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Letter
Nature Medicine 14, 681 - 687 (2008)
Published online: 1 June 2008 | doi:10.1038/nm1781
Blocking TGF-
–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
Abstract
Alzheimer's disease is the most common dementia and is pathologically characterized by deposition of amyloid-
peptide (A) into -amyloid plaques, neuronal injury and low-level, chronic activation of brain immunity1. Transforming growth factor-s (TGF-s) are pleiotropic cytokines that have key roles in immune cell activation, inflammation and repair after injury2. We genetically interrupted TGF- and downstream Smad2/3 signaling (TGF-–Smad2/3) in innate immune cells by inducing expression of CD11c promoter–driven dominant-negative TGF- 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 -amyloid deposits and A abundance were markedly (up to 90%) attenuated in Tg2576–CD11c-DNR mice. This was associated with increased infiltration of A-containing peripheral macrophages around cerebral vessels and -amyloid plaques. In vitro, cultures of peripheral macrophages, but not microglia, from CD11c-DNR mice showed blockade of classical TGF-–activated Smad2/3 but also showed hyperactivation of alternative bone morphogenic protein–activated Smad1/5/8 signaling and increased A phagocytosis. Similar effects were noted after pharmacological inhibition of activin-like kinase-5, a type I TGF- receptor. Taken together, our results suggest that blockade of TGF-–Smad2/3 signaling in peripheral macrophages represents a new therapeutic target for Alzheimer's disease.
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