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-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.

Methylene Blue Modulates β-Secretase, Reverses Cerebral Amyloidosis, and Improves Cognition in Transgenic Mice

“…This behavioral phenotype has been reported in cerebral amyloidosis mouse models (e.g. Tg2576 or PSAPP mice) (20,22,23,26,35), and it may reflect disinhibition because of cortical and/or hippocampal damage (25). Overall ANOVA disclosed the main effects of genotype (p Ͻ 0.001 for both locomotion and rearing scores) and treatment (p Ͻ 0.001 for both locomotion and rearing scores), and repeated-measures ANOVA followed by post hoc comparison revealed statistically significant differences between PSAPP-V mice and the other three groups of mice for both locomotion and rearing scores (Fig.…”

“…Subsequently, Y-maze total arm entry and spontaneous alternation were assessed to measure exploratory activity and spatial working memory (20,26). Briefly, mice were individually placed in one arm of a radially symmetric Y-maze made of opaque gray acrylic (arms: 40 cm long and 4 cm wide; walls, 30 cm tall), and the sequence of arm entries and total number of entries were recorded over a period of 8 min, beginning when the animal first entered the central area.…”

“…According to previously described methods (22,23,26,36,37), ␤-amyloid deposits were assigned to one of three mutually exclusive categories according to maximum diameter as follows: small (Ͻ 25 m), medium (between 25 and 50 m), or large (Ͼ 50 m). Mean numbers of deposits in all three subsets showed statistically significant decreases in PSAPP-MB versus PSAPP-V mice across all three brain regions examined, with the greatest reduction in the large sized subset, especially in the EC (Figs.…”

Microglial repopulation model reveals a robust homeostatic process for replacing CNS myeloid cells

“…Indeed, CCR2 expression was encountered in the infiltrating monocytes. Expression of CD11c was not encountered in the engrafted monocytes, in contrast to other models of peripheral macrophage infiltration (38)(39)(40).…”

Tannic Acid Is a Natural β-Secretase Inhibitor That Prevents Cognitive Impairment and Mitigates Alzheimer-like Pathology in Transgenic Mice

“…Tissue Preparation-Tissue was processed according to our previously described methods (16,18,42,43). At 12 months of age, animals were anesthetized with sodium pentobarbital (50 mg/kg) and euthanized by transcardial perfusion with ice-cold physiological saline containing heparin (10 units/ml).…”