Deficiency in neuronal TGF-beta signaling promotes neurodegeneration and Alzheimer's pathology.
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.
Tesseur
Ina
I
Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California 94305, USA.
Zou
Kun
K
Esposito
Luke
L
Bard
Frederique
F
Berber
Elisabeth
E
Can
Judith Van
JV
Lin
Amy H
AH
Crews
Leslie
L
Tremblay
Patrick
P
Mathews
Paul
P
Mucke
Lennart
L
Masliah
Eliezer
E
Wyss-Coray
Tony
T
D000375:Aging / Q000502:physiology; D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D003712:Dendrites / Q000378:metabolism / Q000473:pathology; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D009447:Neuroblastoma / Q000378:metabolism / Q000473:pathology; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II