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ResearchIn-Press PreviewNeuroscience Open Access | 10.1172/JCI152565

Peripheral monocyte-derived cells counter amyloid plaque pathogenesis in a mouse model of Alzheimer’s disease

Ping Yan,1 Ki-Wook Kim,2 Qingli Xiao,3 Xiucui Ma,4 Leah R. Czerniewski,3 Haiyan Liu,5 David R. Rawnsley,4 Yan Yan,6 Gwendalyn J. Randolph,7 Slava Epelman,8 Jin-Moo Lee,1 and Abhinav Diwan5

1Washington University School of Medicine, St. Louis, United States of America

2Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, United States of America

3Department of Neurology, Washington University School of Medicine, St. Louis, United States of America

4Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

5Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States of America

6Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

7Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

8Cardiology, University Health Network, Toronto, Canada

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1Washington University School of Medicine, St. Louis, United States of America

2Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, United States of America

3Department of Neurology, Washington University School of Medicine, St. Louis, United States of America

4Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

5Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States of America

6Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

7Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

8Cardiology, University Health Network, Toronto, Canada

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1Washington University School of Medicine, St. Louis, United States of America

2Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, United States of America

3Department of Neurology, Washington University School of Medicine, St. Louis, United States of America

4Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

5Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States of America

6Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

7Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

8Cardiology, University Health Network, Toronto, Canada

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1Washington University School of Medicine, St. Louis, United States of America

2Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, United States of America

3Department of Neurology, Washington University School of Medicine, St. Louis, United States of America

4Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

5Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States of America

6Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

7Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

8Cardiology, University Health Network, Toronto, Canada

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1Washington University School of Medicine, St. Louis, United States of America

2Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, United States of America

3Department of Neurology, Washington University School of Medicine, St. Louis, United States of America

4Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

5Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States of America

6Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

7Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

8Cardiology, University Health Network, Toronto, Canada

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1Washington University School of Medicine, St. Louis, United States of America

2Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, United States of America

3Department of Neurology, Washington University School of Medicine, St. Louis, United States of America

4Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

5Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States of America

6Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

7Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

8Cardiology, University Health Network, Toronto, Canada

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1Washington University School of Medicine, St. Louis, United States of America

2Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, United States of America

3Department of Neurology, Washington University School of Medicine, St. Louis, United States of America

4Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

5Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States of America

6Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

7Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

8Cardiology, University Health Network, Toronto, Canada

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1Washington University School of Medicine, St. Louis, United States of America

2Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, United States of America

3Department of Neurology, Washington University School of Medicine, St. Louis, United States of America

4Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

5Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States of America

6Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

7Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

8Cardiology, University Health Network, Toronto, Canada

Find articles by Yan, Y. in: JCI | PubMed | Google Scholar

1Washington University School of Medicine, St. Louis, United States of America

2Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, United States of America

3Department of Neurology, Washington University School of Medicine, St. Louis, United States of America

4Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

5Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States of America

6Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

7Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

8Cardiology, University Health Network, Toronto, Canada

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1Washington University School of Medicine, St. Louis, United States of America

2Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, United States of America

3Department of Neurology, Washington University School of Medicine, St. Louis, United States of America

4Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

5Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States of America

6Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

7Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

8Cardiology, University Health Network, Toronto, Canada

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1Washington University School of Medicine, St. Louis, United States of America

2Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, United States of America

3Department of Neurology, Washington University School of Medicine, St. Louis, United States of America

4Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

5Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States of America

6Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

7Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

8Cardiology, University Health Network, Toronto, Canada

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1Washington University School of Medicine, St. Louis, United States of America

2Department of Pharmacology and Regenerative Medicine, University of Illinois College of Medicine, Chicago, United States of America

3Department of Neurology, Washington University School of Medicine, St. Louis, United States of America

4Department of Medicine, Washington University School of Medicine, St. Louis, United States of America

5Department of Internal Medicine, Washington University School of Medicine, St. Louis, United States of America

6Department of Surgery, Washington University School of Medicine, St. Louis, United States of America

7Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, United States of America

8Cardiology, University Health Network, Toronto, Canada

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Published May 5, 2022 - More info

J Clin Invest. https://doi.org/10.1172/JCI152565.
Copyright © 2022, Yan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published May 5, 2022 - Version history
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Abstract

Microglia, the parenchymal tissue macrophages in the brain, surround amyloid plaques in Alzheimer’s disease (AD) but are ineffective at clearing amyloid to mitigate disease progression. Recent studies in mice indicate that microglia are exclusively derived from primitive yolk-sac hematopoiesis and self-renew without contribution from ontogenically-distinct monocytes/macrophages of definitive ‘adult’ hematopoietic origin. Using genetic fate-mapping to label cells of definitive hematopoietic-origin throughout the life-span, we discovered that circulating monocytes contribute 6% of plaque-associated macrophages in aged AD mice. Moreover, peripheral monocytes contributed to a higher fraction of macrophages in the choroid plexus, meninges and perivascular spaces of aged AD mice versus wild-type controls, indicating enrichment at potential sites for entry into the brain parenchyma. Splenectomy, which markedly reduced circulating Ly6Chi monocytes, also reduced abundance of plaque-associated macrophages of definitive-hematopoietic origin, resulting in increased amyloid plaque load. Together, these results indicate that peripherally-derived monocytes invade the brain parenchyma, targeting amyloid plaques to reduce plaque load.

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