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Cited by 10Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsBone and Dental Protein Studies

Osteopontin in Alzheimer's disease: A double-edged sword in neurodegeneration and neuroprotection-A systematic review

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Azizan, Zahra, Bazrgar, Maryam, Bazgir, Narges, Moini, Sadra Habibi, Ghaseminejad‐Kermani, Sara, Safa, Kamran, Eshaghian‐dorcheh, Azam, Harirchian, Mohammad Hossein·2025·CNS Neuroscience & Therapeutics
DOI 10.1111/cns.70269PMC PMC11831194
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Abstract

Background: Osteopontin (OPN) has emerged as a pivotal molecule in Alzheimer's disease (AD), with studies indicating its potential to act as both a neuroprotective agent and a contributor to neurodegeneration. This systematic review aims to elucidate the roles of OPN in AD pathogenesis through inflammatory pathways. Methods: We conducted a comprehensive analysis of current literature on OPN's involvement in AD, focusing on its signaling pathways, cellular interactions, and regulatory mechanisms. We searched PubMed, EMBASE, and Scopus databases by the keyword of Alzheimer's Disease and Osteopontin. Our date search was in 1990 until July 1, 2024 with no language limitation. Results: In a review of 758 studies, a total of 15 reports met the eligibility criteria and were included. Among the findings, four studies provided evidence supporting the protective mechanism of OPN within the context of AD. Eleven studies explain the inflammatory role of OPN. OPN has been shown to play a role in synaptic pruning, microglial activation, and the inflammatory processes associated with AD. Additionally, OPN is implicated in facilitating cellular communication and serves as a chemotactic molecule. It is suggested that the protective effects of OPN are predominantly mediated by the c fragment of the protein and are most prominent in the early stages of AD progression. Conclusion: OPN in AD has dual effects—protecting neurons and contributing to their degeneration. Future research should enhance its protective mechanisms, target specific signaling pathways, and develop therapies to slow AD progression.

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  • Osteopontin is known to leverage focal adhesion signaling to influence cellular responses and wound healing.

    “another molecule known to leverage focal adhesion signaling to influence cellular responses and wound healing (Azizan et al., 2025; Dashdulam et al., 2020).”

    From Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis (2026) · cites this paper as Azizan et al., 2025

    The Introduction (page unavailable) describes osteopontin's roles in cell adhesion and signaling, and the Discussion (page unavailable) describes cellular responses to its binding to integrin receptors. Our copy does not identify focal adhesion signaling as the mechanism or connect these effects to wound healing. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Osteopontin has a bidirectional role in neurodegeneration, inducing harmful proinflammatory cascades in some contexts while mediating neuroprotective Aβ clearance in others.

    “osteopontin has been suggested to have a bidirectional role in neurodegeneration, such as inducing harmful proinflammatory cascades in some contexts while mediating neuroprotective Aβ clearance in others (Azizan et al., 2025).”

    From Alzheimer’s genetic risk factor CASS4 controls microglial focal adhesion biology and amyloidosis (2026) · cites this paper as Azizan et al., 2025

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Research works printed but not linked: 45

