DEAD-Box Helicase 6 Blockade in Brain-Derived Aβ Oligomers From Alzheimer's Disease Patients Attenuates Neurotoxicity
Xiaoxu Wang
Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Search for more papers by this authorLu Dai
Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Search for more papers by this authorNa Wu
Laboratory Animal Resource Center, Capital Medical University, Beijing, China
Search for more papers by this authorDonghui Wu
Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Search for more papers by this authorXinyuan Wang
Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Search for more papers by this authorXia Meng
Laboratory Animal Resource Center, Capital Medical University, Beijing, China
Search for more papers by this authorQilei Zhang
Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan, China
Search for more papers by this authorJing Lu
Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Laboratory Animal Resource Center, Capital Medical University, Beijing, China
Search for more papers by this authorXiaoxin Yan
Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan, China
Search for more papers by this authorCorresponding Author
Jing Zhang
Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Laboratory Animal Resource Center, Capital Medical University, Beijing, China
Search for more papers by this authorCorresponding Author
Baian Chen
Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Laboratory Animal Resource Center, Capital Medical University, Beijing, China
Center of Alzheimer's Disease, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
Search for more papers by this authorXiaoxu Wang
Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Search for more papers by this authorLu Dai
Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Search for more papers by this authorNa Wu
Laboratory Animal Resource Center, Capital Medical University, Beijing, China
Search for more papers by this authorDonghui Wu
Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Search for more papers by this authorXinyuan Wang
Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Search for more papers by this authorXia Meng
Laboratory Animal Resource Center, Capital Medical University, Beijing, China
Search for more papers by this authorQilei Zhang
Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan, China
Search for more papers by this authorJing Lu
Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Laboratory Animal Resource Center, Capital Medical University, Beijing, China
Search for more papers by this authorXiaoxin Yan
Department of Anatomy and Neurobiology, Central South University Xiangya School of Medicine, Changsha, Hunan, China
Search for more papers by this authorCorresponding Author
Jing Zhang
Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Laboratory Animal Resource Center, Capital Medical University, Beijing, China
Search for more papers by this authorCorresponding Author
Baian Chen
Department of Laboratory Animal Sciences, School of Basic Medical Sciences, Capital Medical University, Beijing, China
Laboratory Animal Resource Center, Capital Medical University, Beijing, China
Center of Alzheimer's Disease, Beijing Institute of Brain Disorders, Capital Medical University, Beijing, China
Search for more papers by this authorXiaoxu Wang and Lu Dai contributed equally to this work.
Funding: This work was supported by the National Natural Science Foundation of China (No. 82001146) and the R&D Program of Beijing Municipal Education Commission (No. KM202110025028). Postmortem human brain tissue samples were collected from the Xiangya Human Brain Tissue Bank, which is funded by the National Natural Science Foundation of China (Nos. 91632116 and 82071223), the Ministry of Science and Technology Innovation 2030: Brain Science and Brain Research Institute major project (No. 2021ZD0201100), and the R&D Support Project No. 3: Construction of Brain Bank Collaborative Network Platform in South-Central China (No. 2021ZD0201103).
ABSTRACT
There are no effective curative treatments for Alzheimer's disease (AD), the most prevalent form of dementia. Amyloid-beta (Aβ) oligomers are considered key neurotoxic molecules that trigger AD. Recent studies have shown that direct antibody targeting of Aβ oligomers is beneficial for early AD patients; however, serious side effects (e.g., brain hemorrhage, edema, and shrinkage) persist. Considering that Aβ oligomers readily bind to other proteins, contributing to neurotoxicity and AD onset, those proteins could represent alternative therapeutic targets. However, proteins that bind to Aβ oligomers in the brains of AD patients have not yet been identified. In this study, we identified four proteins (DDX6, DSP, JUP, and HRNR) that bind to Aβ oligomers derived from the brains of AD patients. Intriguingly, among these four proteins, only the blockade of DEAD-box helicase 6 (DDX6) in human-derived Aβ oligomers attenuated their neurotoxicity both in vitro and in vivo. Mechanistic analysis revealed that DDX6 promotes the formation of Aβ oligomers, likely due to DDX6 bind to Aβ oligomers at four distinct sites. These findings suggest that DDX6 could serve as a potential therapeutic target to reduce the neurotoxicity of Aβ oligomers in the brain and prevent the progression of AD.
Conflicts of Interest
The authors declare no conflicts of interest.
Open Research
Data Availability Statement
All data generated or analyzed during this study are included in this published article and its Supporting Information.
