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

Abstract

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.