akt and JNK pathways | Increased HO-1, GSH, and nuclear translocation of Nrf2 | [219] |
Berberine | Roots, rhizome and stems of Coptis chinensis, barberry, goldenseal species | Nfr2/ARE pathway | Increased SOD and GSH, decreased ROS formation and markers of lipid peroxidation | [220] |
Lycopene | Carotenoid in tomatoes, grapefruit | Nrf2/ARE pathway | Increased HO-1, SOD, catalase, GSH, | [221] |
Agent | Mechanism of Action | Trial Identifier | Sponsor |
---|---|---|---|
Phase 1 trials | |||
Edicotinib (JNJ-40346527) | Colony-stimulating factor 1 receptor antagonist, attenuates microglial proliferation | NCT04121208 | Janssen, University of Oxford |
Emtricitabine | Nucleoside reverse transcriptase inhibitor, reduces neuroinflammation | NCT04500847 | Butler Hospital, Alzheimer’s Association, Brown University |
Salsalate | Non-steroidal anti-inflammatory drug | NCT03277573 | University of California, San Francisco |
VT301 | Targets regulatory T cells | NCT05016427 | VTBIO Co. |
XPro1595 | TNF inhibitor | NCT03943264 | Immune Bio, Alzheimer’s Association |
Phase 2 trials | |||
AL002 | Monoclonal antibody targeting TREM2Rs | NCT04592874 | Alector, AbbVie |
Baricitinib | Janus kinase inhibitor | NCT05189106 | Massachusetts General Hospital |
Canakinumab | Monoclonal antibody against IL-1β | NCT04795466 | Novartis |
Curcumin + aerobic yoga | Herbal extract with antioxidant and anti-inflammatory actions | NCT01811381 | VA Office of Research and Development |
Daratumumab | Monoclonal antibody targeting CD38 and regulating microglial activity | NCT04070378 | Northwell Health, Janssen |
Dasatinib + Quercetin | Tyrosine kinase inhibitor (dasatinib) and flavonoid with antioxidant action | NCT04063124 | The University of Texas at San Antonio, Mayo Clinic |
GB301 | Targets regulatory T cells to reduce neuroinflammation | NCT03865017 | Lifescience Australia |
Lenalidomide | Reduces inflammatory cytokines | NCT04032626 | Cleveland Clinic |
Pepinemab (VX15) | Monoclonal antibody targeting semaphorin 4D | NCT04381468 | Vaccinex, Alzheimer’s Association |
Sargramostim | Granulocyte macrophage colony stimulating factor | NCT04902703 | University of Colorado, Alzheimer’s association |
TB006 | Monoclonal antibody targeting galactin 3 | NCT05074498 | TrueBinding, Inc. |
Phase 3 trials | |||
NE3107 | MAPK inhibitor; reduces NFκB activation | NCT04669028 | BioVie Inc. |
Agent | Trial identifier | Phase | Sponsor |
---|---|---|---|
Allogenic human mesenchymal stem cells | NCT04040348 | 1 | University of Miami |
Autologous natural killer cells (SNK01) | NCT04678453 | 1 | NKMax America |
Human umbilical cord blood-derived mesenchymal stem cells (NEUROSTEM) | NCT03172117 | 1/2; extension phase | Medipost |
CB-AC-02 (placenta derived mesenchymal stem cells) | NCT02899091 | 1/2 | CHABiotech Co. |
Allogenic adipose mesenchymal stem cell-derived exosomes | NCT04388982 | 1/2 | Ruijin Hospital, Cellular Biomedicine Group |
Allogenic human mesenchymal stem cells | NCT02833792 | 2 | Stemedica |
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Jurcău, M.C.; Andronie-Cioara, F.L.; Jurcău, A.; Marcu, F.; Ţiț, D.M.; Pașcalău, N.; Nistor-Cseppentö, D.C. The Link between Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation in the Pathophysiology of Alzheimer’s Disease: Therapeutic Implications and Future Perspectives. Antioxidants 2022, 11, 2167. https://doi.org/10.3390/antiox11112167
Jurcău MC, Andronie-Cioara FL, Jurcău A, Marcu F, Ţiț DM, Pașcalău N, Nistor-Cseppentö DC. The Link between Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation in the Pathophysiology of Alzheimer’s Disease: Therapeutic Implications and Future Perspectives. Antioxidants. 2022; 11(11):2167. https://doi.org/10.3390/antiox11112167
Chicago/Turabian StyleJurcău, Maria Carolina, Felicia Liana Andronie-Cioara, Anamaria Jurcău, Florin Marcu, Delia Mirela Ţiț, Nicoleta Pașcalău, and Delia Carmen Nistor-Cseppentö. 2022. "The Link between Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation in the Pathophysiology of Alzheimer’s Disease: Therapeutic Implications and Future Perspectives" Antioxidants 11, no. 11: 2167. https://doi.org/10.3390/antiox11112167