Supporting Information
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| mco270156-sup-0004-Table.xls221.5 KB | Supporting Information |
| mco270156-sup-0002-Tables.xlsx2.2 MB | Supporting Information |
| mco270156-sup-0003-Tables.xlsx333.7 KB | Supporting Information |
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References
- 1G. M. Shankar, S. Li, T. H. Mehta, et al., “Amyloid-β Protein Dimers Isolated Directly From Alzheimer's Brains Impair Synaptic Plasticity and Memory,” Nature Medicine 14, no. 8 (2008): 837–842.
- 2H. Zempel, E. Thies, E. Mandelkow, and E. M. Mandelkow, “Abeta Oligomers Cause Localized Ca(2+) Elevation, Missorting of Endogenous Tau Into Dendrites, Tau Phosphorylation, and Destruction of Microtubules and Spines,” Journal of Neuroscience 30, no. 36 (2010): 11938–11950.
- 3Y. Gong, L. Chang, K. L. Viola, et al., “Alzheimer's Disease-Affected Brain: Presence of Oligomeric A Beta Ligands (ADDLs) Suggests a Molecular Basis for Reversible Memory Loss,” PNAS 100, no. 18 (2003): 10417–10422.
- 4U. Sengupta, A. N. Nilson, and R. Kayed, “The Role of Amyloid-β Oligomers in Toxicity, Propagation, and Immunotherapy,” Ebiomedicine 6 (2016): 42–49.
- 5M. Tolar, J. Hey, A. Power, and S. Abushakra, “Neurotoxic Soluble Amyloid Oligomers Drive Alzheimer's Pathogenesis and Represent a Clinically Validated Target for Slowing Disease Progression,” International Journal of Molecular Sciences 22, no. 12 (2021): 6355.
- 6B. Zott, M. M. Simon, W. Hong, et al., “A Vicious Cycle of Beta Amyloid-Dependent Neuronal Hyperactivation,” Science 365, no. 6453 (2019): 559–565.
- 7S. J. C. Lee, E. Nam, H. J. Lee, M. G. Savelieff, and M. H. Lim, “Towards an Understanding of Amyloid-β Oligomers: Characterization, Toxicity Mechanisms, and Inhibitors,” Chemical Society Reviews 46, no. 2 (2017): 310–323.
- 8Y. Muñoz, A. C. Paula-Lima, and M. T. Núñez, “Reactive Oxygen Species Released From Astrocytes Treated With Amyloid Beta Oligomers Elicit Neuronal Calcium Signals That Decrease Phospho-Ser727-STAT3 Nuclear Content,” Free Radical Biology and Medicine 117 (2018): 132–144.
- 9W. Wang, T. Hou, L. Jia, et al., “Toxic Amyloid-β Oligomers Induced Self-Replication in Astrocytes Triggering Neuronal Injury,” Ebiomedicine 42 (2019): 174–187.
- 10M. Townsend, G. M. Shankar, T. Mehta, D. M. Walsh, and D. J. Selkoe, “Effects of Secreted Oligomers of Amyloid β-Protein on Hippocampal Synaptic Plasticity: A Potent Role for Trimers,” The Journal of Physiology 572, no. 2 (2006): 477–492.
- 11M. Shi, F. Chu, F. Zhu, and J. Zhu, “Impact of Anti-Amyloid-β Monoclonal Antibodies on the Pathology and Clinical Profile of Alzheimer's Disease: A Focus on Aducanumab and Lecanemab,” Frontiers in Aging Neuroscience 14 (2022): 870517.
- 12K. I. Avgerinos, L. Ferrucci, and D. Kapogiannis, “Effects of Monoclonal Antibodies Against Amyloid-β on Clinical and Biomarker Outcomes and Adverse Event Risks: A Systematic Review and Meta-Analysis of Phase III RCTs in Alzheimer's Disease,” Ageing Research Reviews 68 (2021): 101339.
- 13D. Jeremic, J. D. Navarro-López, and L. Jiménez-Díaz, “Efficacy and Safety of Anti-Amyloid-β Monoclonal Antibodies in Current Alzheimer's Disease Phase III Clinical Trials: A Systematic Review and Interactive Web App-Based Meta-Analysis,” Ageing Research Reviews 90 (2023): 102012.
- 14S. Salloway, S. Chalkias, F. Barkhof, et al., “Amyloid-Related Imaging Abnormalities in 2 Phase 3 Studies Evaluating Aducanumab in Patients With Early Alzheimer Disease,” JAMA Neurology 79, no. 1 (2022): 13.
- 15C. H. van Dyck, C. J. Swanson, P. Aisen, et al., “Lecanemab in Early Alzheimer's Disease,” New England Journal of Medicine 388, no. 1 (2023): 9–21.
- 16J. Couzin-Frankel, “Promising Alzheimer's Therapies Shrink Brains,” Science 380, no. 6640 (2023): 19.