  1. [1]“ 2020 Alzheimer's Disease Facts and Figures,” Alzheimer's & Dementia 16 (2020): 391– 460, 10.1002/alz.12068. 32157811 · DOI · Paper page
  2. [2]X. Zhang, Z. Fu, L. Meng, M. He, and Z. Zhang, “ The Early Events That Initiate β‐Amyloid Aggregation in Alzheimer's Disease,” Frontiers in Aging Neuroscience 10 (2018): 359, 10.3389/fnagi.2018.00359. 30542277 PMC6277872 · DOI
  3. [3]P. Khodabakhsh, M. Bazrgar, F. Mohagheghi, S. Parvardeh, and A. Ahmadiani, “ MicroRNA‐140‐5p Inhibitor Attenuates Memory Impairment Induced by Amyloid‐ß Oligomer In Vivo Possibly Through Pin1 Regulation,” CNS Neuroscience & Therapeutics 29 (2023): 91– 103, 10.1111/cns.13980. 36184817 PMC9804077 · DOI
  4. [4]J. Miao, H. Ma, Y. Yang, et al., “ Microglia in Alzheimer's Disease: Pathogenesis, Mechanisms, and Therapeutic Potentials,” Frontiers in Aging Neuroscience 15 (2023): 1201982, 10.3389/fnagi.2023.1201982. 37396657 PMC10309009 · DOI · Paper page
  5. [5]M. Y. Wendimu and S. B. Hooks, “ Microglia Phenotypes in Aging and Neurodegenerative Diseases,” Cells 11, no. 13 (2022): 2091, 10.3390/cells11132091. 35805174 PMC9266143 · DOI · Paper page
  6. [6]A. Yim, C. Smith, and A. M. Brown, “ Osteopontin/Secreted Phosphoprotein‐1 Harnesses Glial‐, Immune‐, and Neuronal Cell Ligand‐Receptor Interactions to Sense and Regulate Acute and Chronic Neuroinflammation,” Immunological Reviews 311 (2022): 224– 233, 10.1111/imr.13081. 35451082 PMC9790650 · DOI
  7. [7]E. Y. H. Lin, W. Xi, N. Aggarwal, and M. L. Shinohara, “ Osteopontin (OPN)/SPP1: From Its Biochemistry to Biological Functions in the Innate Immune System and the Central Nervous System (CNS),” International Immunology 35 (2023): 171– 180, 10.1093/intimm/dxac060. 36525591 PMC10071791 · DOI
  8. [8]F. Kahles, H. M. Findeisen, and D. Bruemmer, “ Osteopontin: A Novel Regulator at the Cross Roads of in Fl Ammation, Obesity and Diabetes,” Molecular Metabolism 3, no. 4 (2014): 1– 10, 10.1016/j.molmet.2014.03.004. 24944898 PMC4060362 · DOI
  9. [9]R. C. Lalwani, C.‐H. Volmar, C. Wahlestedt, K. A. Webster, and L. A. Shehadeh, “ Contextualizing the Role of Osteopontin in the Inflammatory Responses of Alzheimer's Disease,” Biomedicine 11, no. 12 (2023): 3232, 10.3390/biomedicines11123232. PMC10741223 38137453 · DOI
  10. [10]“53rd EASD Annual Meeting of the European Association for the Study of Diabetes: Lisbon, Portugal, 11–15 September 2017,” 60, 2017, 10.1007/s00125-017-4350-z. PMC7095843 28795195 · DOI
  11. [12]S.‐S. Zhang, L. Zhu, Y. Peng, et al., “ Long‐Term Running Exercise Improves Cognitive Function and Promotes Microglial Glucose Metabolism and Morphological Plasticity in the Hippocampus of APP/PS1 Mice,” Journal of Neuroinflammation 19 (2022): 34, 10.1186/s12974-022-02401-5. 35123512 PMC8817568 · DOI
  12. [13]A. Y. Lai, I. L. Joo, A. U. Trivedi, et al., “ Cerebrovascular Damage After Midlife Transient Hypertension in Non‐Transgenic and Alzheimer's Disease Rats,” Brain Research 1758 (2021): 147369, 10.1016/j.brainres.2021.147369. 33582120 PMC8005286 · DOI
  13. [15]S. De Schepper, J. Z. Ge, G. Crowley, et al., “ Perivascular Cells Induce Microglial Phagocytic States and Synaptic Engulfment via SPP1 in Mouse Models of Alzheimer's Disease,” Nature Neuroscience 26 (2023): 406– 415, 10.1038/s41593-023-01257-z. 36747024 PMC9991912 · DOI · Paper page
  14. [16]D. D. Rosmus, C. Lange, F. Ludwig, B. Ajami, and P. Wieghofer, “ The Role of Osteopontin in Microglia Biology: Current Concepts and Future Perspectives,” Biomedicine 10, no. 4 (2022): 840, 10.3390/biomedicines10040840. PMC9027630 35453590 · DOI
  15. [17]Y. Qiu, X. Shen, O. Ravid, et al., “ Definition of the Contribution of an Osteopontin‐Producing CD11c(+) Microglial Subset to Alzheimer's Disease,” Proceedings of the National Academy of Sciences of the United States of America 120 (2023): e2218915120, 10.1073/pnas.2218915120. 36730200 PMC9963365 · DOI
