Poster Presentations

Session Title: Inflammation
Presentation Date: Friday, March 14 – Saturday, March 15, 2009

AMYLOID-BETA PEPTIDE INDUCES HIF TRANSCRIPTION FACTOR AND VEGF EXPRESSION IN CULTURED NORMAL ADULT HUMAN ASTROCYTES

A. Chiarini¹, U. Armato¹, M. Marconi¹, R. Pacchiana¹, C. Bonafini¹, B. Chakravarthy², J.F. Whitfield², I. Dal Pra^1
1Histology & Embryology, Biomedical & Surgical Sciences, Verona, Italy, ²Biological Sciences, National Reasearch Council of Canada, Ottawa, Canada

Little is known about glial cells´ roles in human late-onset Alzheimer's Disease (LOAD). Therefore, we have explored possible roles of astrocytes in amyloid-beta (A-beta)-driven LOAD using cultures of primary, stably differentiated astrocytes from adult human temporal cortex. It has been shown that astrocytes express immunoreactive VEGF in human AD brains and that injected A-beta stimulates VEGF expression by rat hippocampal astrocytes. Since the principal activator of VEGF expression is the hypoxia-inducible heterodimeric HIF-1alpha·ARNT1 factor, A-beta might stimulate HIF and with it VEGF production. Indeed, A-beta strongly stimulates our cultured normal human astrocytes to make VEGF and 20 microM A-beta(25-35), the A-beta active fragment, rapidly and strongly induces these astrocytes to make both HIF-1alpha and ARNT1 subunits. The simultaneous addition of three proinflammatory cytokines, IL-1beta, TGF-alpha and IFN-gamma, which are made in the AD brain, enhanced but did not by themselves significantly stimulate, the HIF subunits expression. This is the first evidence linking the induction of HIF-1alpha and ARNT1 to the exposure of human adult astrocytes to A-beta peptides. The present findings open a new avenue to a better understanding of the pathophysiology of human adult astrocytes in AD. Thus, a surge of A-beta-induced HIF-mediated VEGF in the AD brain could stimulate the proliferation of neuronal progenitor cells and neurogenesis in the adult hippocampal granular cell zone. Also since HIF binds to the BACE-1 gene's HIF-responsive element, A-beta stimulation of HIF expression could accelerate LOAD development by inducing astrocytes that are associated with neurons to become dangerous A-beta producers.