Skip to content
2000
  1. Home
  2. A-Z Publications
  3. Current Aging Science
  4. Fast Track Articles
  5. Fast Track Article
image of The Therapeutic Potential of Targeting the Pd-L1/Pd-1 Immune Checkpoint Pathway in Alzheimer's Disease

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of amyloid-β plaques, neurofibrillary tangles, and chronic neuroinflammation. Emerging evidence suggests that the PD-L1/PD-1 immune checkpoint pathway plays a critical role in modulating neuroinflammation, microglial function, and amyloid-β clearance in AD. This review summarizes the current understanding of the PD-L1/PD-1 pathway in AD and discusses its potential as a therapeutic target. Preclinical studies and clinical trials have demonstrated that targeting the PD-L1/PD-1 axis can enhance microglial phagocytosis, promote amyloid-β clearance, and reduce neuroinflammation. We examine the potential benefits and challenges of using existing immunotherapy drugs, such as anti-PD-L1 and anti-PD-1 antibodies, in the context of AD.

Additionally, we explore the development of novel, more specific agents targeting the PD-L1/PD-1 pathway, as well as potential synergistic approaches with other immunomodulatory or amyloid-β-targeting treatments. This review provides a comprehensive and up-to-date analysis of the PD-L1/PD-1 immune checkpoint pathway's role in Alzheimer's disease, highlighting its promising therapeutic potential for improving patient outcomes. Further research is warranted to optimize treatment strategies and evaluate the long-term safety and efficacy of targeting this axis in clinical settings.

© 2024 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cas/10.2174/0118746098342537241121042621
2024-12-06
2025-01-17

