Transcriptional activation of Alzheimer's 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.
Dewji
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Department of Medicine, University of California at San Diego, La Jolla 92093, USA.
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Bayney
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D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis* / Q000235:genetics; D018053:Arsenites / Q000494:pharmacology; D001483:Base Sequence; D018236:Carcinoma, Embryonal; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D016384:Consensus Sequence; D006367:HeLa Cells; D006358:Hot Temperature; D006801:Humans; D008156:Luciferases / Q000096:biosynthesis; D008969:Molecular Sequence Data; D010957:Plasmids; D011401:Promoter Regions, Genetic; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D015183:Restriction Mapping; D017670:Sodium Compounds / Q000494:pharmacology; D013312:Stress, Physiological; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014407:Tumor Cells, Cultured
D016564:Amyloid beta-Protein Precursor; D018053:Arsenites; D011993:Recombinant Fusion Proteins; D017670:Sodium Compounds; C017947:sodium arsenite; D008156:Luciferases