Amyloidogenic role of cytokine TGF-beta1 in transgenic mice and in Alzheimer's disease.
Deposition of amyoid-beta peptide in the central nervous system is a hallmark of Alzheimer's disease and a possible cause of neurodegeneration. The factors that initiate or promote deposition of amyloid-beta peptide are not known. The transforming growth factor TGF-beta1 plays a central role in the response of the brain to injury, and increased TGF-beta1 has been found in the central nervous system of patients with Alzheimer's disease. Here we report that TGF-beta1 induces amyloid-beta deposition in cerebral blood vessels and meninges of aged transgenic mice overexpressing this cytokine from astrocytes. Co-expression of TGF-beta1 in transgenic mice overexpressing amyloid-precursor protein, which develop Alzheimer's like pathology, accelerated the deposition of amyloid-beta peptide. More TGF-beta1 messenger RNA was present in post-mortem brain tissue of Alzheimer's patients than in controls, the levels correlating strongly with amyloid-beta deposition in the damaged cerebral blood vessels of patients with cerebral amyloid angiopathy. These results indicate that overexpression of TGF-beta1 may initiate or promote amyloidogenesis in Alzheimer's disease and in experimental models and so may be a risk factor for developing Alzheimer's disease.
Wyss-Coray
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Gladstone Molecular Neurobiology Program and Department of Neurology, University of California, San Francisco 94141-9100, USA. Tony_Wyss@quickmail.ucsf.edu
Masliah
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E
Mallory
M
M
McConlogue
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L
Johnson-Wood
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K
Lin
C
C
Mucke
L
L
D000368:Aged; D000375:Aging / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000686:Amyloidosis / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D052160:Benzothiazoles; D001921:Brain / Q000378:metabolism / Q000473:pathology; D016657:Cerebral Amyloid Angiopathy / Q000378:metabolism / Q000473:pathology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D013844:Thiazoles / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000502:physiology*
D016229:Amyloid beta-Peptides; D052160:Benzothiazoles; D013844:Thiazoles; D016212:Transforming Growth Factor beta; C009462:thioflavin T