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


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

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Figure 1: Reduced behavioral impairment in Tg2576–CD11c-DNR mice at 16–17 months of age.
Figure 2: Reduced cerebral parenchymal and vascular β-amyloid deposits in Tg2576–CD11c-DNR mice at 17–18 months of age.
Figure 3: The CD11c-DNR transgene reduces astrocytosis but increases infiltrating macrophages in Alzheimer's disease mouse models.
Figure 4: TGF-β1 shifts CD11c-DNR macrophages from canonical to alternate Smad signaling and increases Aβ phagocytosis in vitro.


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We thank F. Manzo for help with preparing this manuscript and A. Ferrandino and S. Sojitra for expert technical assistance. We are grateful to Y. Wan, P. Rakic and J.J. Breunig for helpful discussion and to P. Rakic and J.J. Breunig for assistance with confocal microscopy. We also thank N. Ruddle for providing the brain FACS protocol. This work was supported by an Alzheimer's Association Grant (to R.A.F. and T.T.), and a US National Institutes of Health Pathway to Independence award (1K99AG029726 and 4R00AG029726 to T.T.). R.A.F. is an Investigator of the Howard Hughes Medical Institute.

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T.T., Y.L., C.P., J.T., R.S.D. and R.A.F. designed all experiments; T.T. carried out all experiments except behavioral analysis (C.P.), brain FACS assay (Y.L.) and β-amyloid plaque morphometric analysis (T.M.); T.T. and C.A.S. conducted statistical analysis of the data; T.T., R.S.D. and R.A.F. supervised the project; T.T. wrote the manuscript and T.T., C.P., J.T., R.S.D. and R.A.F. edited the manuscript.

Corresponding authors

Correspondence to Terrence Town or Richard A Flavell.

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Supplementary Figs. 1–5, Supplementary Tables 1 and 2, and Supplementary Methods (PDF 2108 kb)

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Town, T., Laouar, Y., Pittenger, C. et al. Blocking TGF-β–Smad2/3 innate immune signaling mitigates Alzheimer-like pathology. Nat Med 14, 681–687 (2008).

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