Letter abstract


Nature Medicine 14, 681 - 687 (2008)
Published online: 1 June 2008 | doi:10.1038/nm1781

Blocking TGF-bold beta–Smad2/3 innate immune signaling mitigates Alzheimer-like pathology

Terrence Town1,2, Yasmina Laouar1,10,11, Christopher Pittenger3,11, Takashi Mori4, Christine A Szekely5,6, Jun Tan7, Ronald S Duman3,8 & Richard A Flavell1,9

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Alzheimer's disease is the most common dementia and is pathologically characterized by deposition of amyloid-beta peptide (Abeta) into beta-amyloid plaques, neuronal injury and low-level, chronic activation of brain immunity1. Transforming growth factor-betas (TGF-betas) are pleiotropic cytokines that have key roles in immune cell activation, inflammation and repair after injury2. We genetically interrupted TGF-beta and downstream Smad2/3 signaling (TGF-beta–Smad2/3) in innate immune cells by inducing expression of CD11c promoter–driven dominant-negative TGF-beta receptor type II in C57BL/6 mice (CD11c-DNR)3, crossed these mice with mice overexpressing mutant human amyloid precursor protein, the Tg2576 Alzheimer's disease mouse model4, and evaluated Alzheimer's disease-like pathology. Aged double-transgenic mice showed complete mitigation of Tg2576-associated hyperactivity and partial mitigation of defective spatial working memory. Brain parenchymal and cerebrovascular beta-amyloid deposits and Abeta abundance were markedly (up to 90%) attenuated in Tg2576–CD11c-DNR mice. This was associated with increased infiltration of Abeta-containing peripheral macrophages around cerebral vessels and beta-amyloid plaques. In vitro, cultures of peripheral macrophages, but not microglia, from CD11c-DNR mice showed blockade of classical TGF-beta–activated Smad2/3 but also showed hyperactivation of alternative bone morphogenic protein–activated Smad1/5/8 signaling and increased Abeta phagocytosis. Similar effects were noted after pharmacological inhibition of activin-like kinase-5, a type I TGF-beta receptor. Taken together, our results suggest that blockade of TGF-beta–Smad2/3 signaling in peripheral macrophages represents a new therapeutic target for Alzheimer's disease.

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  1. Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06520-8011, USA.
  2. Departments of Biomedical Sciences and Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, USA.
  3. Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, Connecticut 06508, USA.
  4. Institute of Medical Science, Saitama Medical Center, Saitama Medical University, 1981 Kamoda, Kawagoe, Saitama 350-8550, Japan.
  5. Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, USA.
  6. Johns Hopkins Bloomberg School of Public Health, 624 North Broadway, Baltimore, Maryland 21205, USA.
  7. Rashid Laboratory for Developmental Neurobiology, Silver Child Development Center, Department of Psychiatry and Behavioral Medicine, University of South Florida College of Medicine, 12901 Bruce B. Downs Boulevard, Tampa, Florida 33612, USA.
  8. Department of Pharmacology, Yale University School of Medicine, 34 Park Street, New Haven, Connecticut 06508, USA.
  9. Howard Hughes Medical Institute, Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06520-8011, USA.
  10. Present address: Department of Microbiology and Immunology, University of Michigan School of Medicine, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0620, USA.
  11. These authors contributed equally to this work.

Correspondence to: Terrence Town1,2 e-mail: terrence.town@cshs.org

Correspondence to: Richard A Flavell1,9 e-mail: richard.flavell@yale.edu



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