Transcriptional activation and increase in expression of Alzheimer's β-amyloid precursor protein gene is mediated by TGF-β in normal human astrocytes

Abstract

The overexpression of the Alzheimer amyloid precursor protein (APP) and its subsequent proteolytic processing may be one of several factors contributing to amyloid β-peptide (Aβ) 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-β (TGF-β) affects the expression of APP in normal human astrocytes. We report that, TGF-β 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-β 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 Aβ. In addition, we observed a significant increase in levels of TGF-β in Aβ plaques and its immediate vicinity in AD-affected brain relative to controls. These results indicate that high levels of TGF-β in the cortex, may serve to up-regulate APP synthesis in reactive astrocytes and indirectly contributes to Aβ deposition. Closely related processes may induce cerebrovascular pathology in AD brain.