  • From This Site

    /content/journals/cas/10.2174/0118746098342537241121042621
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Querfurth H.W. LaFerla F.M. Alzheimer’s disease. N. Engl. J. Med. 2010 362 4 329 344 20107219
    [Google Scholar]
  2. Selkoe D.J. Hardy J. The amyloid hypothesis of Alzheimer’s disease: Progress and problems on the road to therapeutics. Science 2016 353 6295 112 118 27387933
    [Google Scholar]
  3. Gate D. Tanne S. Gupta V. Bhaskar K. Hauser P. Khanna S. Therapeutic opportunities in alzheimer’s disease: Disease modifiers focusing on inhibiting Amyloid deposition. CNS Drugs 2021 35 1 5 20
    [Google Scholar]
  4. Klein M. Botsios C. Kotsiou E. Tsolaki M. Paraskevas G.P. Immune checkpoint proteins in alzheimer’s disease: A potential therapeutic target. Curr. Alzheimer Res. 2020 17 4 368 373
    [Google Scholar]
  5. Chen W. He W. Li J. Immune checkpoint blockade in cancer immunotherapy: Novel insights and current challenges. J. Immunol. Res. 2021 2021 1812106
    [Google Scholar]
  6. Tringler S. Lönnerfors C. Jacquemier J. Khadir A. Tchernitsa O. Lanier L.L. The soluble programmed death ligand 1 (sPD-L1) isoform lacks immune suppressive function and promotes anti-tumour immune responses. OncoImmunology 2021 10 1 1935218
    [Google Scholar]
  7. Zhao J. Zhao X. Chu C. Gu J. Ma L. Jia Y. Blockade of the PD-L1/PD-1 pathway promotes phagocytosis of myelin debris by microglia in vitro. Brain Res. Bull. 2021 172 152 163
    [Google Scholar]
  8. Liu H. Qin X. Zhou C. Chen J. Xie L. Liu Z. The role of PD-L1/PD-1 pathway in the inflammatory reaction of microglia after oxygen-glucose deprivation/reperfusion in vitro. J. Neuroinflammation 2020 17 1 84 32171317
    [Google Scholar]
  9. Jin K. Wang Z. Yuan Y. Liu P. Zhang L. Sun X. Regulatory T cells modulate brain microglia in a mouse model of alzheimer’s disease via the PD-L1 pathway. Brain Res. Bull. 2020 159 119 128
    [Google Scholar]
  10. Chen Y. Yin Y. Zhou D. Wang Y. Chen J. Zhou J. Enhanced Amyloid-β phagocytosis by Microglia via blocking PD-L1/PD-1 signaling pathway in alzheimer’s disease mouse model. Mol. Neurobiol. 2021 58 9 5379 5392
    [Google Scholar]
  11. Meng F. Wu L. Liu H. Liu G. Sun J. Zhao J. Microglial NLRP3 inflammasome activation mediated by the PD-1/PD-L1 pathway promotes Amyloidogenesis in the 5xFAD mouse model of alzheimer’s disease. Mol. Neurobiol. 2021 58 9 5393 5413
    [Google Scholar]
  12. Tan J. Li J. Guo Y. Tan L. PD-1/PD-L1 axis deficiency aggravates cognitive impairment and Tauopathy in an alzheimer’s disease model. Mol. Neurobiol. 2022 59 1 257 269
    [Google Scholar]
  13. Han S. He W. Yang X. Nie H. Liu Y. Gao F. Deficiency of PD-L1 aggravates inflammatory response in Cuprizone-induced Demyelinating disease Model through modulating Treg/Th17 cell balance. Mol. Neurobiol. 2019 56 8 5306 5317
    [Google Scholar]
  14. Zhang F. Deng Z. Feng X. Li B. Yang P. Bai Y. T cells exacerbate neuroinflammation in a mouse model of alzheimer’s disease via IFN-γ/IL-17 secretion and microglial activation. Brain Behav. Immun. 2022 101 508 520
    [Google Scholar]
  15. Gate D. Christie D. Karnam A. Shiino A. Guillemin G.J. McGeer P.L. Adaptive immune cells as an unrecognized source of immunomodulatory factors in alzheimer’s disease brain. J. Neuroinflammation 2020 17 1 132 32334630
    [Google Scholar]
  16. Wang Y. Meng F. Ma L. Zhang Y. Zhao J. Li X. PD-1/PD-L1 inhibition reduces Aβ load by enhancing Phagocytosis of Aβ-associated Microglia. Mol. Neurobiol. 2022 59 9 4919 4932
    [Google Scholar]
  17. Patnaik A. Kang Y.J. Cho N.H. PD-L1/PD-1 Immunotherapy: Emerging biomarkers for tumor microenvironment and clinical outcome. Cancers (Basel) 2020 12 3 752 32235770
    [Google Scholar]
