Blocking TGF-b–Smad2/3 innate immune signaling mitigates Alzheimer’s-like pathology

Alzheimer’s disease is the most common dementia and is pathologically characterized by deposition of amyloid-b peptide (Ab) into b-amyloid plaques, neuronal injury and low-level, chronic activation of brain immunity1. Transforming growth factor-bs (TGF-bs) are pleiotropic cytokines that have key roles in immune cell activation, inflammation and repair after injury2. We genetically interrupted TGF-b and downstream Smad2/3 signaling (TGF-b–Smad2/3) in innate immune cells by inducing expression of CD11c promoter–driven dominant-negative TGF-b 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. Q1 Aged doubletransgenic mice showed complete mitigation of Tg2576associated hyperactivity and partial mitigation of defective spatial working memory. Brain parenchymal and cerebrovascular b-amyloid deposits and Ab abundance were markedly (up to 90%) attenuated in Tg2576–CD11c-DNR mice. This was associated with increased infiltration of Ab-containing peripheral macrophages around cerebral vessels and b-amyloid plaques. In vitro, cultures of peripheral macrophages, but not microglia, from CD11c-DNR mice showed blockade of classical TGF-b– activated Smad2/3 but also showed hyperactivation of alternative bone morphogenic protein–activated Smad1/5/8 signaling and increased Ab phagocytosis. Similar effects were noted after pharmacological inhibition of activin-like kinase-5, a type I TGFb receptor. Taken together, our results suggest that blockade of TGF-b–Smad2/3 signaling in peripheral macrophages represents a new therapeutic target for Alzheimer’s disease.