Transcriptional activation and increase in expression of Alzheimer's beta-amyloid precursor protein gene is mediated by TGF-beta in normal human astrocytes.
The overexpression of the Alzheimer amyloid precursor protein (APP) and its subsequent proteolytic processing may be one of several factors contributing to amyloid beta-peptide (Abeta) deposition in plaques and microvasculature in Alzheimer's disease (AD) brain. Cytokines and growth factors can influence the expression of APP in response to brain injury, but the underlying mechanisms are largely unknown. We examined the mechanisms by which transforming growth factor-beta (TGF-beta) affects the expression of APP in normal human astrocytes. We report that, TGF-beta up-regulated the expression of APP at the transcription level as determined by nuclear run-on experiments. Transient transfection of astrocytes with APP gene promoter (-2832 bp) chloramphenicol acetyltransferase (CAT) reporter constructs led to increased reporter activity upon TGF-beta stimulation. This reporter activity was mainly attributed to the APP proximal domain (-488 bp). The increase in APP gene transcription was associated with significant accumulation of intracellular APP, APP carboxyl terminal derived fragments, and total secreted Abeta. In addition, we observed a significant increase in levels of TGF-beta in Abeta plaques and its immediate vicinity in AD-affected brain relative to controls. These results indicate that high levels of TGF-beta in the cortex, may serve to up-regulate APP synthesis in reactive astrocytes and indirectly contributes to Abeta deposition. Closely related processes may induce cerebrovascular pathology in AD brain.
Burton
Teralee
T
The Dr. John Foerster Centre for Health Research on Aging, St. Boniface General Hospital Research Centre, 351 Taché Avenue, Winnipeg, MB, Canada R3T 3B3.
Liang
Binhua
B
Dibrov
Alex
A
Amara
Francis
F
D000544:Alzheimer Disease / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D001253:Astrocytes / Q000378:metabolism*; D015152:Blotting, Northern; D001921:Brain / Q000196:embryology / Q000378:metabolism / Q000473:pathology; D002455:Cell Division; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D007150:Immunohistochemistry; D010957:Plasmids / Q000378:metabolism; D012313:RNA / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
D016564:Amyloid beta-Protein Precursor; D016212:Transforming Growth Factor beta; D012313:RNA