- 17M. Filippi, G. Cecchetti, E. G. Spinelli, et al., “Amyloid-Related Imaging Abnormalities and β-Amyloid–Targeting Antibodies,” JAMA Neurology 79, no. 3 (2022): 291.
- 18M. Roytman, F. Mashriqi, K. Al-Tawil, et al., “Amyloid-Related Imaging Abnormalities: An Update,” American Journal of Roentgenology 220, no. 4 (2023): 562–574.
- 19T. Kim, G. S. Vidal, M. Djurisic, et al., “Human LilrB2 Is a β-Amyloid Receptor and Its Murine Homolog PirB Regulates Synaptic Plasticity in an Alzheimer's Model,” Science 341, no. 6152 (2013): 1399–1404.
- 20F. H. Beraldo, V. G. Ostapchenko, F. A. Caetano, et al., “Regulation of Amyloid β Oligomer Binding to Neurons and Neurotoxicity by the Prion Protein-mGluR5 Complex,” Journal of Biological Chemistry 291, no. 42 (2016): 21945–21955.
- 21L. M. Smith and S. M. Strittmatter, “Binding Sites for Amyloid-β Oligomers and Synaptic Toxicity,” Cold Spring Harbor Perspectives in Medicine 7, no. 5 (2017): a024075.
- 22J. W. Um, H. B. Nygaard, J. K. Heiss, et al., “Alzheimer Amyloid-β Oligomer Bound to Postsynaptic Prion Protein Activates Fyn to Impair Neurons,” Nature Neuroscience 15, no. 9 (2012): 1227–1235.
- 23T. Kawarabayashi, M. Shoji, L. H. Younkin, et al., “Dimeric Amyloid β Protein Rapidly Accumulates in Lipid Rafts Followed by Apolipoprotein E and Phosphorylated Tau Accumulation in the Tg2576 Mouse Model of Alzheimer's Disease,” The Journal of Neuroscience 24, no. 15 (2004): 3801–3809.
- 24P. Rodriguez-Rodriguez, A. Sandebring-Matton, P. Merino-Serrais, et al., “Tau Hyperphosphorylation Induces Oligomeric Insulin Accumulation and Insulin Resistance in Neurons,” Brain 140, no. 12 (2017): 3269–3285.
- 25S. Ghosh, R. Ali, and S. Verma, “Aβ-Oligomers: A Potential Therapeutic Target for Alzheimer's Disease,” International Journal of Biological Macromolecules 239 (2023): 124231.
- 26E. Hlavanda, E. Klement, E. Kokai, et al., “Phosphorylation Blocks the Activity of Tubulin Polymerization-Promoting Protein (TPPP): Identification of Sites Targeted by Different Kinases,” Journal of Biological Chemistry 282, no. 40 (2007): 29531–29539.
- 27S. Frykman, Y. Teranishi, J. Hur, et al., “Identification of Two Novel Synaptic γ-Secretase Associated Proteins That Affect Amyloid β-Peptide Levels Without Altering Notch Processing,” Neurochemistry International 61, no. 1 (2012): 108–118.
- 28J. Olah, O. Vincze, D. Virok, et al., “Interactions of Pathological Hallmark Proteins: Tubulin Polymerization Promoting Protein/p25, Beta-Amyloid, and Alpha-Synuclein,” Journal of Biological Chemistry 286, no. 39 (2011): 34088–34100.
- 29L. K. Habib, M. T. C. Lee, and J. Yang, “Inhibitors of Catalase-Amyloid Interactions Protect Cells From β-Amyloid-Induced Oxidative Stress and Toxicity,” Journal of Biological Chemistry 285, no. 50 (2010): 38933–38943.
- 30A. Mendsaikhan, I. Tooyama, J. Bellier, et al., “Characterization of Lysosomal Proteins Progranulin and Prosaposin and Their Interactions in Alzheimer's Disease and Aged Brains: Increased Levels Correlate With Neuropathology,” Acta Neuropathologica Communications 7, no. 1 (2019): 215.
- 31H. Choi, B. Larsen, Z. Lin, et al., “SAINT: Probabilistic Scoring of Affinity Purification–Mass Spectrometry Data,” Nature Methods 8, no. 1 (2011): 70–73.
- 32A. Breitkreutz, H. Choi, J. R. Sharom, et al., “A Global Protein Kinase and Phosphatase Interaction Network in Yeast,” Science 328, no. 5981 (2010): 1043–1046.
- 33G. Teo, G. Liu, J. Zhang, et al., “SAINTexpress: Improvements and Additional Features in Significance Analysis of INTeractome Software,” Journal of Proteomics 100 (2014): 37–43.