  16. [18]H. Yang, L. C. Graham, A. M. Reagan, W. A. Grabowska, W. H. Schott, and G. R. Howell, “ Transcriptome Profiling of Brain Myeloid Cells Revealed Activation of Itgal, Trem1, and Spp1 in Western Diet‐Induced Obesity,” Journal of Neuroinflammation 16 (2019): 169, 10.1186/s12974-019-1527-z. 31426806 PMC6700800 · DOI
  17. [19]M. Sharma and C. S. Dey, “ Role of Akt Isoforms in Neuronal Insulin Signaling and Resistance,” Cellular and Molecular Life Sciences 78 (2021): 7873– 7898, 10.1007/s00018-021-03993-6. 34724097 PMC11073101 · DOI
  18. [20]S. A. L. Corrêa and K. L. Eales, “ The Role of p38 MAPK and Its Substrates in Neuronal Plasticity and Neurodegenerative Disease,” Journal of Signal Transduction 2012 (2012): 649079, 10.1155/2012/649079. 22792454 PMC3389708 · DOI · Paper page
  19. [22]O. Wirths, H. Breyhan, A. Marcello, M.‐C. Cotel, W. Brück, and T. A. Bayer, “ Inflammatory Changes Are Tightly Associated With Neurodegeneration in the Brain and Spinal Cord of the APP/PS1KI Mouse Model of Alzheimer's Disease,” Neurobiology of Aging 31 (2010): 747– 757, 10.1016/j.neurobiolaging.2008.06.011. 18657882 · DOI
  20. [23]A. D. Feuerbach, P. Schindler, S. Kommineni, A. Kaykas, and J. Daniel, “ ADAM17 Is the Main Sheddase for the Generation of Human Triggering Receptor Expressed in Myeloid Cells (hTREM2) Ectodomain and Cleaves TREM2 After Histidine 157,” Neuroscience Letters 660 (2017): 109– 114, 10.1016/j.neulet.2017.09.034. 28923481 · DOI
  21. [24]K. Wang, Z. Xuan, X. Liu, M. Zheng, C. Yang, and H. Wang, “ Immunomodulatory Role of Metalloproteinase ADAM17 in Tumor Development,” Frontiers in Immunology 13 (2022): 1059376, 10.3389/fimmu.2022.1059376. 36466812 PMC9715963 · DOI
  22. [25]F. Filipello, C. Goldsbury, S. F. You, A. Locca, C. M. Karch, and L. Piccio, “ Soluble TREM2: Innocent Bystander or Active Player in Neurological Diseases?,” Neurobiology of Disease 165 (2022): 1– 28, 10.1016/j.nbd.2022.105630. PMC10108835 35041990 · DOI · Paper page
  23. [26]D. Plantone, M. Pardini, D. Righi, C. Manco, B. M. Colombo, and N. De Stefano, “ The Role of TNF‐α in Alzheimer's Disease: A Narrative Review,” Cells 13, no. 1 (2023): 54, 10.3390/cells13010054. 38201258 PMC10778385 · DOI
  24. [27]S. Wang, M. Mustafa, C. M. Yuede, et al., “ Anti‐Human TREM2 Induces Microglia Proliferation and Reduces Pathology in an Alzheimer's Disease Model,” Journal of Experimental Medicine 217 (2020): e20200785, 10.1084/jem.20200785. 32579671 PMC7478730 · DOI · Paper page
  25. [28]M. Gharpure, S. Vyavahare, P. Ahluwalia, et al., “ Alterations in Alzheimer's Disease Microglia Transcriptome Might Be Involved in Bone Pathophysiology,” Neurobiology of Disease 191 (2024): 106404, 10.1016/j.nbd.2024.106404. 38184014 · DOI
  26. [29]E. N. Wilson, C. Wang, M. S. Swarovski, et al., “ TREM1 Disrupts Myeloid Bioenergetics and Cognitive Function in Aging and Alzheimer Disease Mouse Models,” Nature Neuroscience 27 (2024): 873– 885, 10.1038/s41593-024-01610-w. 38539014 PMC11102654 · DOI
  27. [30]S. Hong, “ Perivascular SPP1 Modulates Microglia‐Synapse Engulfment in Alzheimer's Disease Models,” Alzheimer's & Dementia 18 (2022): 1895, 10.1002/alz.061895. · DOI
  28. [31]A. Rentsendorj, J. Sheyn, D. T. Fuchs, et al., “ A Novel Role for Osteopontin in Macrophage‐Mediated Amyloid‐β Clearance in Alzheimer's Models,” Brain, Behavior, and Immunity 67 (2018): 163– 180, 10.1016/j.bbi.2017.08.019. 28860067 PMC5865478 · DOI
  29. [32]S. Li, E. Y. Hayden, V. J. Garcia, et al., “ Activated Bone Marrow‐Derived Macrophages Eradicate Alzheimer's‐Related Aβ42 Oligomers and Protect Synapses,” Frontiers in Immunology 11 (2020): 49, 10.3389/fimmu.2020.00049. 32082319 PMC7005081 · DOI
  30. [34]W. Quan, Q. Luo, W. Hao, et al., “ Haploinsufficiency of Microglial MyD88 Ameliorates Alzheimer's Pathology and Vascular Disorders in APP/PS1‐Transgenic Mice,” Glia 69 (2021): 1987– 2005, 10.1002/glia.24007. 33934399 · DOI
