Blocking TGF-beta-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-beta peptide (A beta) into beta-amyloid plaques, neuronal injury and low-level, chronic activation of brain immunity(1). Transforming growth factor-beta s (TGF-beta s) are pleiotropic cytokines that have key roles in immune cell activation, inflammation and repair after injury(2). 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 model(4), 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 A beta abundance were markedly (up to 90%) attenuated in Tg2576-CD11c-DNR mice. This was associated with increased infiltration of A beta-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 A beta 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.