- 34L. H. Mujawar, A. Moers, W. Norde, and A. van Amerongen, “Rapid Mastitis Detection Assay on Porous Nitrocellulose Membrane Slides,” Analytical and Bioanalytical Chemistry 405, no. 23 (2013): 7469–7476.
- 35S. G. De-Simone, P. Napoleão-Pêgo, L. A. L. Teixeira-Pinto, et al., “IgE and IgG Epitope Mapping by Microarray Peptide-Immunoassay Reveals the Importance and Diversity of the Immune Response to the IgG3 Equine Immunoglobulin,” Toxicon 78 (2014): 83–93.
- 36R. Simon, H. Brylka, H. Schwegler, et al., “A Dual Function of Bcl11b/Ctip2 in Hippocampal Neurogenesis,” Embo Journal 31, no. 13 (2012): 2922–2936.
- 37F. Negoita, M. Vavakova, J. Säll, J. Laurencikiene, and O. Göransson, “JUP/Plakoglobin Is Regulated by Salt-Inducible Kinase 2, and Is Required for Insulin-Induced Signalling and Glucose Uptake in Adipocytes,” Cellular Signalling 76 (2020): 109786.
- 38H. Park, T. Yamanaka, Y. Toyama, et al., “Hornerin Deposits in Neuronal Intranuclear Inclusion Disease: Direct Identification of Proteins With Compositionally Biased Regions in Inclusions,” Acta Neuropathologica Communications 10, no. 1 (2022): 1–17.
- 39R. Bish, N. Cuevas-Polo, Z. Cheng, et al., “Comprehensive Protein Interactome Analysis of a Key RNA Helicase: Detection of Novel Stress Granule Proteins,” Biomolecules 5, no. 3 (2015): 1441–1466.
- 40K. Saito, E. Kondo, and M. Matsushita, “MicroRNA 130 Family Regulates the Hypoxia Response Signal Through the P-Body Protein DDX6,” Nucleic Acids Research 39, no. 14 (2011): 6086–6099.
- 41T. C. T. Michaels, A. Šarić, S. Curk, et al., “Dynamics of Oligomer Populations Formed During the Aggregation of Alzheimer's Aβ42 Peptide,” Nature Chemistry 12, no. 5 (2020): 445–451.
- 42M. Hondele, R. Sachdev, S. Heinrich, et al., “DEAD-Box ATPases Are Global Regulators of Phase-Separated Organelles,” Nature 573, no. 7772 (2019): 144–148.
- 43L. Molitor, M. Klostermann, S. Bacher, et al., “Depletion of the RNA-Binding Protein PURA Triggers Changes in Posttranscriptional Gene Regulation and Loss of P-Bodies,” Nucleic Acids Research 51, no. 3 (2023): 1297–1316.
- 44W. Huang, Y. Yan, Y. Liu, et al., “Exosomes With Low miR-34c-3p Expression Promote Invasion and Migration of Non-Small Cell Lung Cancer by Upregulating Integrin α2β1,” Signal Transduction and Targeted Therapy 5, no. 1 (2020): 39.
- 45X. Zheng, Q. Wang, Y. Zhou, et al., “N-Acetyltransferase 10 Promotes Colon Cancer Progression by Inhibiting Ferroptosis Through N4-Acetylation and Stabilization of Ferroptosis Suppressor Protein 1 (FSP1) mRNA,” Cancer Communications 42, no. 12 (2022): 1347–1366.
- 46R. He, Z. Wang, M. Cui, et al., “HIF1A Alleviates Compression-Induced Apoptosis of Nucleus Pulposus Derived Stem Cells via Upregulating Autophagy,” Autophagy 17, no. 11 (2021): 3338–3360.
- 47T. Jiang, Y. Li, S. He, et al., “Reprogramming Astrocytic NDRG2/NF-kappaB/C3 Signaling Restores the Diabetes-Associated Cognitive Dysfunction,” Ebiomedicine 93 (2023): 104653.
- 48J. L. Verpeut, S. Bergeler, M. Kislin, et al., “Cerebellar Contributions to a Brainwide Network for Flexible Behavior in Mice,” Communications Biology 6, no. 1 (2023): 605.
- 49L. Huang, T. Agrawal, G. Zhu, et al., “DAXX Represents a New Type of Protein-Folding Enabler,” Nature 597, no. 7874 (2021): 132–137.
- 50D. Yang, J. Li, Z. Li, et al., “Cardiolipin Externalization Mediates Prion Protein (PrP) Peptide 106–126-Associated Mitophagy and Mitochondrial Dysfunction,” Frontiers in Molecular Neuroscience 16 (2023): 1163981.