  31. [35]G. Cappellano, D. Vecchio, L. Magistrelli, et al., “ The Yin‐Yang of Osteopontin in Nervous System Diseases: Damage Versus Repair,” Neural Regeneration Research 16 (2021): 1131– 1137, 10.4103/1673-5374.300328. 33269761 PMC8224140 · DOI
  32. [36]S. A. Lund, C. M. Giachelli, and M. Scatena, “ The Role of Osteopontin in Inflammatory Processes,” Journal of Cell Communication and Signaling 3 (2009): 311– 322, 10.1007/s12079-009-0068-0. 19798593 PMC2778587 · DOI
  33. [37]W. E. Sonntag, F. Deak, N. Ashpole, P. Toth, A. Csiszar, and W. Freeman, “ Insulin‐Like Growth Factor‐1 in CNS and Cerebrovascular Aging,” Frontiers in Aging Neuroscience 5 (2013): 27, 10.3389/fnagi.2013.00027. 23847531 PMC3698444 · DOI
  34. [38]X. Weng, S. Maxwell‐Warburton, A. Hasib, L. Ma, and L. Kang, “ The Membrane Receptor CD44: Novel Insights Into Metabolism,” Trends in Endocrinology and Metabolism 33 (2022): 318– 332, 10.1016/j.tem.2022.02.002. 35249813 · DOI · Paper page
  35. [39]Z. Azizan, H. Zali, S. A. Mirmotalebisohi, M. Bazrgar, and A. Ahmadiani, “ Deciphering Molecular Bridges: Unveiling the Interplay Between Metabolic Syndrome and Alzheimer's Disease Through a Systems Biology Approach and Drug Repurposing,” PLoS One 19 (2024): e0304410, 10.1371/journal.pone.0304410. 38809924 PMC11135670 · DOI
  36. [40]M. C. Dalakas, H. Alexopoulos, and P. J. Spaeth, “ Complement in Neurological Disorders and Emerging Complement‐Targeted Therapeutics,” Nature Reviews Neurology 16, no. 11 (2020): 601– 617, 10.1038/s41582-020-0400-0. 33005040 PMC7528717 · DOI
  37. [41]B. Dejanovic, T. Wu, M. Tsai, et al., “ Complement C1q‐Dependent Excitatory and Inhibitory Synapse Elimination by Astrocytes and Microglia in Alzheimer's Disease Mouse Models,” Nature Aging 2, no. 9 (2022): 837– 850, 10.1038/s43587-022-00281-1. 37118504 PMC10154216 · DOI · Paper page
  38. [43]H. Hampel, J. Hardy, K. Blennow, et al., “ The Amyloid‐β Pathway in Alzheimer's Disease,” Molecular Psychiatry 26 (2021): 5481– 5503, 10.1038/s41380-021-01249-0. 34456336 PMC8758495 · DOI · Paper page
  39. [45]K. P. Lopes, L. Yu, X. Shen, et al., “ Associations of Cortical SPP1 and ITGAX With Cognition and Common Neuropathologies in Older Adults,” Alzheimer's & Dementia 20 (2024): 525– 537, 10.1002/alz.13474. PMC10841499 37727065 · DOI
  40. [46]R. Von Bernhardi, F. Cornejo, G. E. Parada, and J. Eugenín, “ Role of TGF β Signaling in the Pathogenesis of Alzheimer's Disease,” Frontiers in Cellular Neuroscience 9 (2015): 426, 10.3389/fncel.2015.00426. 26578886 PMC4623426 · DOI · Paper page
  41. [47]H. Lee, Y. Jin, S. Kim, I. Kim, H. Lee, and J. Lee, “ Proangiogenic Functions of an RGD‐SLAY‐Containing Osteopontin Icosamer Peptide in HUVECs and in the Postischemic Brain,” Experimental & Molecular Medicine 50, no. 1 (2018): e430, 10.1038/emm.2017.241. 29350679 PMC5799800 · DOI
  42. [48]M. J. Quesnel, A. Labonté, C. Picard, et al., “ Osteopontin: A Novel Marker of Pre‐Symptomatic Sporadic Alzheimer's Disease,” Alzheimer's & Dementia 20 (2024): 6008– 6031, 10.1002/alz.14065. PMC11497655 39072932 · DOI
  43. [49]W. Likui, W. Hong, and Z. Shuwen, “ The Potential of Osteopontin as a Therapeutic Target for Human Colorectal Cancer,” Journal of Gastrointestinal Surgery 15, no. 4 (2011): 652– 659, 10.1007/s11605-011-1445-6. 21318445 · DOI
  44. [50]Y. Gu, T. Taifour, T. Bui, et al., “ Osteopontin Is a Therapeutic Target That Drives Breast Cancer Recurrence,” Nature Communications 15, no. 1 (2024): 9174, 10.1038/s41467-024-53023-9. PMC11502809 39448577 · DOI
  45. [51]D. Davaanyam, I.‐D. Kim, and J.‐K. Lee, “ Intranasal Delivery of RGD‐Containing Osteopontin Heptamer Peptide Confers Neuroprotection in the Ischemic Brain and Augments Microglia M2 Polarization,” International Journal of Molecular Sciences 22, no. 18 (2021): 9999, 10.3390/ijms22189999. 34576163 PMC8466884 · DOI

