Blocking TGF-β–Smad2/3 innate immune signaling mitigates Alzheimer-like pathology
Open accessAbstract
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 phagocytosi…
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Peripheral macrophages are capable of traversing the blood-brain barrier during times of injury and disease.
“Furthermore, peripheral macrophages may not just be bystanders in the progression of AD, as it has been shown that they are not only more efficient phagocytes of Aβ than microglia, but they are also capable of traversing the blood-brain barrier during times of injury and disease [17–21].”
From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [18]
Peripheral macrophages are more efficient phagocytes of Aβ than microglia.
“Furthermore, peripheral macrophages may not just be bystanders in the progression of AD, as it has been shown that they are not only more efficient phagocytes of Aβ than microglia, but they are also capable of traversing the blood-brain barrier during times of injury and disease [17–21].”
From Alzheimer’s disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner (2024) · cites this paper as [18]
Inhibition of anti-inflammatory stimuli has beneficial effects on Aβ phagocytosis, β-amyloidosis, and cognitive function.
“There are also indications that inhibition of anti-inflammatory stimuli has beneficial effects on A phagocytosis, -amyloidosis, and cognitive function (Town et al., 2008).”
From PPARγ/RXRα-Induced and CD36-Mediated Microglial Amyloid-β Phagocytosis Results in Cognitive Improvement in Amyloid Precursor Protein/Presenilin 1 Mice (2012) · cites this paper as Town et al., 2008
Altering the proliferation, signaling, and migration of microglia directly impacts development of Aβ pathology.
“numerous other studies have suggested that altering the proliferation, 58 signaling, 8,9,11 and migration 7,59 of microglia directly impact development of A pathology.”
From CX3CR1 Deficiency Alters Microglial Activation and Reduces Beta-Amyloid Deposition in Two Alzheimer's Disease Mouse Models (2010) · cites this paper as [8]
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References 30 · Cited by 422
- Authors
- Town, T., Laouar, Y., Pittenger, C., Mori, T., Szekely, C. A., Tan, J., Duman, R. S., & Flavell, R. A.
- Affiliations
- Yale University (US)
- University of Michigan (US)
- Saitama Medical Center, Saitama Medical University (JP)
- Cedars-Sinai Medical Center (US)
- University of South Florida (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Town, Terrence
- Flavell, Richard A
- Venue
- Nature Medicine
- Published
- 2008-06
- Volume
- 14
- Issue
- 6
- Pages
- 681-687
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC2649699
- OpenAlex
- W1595078459
- Cited by
- 422
- References
- 30
- Citations by year
- 2026: 8 · 2025: 9 · 2024: 10 · 2023: 13 · 2022: 17 · 2021: 23 · 2020: 14 · 2019: 23 · 2018: 12 · 2017: 22 · 2016: 28 · 2015: 38 · 2014: 23 · 2013: 31 · 2012: 36
- FWCI
- 25.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute on Aging (K99AG029726, R00AG029726)
- National Institute of Neurological Disorders and Stroke (R01NS048335)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- Alzheimer's disease, TGF-beta signaling, Smad2/3, innate immunity, peripheral macrophages, amyloid plaques, amyloid-beta phagocytosis, TGFBR2, dominant negative receptor, Tg2576 mice, Smad1/5/8, spatial working memory, neuroinflammation
- MeSH terms
- Alzheimer Disease, Animals, Crosses, Genetic, Disease Models, Animal, Female, Heterozygote, Humans, Immunity, Innate, Immunohistochemistry, Male, Mice, Inbred C57BL, Mice, Transgenic, Signal Transduction, Transforming Growth Factor beta, Mice, Smad2 Protein, Smad3 Protein
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