Deficiency in neuronal TGF-β signaling promotes neurodegeneration and Alzheimer’s pathology
Open accessAbstract
Alzheimer's disease (AD) is characterized by progressive neurodegeneration and cerebral accumulation of the beta-amyloid peptide (Abeta), but it is unknown what makes neurons susceptible to degeneration. We report that the TGF-beta type II receptor (TbetaRII) is mainly expressed by neurons, and that TbetaRII levels are reduced in human AD brain and correlate with pathological hallmarks of the disease. Reducing neuronal TGF-beta signaling in mice resulted in age-dependent neurodegeneration and promoted Abeta accumulation and dendritic loss in a mouse model of AD. In cultured cells, reduced TGF-beta signaling caused neuronal degeneration and resulted in increased levels of secreted Abeta and beta-secretase-cleaved soluble amyloid precursor protein. These results show that reduced neuronal TGF-beta signaling increases age-dependent neurodegeneration and AD-like disease in vivo. Increasing neuronal TGF-beta signaling may thus reduce neurodegeneration and be beneficial in AD.
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The TGF-β signaling downregulation in APOE4 is likely connected to its neuroprotective role.
“in line with a study showing dysfunction in TGF-β signaling in models of early AD and in human AD brain (Tesseur et al., 2006), likely connected to its neuroprotective role.”
From APOE2, E3, and E4 differentially modulate cellular homeostasis, cholesterol metabolism, and inflammatory response in isogenic iPSC-derived astrocytes (2022) · cites this paper as Tesseur et al., 2006
The Discussion reports reduced TGF-β receptor levels in human AD brain, including mild AD, and links impaired neuronal signaling to neurodegeneration in mouse models. It also proposes that increasing neuronal TGF-β signaling could be protective. The paper does not establish that TGF-β signaling is downregulated specifically in APOE4, so that part of the claim is unsupported. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTGFβ signaling was suggested to play both beneficial and detrimental roles in AD.
“Although TGFβ signaling was suggested to play both beneficial and detrimental roles in AD 57 , its overproduction in astrocytes promotes cerebrovascular fibrosis and amyloidosis 58 .”
From APOE4 impairs the microglial response in Alzheimer’s disease by inducing TGFβ-mediated checkpoints (2023) · cites this paper as [57]
Pathways neuroprotective in Alzheimer's disease appeared more cohesive in AD resistant neurons than in vulnerable neurons, namely the transforming growth factor beta receptor signaling pathway (in DG) and the canonical Wnt signaling pathway (in DG, S1 and V1).
“We found that pathways neuroprotective in AD (Caraci et al., 2008; Liu et al., 2014; Tesseur et al., 2006)appeared more cohesive in AD resistant neurons than in vulnerable neurons, namely the transforming growth factor beta receptor signaling pathway (in DG) and the canonical Wnt signaling pathway (in DG, S1 and V1).”
From Selective Neuronal Vulnerability in Alzheimer’s Disease: A Network-Based Analysis (2020) · cites this paper as Tesseur et al., 2006
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References 70 · Cited by 355
- Authors
- Tesseur, I., Zou, K., Esposito, L., Bard, F., Berber, E., Can, J. V., Lin, A. H., Crews, L., Tremblay, P., Mathews, P., Mucke, L., Masliah, E., & Wyss-Coray, T.
- Affiliations
- Stanford Medicine (US)
- Gladstone Institutes (US)
- University of California San Diego (US)
- University of California, San Francisco (US)
- New York University (US)
- Venue
- Journal of Clinical Investigation
- Published
- 2006-11-01
- Volume
- 116
- Issue
- 11
- Pages
- 3060-3069
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2161964141
- Cited by
- 355
- References
- 70
- Citations by year
- 2026: 17 · 2025: 17 · 2024: 23 · 2023: 16 · 2022: 22 · 2021: 22 · 2020: 21 · 2019: 16 · 2018: 19 · 2017: 14 · 2016: 20 · 2015: 16 · 2014: 21 · 2013: 24 · 2012: 19
- FWCI
- 8.19
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Mayo Clinic
- Alzheimer's Association
- John Douglas French Alzheimer's Foundation
- National Institutes of Health (NS40994)
- University of California, San Francisco
- University of California, Irvine
- National Institute on Aging (AG20603, R01AG020603)
- National Institute of Neurological Disorders and Stroke (NS40994, R01NS040994)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, TGF-beta signaling, TGFBR2, neurodegeneration, amyloid-beta deposition, beta-secretase, age-related neurodegeneration, mouse models of Alzheimer's disease
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type II, Aging, Alzheimer Disease, Animals, Cells, Cultured, Dendrites, Gliosis, Humans, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration, Neuroblastoma, Signal Transduction, Transforming Growth Factor beta, Amyloid beta-Peptides, Protein Serine-Threonine Kinases, Receptors, Transforming Growth Factor beta, Mice
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