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Authors
Azizan, Z., Bazrgar, M., Bazgir, N., Moini, S. H., Ghaseminejad‐Kermani, S., Safa, K., Eshaghian‐dorcheh, A., & Harirchian, M. H.
Affiliations
  • Imam Khomeini Hospital (IR)
  • Shahid Beheshti University of Medical Sciences (IR)
  • Shahid Beheshti University (IR)
  • Emergency Medicine Department Shahid Beheshti University of Medical Science Tehran Iran
  • Isfahan University of Medical Sciences (IR)
Corresponding author
  • Bazrgar, Maryam
  • Harirchian, Mohammad Hossein
ORCID
Venue
CNS Neuroscience & Therapeutics
Publisher
Wiley
Published
2025-02
Volume
31
Issue
2
Pages
e70269-e70269
ISSN
  • 1755-5930 (ISSN-L)
  • 1755-5949
DOI
10.1111/cns.70269
PMC
PMC11831194
OpenAlex
W4407660806
Cited by
10
References
6
Citations by year
2026: 9 · 2025: 1
FWCI
1.31
Type
journal article
Language
en
Open access
Licence
Locations
  • CNS Neuroscience & Therapeutics (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Tehran University of Medical Sciences and Health Services
  • Shahid Beheshti University of Medical Sciences
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Rheumatology › Bone and Dental Protein Studies
Keywords
osteopontin, Alzheimer's disease, neuroprotection, neurodegeneration, neuroinflammation, microglial activation, synaptic pruning, chemotaxis, signaling pathways, disease progression
MeSH terms
Neuroprotection, Alzheimer Disease, Animals, Humans, Nerve Degeneration, Neuroprotective Agents, Osteopontin

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