1. Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology.
- Author
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Tesseur I, Zou K, Esposito L, Bard F, Berber E, Can JV, Lin AH, Crews L, Tremblay P, Mathews P, Mucke L, Masliah E, and Wyss-Coray T
- Subjects
- Aging physiology, Alzheimer Disease genetics, Amyloid beta-Peptides genetics, Amyloid beta-Peptides metabolism, Animals, Cells, Cultured, Dendrites metabolism, Dendrites pathology, Gliosis metabolism, Gliosis pathology, Humans, Mice, Mice, Inbred C57BL, Mice, Transgenic, Nerve Degeneration genetics, Neuroblastoma metabolism, Neuroblastoma pathology, Protein Serine-Threonine Kinases, Receptor, Transforming Growth Factor-beta Type II, Receptors, Transforming Growth Factor beta metabolism, Alzheimer Disease metabolism, Alzheimer Disease pathology, Nerve Degeneration metabolism, Nerve Degeneration pathology, Signal Transduction, Transforming Growth Factor beta metabolism
- Abstract
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.
- Published
- 2006
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