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 (Abeta) into beta-amyloid plaques, neuronal injury and low-level, chronic activation of brain immunity. Transforming growth factor-betas (TGF-betas) are pleiotropic cytokines that have key roles in immune cell activation, inflammation and repair after injury. 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), crossed these mice with mice overexpressing mutant human amyloid precursor protein, the Tg2576 Alzheimer's disease mouse model, 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 Abeta abundance were markedly (up to 90%) attenuated in Tg2576-CD11c-DNR mice. This was associated with increased infiltration of Abeta-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 Abeta 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.
Town
Terrence
T
Department of Immunobiology, Yale University School of Medicine, 300 Cedar Street, New Haven, Connecticut 06520-8011, USA. terrence.town@cshs.org
Laouar
Yasmina
Y
Pittenger
Christopher
C
Mori
Takashi
T
Szekely
Christine A
CA
Tan
Jun
J
Duman
Ronald S
RS
Flavell
Richard A
RA
D000544:Alzheimer Disease / Q000473:pathology*; D000818:Animals; D003433:Crosses, Genetic; D004195:Disease Models, Animal; D005260:Female; D006579:Heterozygote; D006801:Humans; D007113:Immunity, Innate; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction; D051899:Smad2 Protein / Q000235:genetics / Q000276:immunology*; D051900:Smad3 Protein / Q000235:genetics / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000235:genetics
D051899:Smad2 Protein; C497783:Smad2 protein, mouse; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016212:Transforming Growth Factor beta