  18. Wang H. Reng S.Y. Wang Y.T. Zhou Y.F. Wang H.Y. PD-1/PD-L1 immunotherapy in cancer treatment. Front. Med. 2020 14 3 378 392 31784918
    [Google Scholar]
  19. Zhuang H. Karsak M. McGivern J.V. Wen P. Hurley B. Lee S.C. Gut microbiome shapes alzheimer’s disease susceptibility in transgenic mice. Alzheimers Dement. 2021 17 6 824 833
    [Google Scholar]
  20. Dodiya H.B. Vaghasiya J.P. Pandya V.B. Joshi R.K. Dodiya J.H. Rupareliya N. Gut-brain axis: A novel therapeutic target for alzheimer’s disease. J. Transl. Med. 2022 20 1 100 35189890
    [Google Scholar]
  21. Sun X. Cheng J. Zong Y. Liu L. Miao J. Wang Y. Probiotic treatment improves cognitive deficits by modulating gut microbiota-related TLR2/4-dependent neuroinflammation in APP/PS1 mice. Alzheimers Res. Ther. 2022 14 1 76 35650632
    [Google Scholar]
  22. Xiu L. Zhao Y. Li Y. Wang X. Sun L. Yang H. PD-L1-PD-1 blockade prevents neuroinflammation and Tau pathology by modulating Microglial JAK2/STAT3 signaling. Cell. Mol. Neurobiol. 2024 44 3 673 688
    [Google Scholar]
  23. Luo Y. Liu X. Zhao H. Jiang Y. Wang X. Liu Y. PD-L1 regulates microglial function in alzheimer’s disease by modulating TREM2 expression. J. Neuroimmunol. 2023 1 1 100050
    [Google Scholar]
  24. Zhao J. Chu C. Wang Y. Meng F. Zhou L. Li X. Peripheral Monocytes contribute to Amyloid Plaque Phagocytosis upon PD-1 inhibition. Mol. Neurobiol. 2023 60 2 914 927 36324051
    [Google Scholar]
  25. Yamanaka K. Tanaka T. Miyazaki T. Okada Y. Yoshimoto T. Hashimoto Y. PD-L1 deficiency aggravates Amyloid β pathology by activating NOD2-mediated inflammatory pathway in a mouse model of alzheimer’s disease. J. Neuroimmunol. 2012 247 1-2 27 33
    [Google Scholar]
  26. Abdel-Wahab M.F. Azab A.F. Zaki K.A. Abou-Zaid A. Zaghloul H.H. Ammar R.A. Development of PD-1/PD-L1 small-molecule inhibitors as promising immunotherapeutic agents. Molecules 2022 27 15 4836 35956787
    [Google Scholar]
  27. Luo Y. Huang X. Liu H. Jin X. Zhao J. Cheng L. Discovery of novel small-molecule inhibitors targeting the PD-1/PD-L1 interaction: An in silico and in vitro combined study. J. Med. Chem. 2021 64 15 10346 10363
    [Google Scholar]
  28. Kijima T. Niwa T. Nakamura T. Hayakawa M. Nawa Y. Nakao A. Therapeutic RNA interference against PD-L1 Ameliorates Murine autoimmune Myocarditis. Sci. Rep. 2021 11 1 13620 34193934
    [Google Scholar]
  29. Liu Z. He R. Wang J. Shen J. Zhu Y. Liu H. Blockade of PD-L1 by shRNA enhances anti-tumor effect of human γδ T cells to lymphoma in vitro. J. Hematol. Oncol. 2021 14 1 131 34425858
    [Google Scholar]
  30. Patil S.S. Narayan R. Gangadaran P. Gadsden J. Ali S.S. Gunasekaran K. Activation of PD-1 signaling in Microglia inhibits Amyloid β uptake and promotes its deposition in alzheimer’s disease. Mol. Neurobiol. 2021 58 10 5762 5777
    [Google Scholar]
  31. Cheng M. Wang X. Zhang X. Guo Y. Xing C. Chen X. Combination therapy targeting PD-1 and NOD2 signaling promotes microglial phagocytosis and ameliorates alzheimer’s disease in mouse model. Mol. Psychiatry 2021 26 9 3973 3984
    [Google Scholar]
  32. Ghareghani M. Rivest S. The synergistic potential of combining PD-1/PD-L1 immune checkpoint inhibitors with NOD2 agonists in alzheimer’s disease treatment. Int. J. Mol. Sci. 2023 24 13 10905 10.3390/ijms241310905 37446081
    [Google Scholar]
  33. Zhou L. Li X. Blocking of PD-1 promotes microglial phagocytosis in alzheimer’s disease mice. Neurosci. Lett. 2020 730 135427
    [Google Scholar]
  34. Mehrabadi S. Effects of Chronic administration of nickel on memory function, hippocampal neuronal morphology and oxidative stress factors in male adult Rats. Archives of Advances in Biosciences 2022 13 1 8
    [Google Scholar]
