TRANSCRIPTIONAL ACTIVATION OF ALZHEIMERS BETA-AMYLOID PRECURSOR PROTEIN GENE BY STRESS

A neuropathological hallmark of Alzheimer's disease (AD) is the neuritic plaque, composed of an extracellular cluster of degenerating nerve terminals with a central core that is in part composed of deposits of a 4 kDa beta-amyloid peptide. Over-expression of the amyloid precursor protein ( beta-APP) gene could be a contributing factor in the aberrant processing of the precursor protein, possibly leading to the formation of beta-amyloid. In AD the brain exhibits several features which indicate that neurons affected by AD exist under conditions of stress. Although the heat shock consensus sequence (CTCGACTTTTCTAG) located at position -317 bp is among the regulatory elements of the beta-APP gene, suggesting that this may act in the regulation of the beta-APP gene in response to stress, an induction of beta-APP as a result of interaction of this element with a heat shock factor has so far not been demonstrated. Moreover, there are conflicting reports in the literature regarding the up-regulation of beta-APP with stress. In this study we have used a fragment of the beta-APP promoter which includes the heat shock element, cloned into a luciferase expression vector pxP2 to transiently transfect cultured human NT2 and HeLa cells. Our findings directly demonstrate that transcription of the beta-APP gene is stimulated by various stresses -increase in temperature, treatment with ethanol and sodium arsenite. Gel mobility shift assays confirm the interaction of the heat shock element with a heat shock factor, induced as a result of stress.