Session Title: Inflammation
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 Pra1
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.