  35. Rosenzweig N. Dvir-Szternfeld R. Tsitsou-Kampeli A. Keren-Shaul H. Ben-Yehuda H. Weill-Raynal P. Cahalon L. Kertser A. Baruch K. Amit I. Weiner A. Schwartz M. PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat. Commun. 2019 10 1 465 10.1038/s41467‑019‑08352‑5 30692527
    [Google Scholar]
  36. Kummer M. P. Ising C. Kummer C. Sarlus H. Griep A. Vieira‐Saecker A. Microglial PD-1 stimulation by astrocytic PD-L1 suppresses neuroinflammation and alzheimer's disease pathology EMBO J. 2021 40 24 e108662 10.15252/embj.2021108662
    [Google Scholar]
  37. Cummings J. Osse A.M.L. Cammann D. Powell J. Chen J. Anti-Amyloid Monoclonal antibodies for the treatment of alzheimer's disease BioDrugs 2024 38 1 5 22
    [Google Scholar]
  38. Baruch K. Kertser A. Matalon O. Forsht O. Braiman S. Shochat E. David C. Yoles E. IBC‐Ab002, an anti‐PD‐L1 monoclonal antibody tailored for treating alzheimer’s disease. Alzheimers Dement. 2020 16 S9 e042978 10.1002/alz.042978
    [Google Scholar]
  39. Acúrcio R.C. Pozzi S. Carreira B. Pojo M. Gómez-Cebrián N. Casimiro S. Therapeutic targeting of PD-1/PD-L1 blockade by novel small-molecule inhibitors recruits cytotoxic T cells into solid tumor microenvironment J Immunother Cancer 2022 10 7 e004695
    [Google Scholar]
  40. Yin S. Chen Z. Chen D. Yan D. Strategies targeting PD-L1 expression and associated opportunities for cancer combination therapy. Theranostics 2023 13 5 1520 1544 10.7150/thno.80091 37056572
    [Google Scholar]
  41. Barati M. Mirzavi F. Atabaki M. Bibak B. Mohammadi M. Jaafari M. R. A review of PD-1/PD-L1 siRNA delivery systems in immune T cells and cancer cells Int. Immunopharmacol. 2022 111 1 109022 10.1016/j.intimp.2022.109022
    [Google Scholar]
  42. Mehrabadi S. Sadr S.S. Assessment of probiotics mixture on memory function, inflammation markers, and oxidative stress in an alzheimer’s disease model of rats. Iran. Biomed. J. 2020 24 4 220 228 10.29252/ibj.24.4.220 32306720
    [Google Scholar]
  43. Obst J. Mancuso R. Simon E. Gomez-Nicola D. PD-1 deficiency is not sufficient to induce myeloid mobilization to the brain or alter the inflammatory profile during chronic neurodegeneration Brain Behav Immun. 2018 73 708 716 10.1016/j.bbi.2018.08.006
    [Google Scholar]
  44. A first in human Study of IBC-Ab002 in persons with early alzheimer's disease (AD) Patent NCT05551741, 2024 https://clinicaltrials.gov/study/NCT05551741
  45. Li X. Zhou Y. Xu B. Qin Y. Zhao J. Li M. Xu J. Li G. Comparison of efficacy discrepancy between early-phase clinical trials and phase III trials of PD-1/PD-L1 inhibitors. J. Immunother. Cancer 2024 12 1 e007959 10.1136/jitc‑2023‑007959 38233100
    [Google Scholar]
  46. Schwartz M. Arad M. Ben-Yehuda H. Potential immunotherapy for Alzheimer disease and age-related dementia. Dialogues Clin. Neurosci. 2019 21 1 21 25 10.31887/DCNS.2019.21.1/mschwartz 31607777
    [Google Scholar]
  47. Ringman J.M. Goate A. Masters C.L. Cairns N.J. Danek A. Graff-Radford N. Ghetti B. Morris J.C. Dominantly Inherited Alzheimer Network Genetic heterogeneity in Alzheimer disease and implications for treatment strategies. Curr. Neurol. Neurosci. Rep. 2014 14 11 499 10.1007/s11910‑014‑0499‑8 25217249
    [Google Scholar]
/content/journals/cas/10.2174/0118746098342537241121042621
Loading
The Therapeutic Potential of Targeting the Pd-L1/Pd-1 Immune Checkpoint Pathway in Alzheimer's Disease
Bentham Science Publishers ; https://doi.org/10.2174/0118746098342537241121042621
/content/journals/cas/10.2174/0118746098342537241121042621
/content/journals/cas/10.2174/0118746098342537241121042621
Loading

Data & Media loading...


  • Article Type:     Review Article
Keywords: microglia ; phagocytosis ; PD-1 ; therapeutic target ; PD-L1 ; neuroinflammation ; amyloid-β ; immune checkpoint ; Alzheimer's disease

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test