Transcriptional activation of Alzheimer's β-amyloid precursor protein gene by stress

• Published in: Brain research. Molecular brain research. 1995-11, Vol.33 (2), p.245-253
• Main Authors: Dewji, Nazneen N., Do, Chau, Bayney, Richard M.
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid beta-Protein Precursor - biosynthesis; Amyloid beta-Protein Precursor - genetics; Arsenites - pharmacology; Base Sequence; Biological and medical sciences; Carcinoma, Embryonal; Cell Line; Cell Nucleus - metabolism; Consensus Sequence; Fundamental and applied biological sciences. Psychology; Heat shock element; HeLa Cells; Hot Temperature; Humans; Luciferases - biosynthesis; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Plasmids; Promoter Regions, Genetic; Recombinant Fusion Proteins - biosynthesis; Restriction Mapping; Sodium Compounds - pharmacology; Stress response; Stress, Physiological; Transcription. Transcription factor. Splicing. Rna processing; Transcriptional Activation - drug effects; Transcriptional regulation; Transfection; Tumor Cells, Cultured; β-Amyloid precursor protein
• ISSN: 0169-328X; 1872-6941
• DOI: 10.1016/0169-328X(95)00131-B

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 β-amyloid peptide. Over-expression of the amyloid precursor protein (β-APP) gene could be a contributing factor in the aberrant processing of the precursor protein, possibly leading to the formation of β-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 β-APP gene, suggesting that this may act in the regulation of the β-APP gene in response to stress, an induction of β-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 β-APP with stress. In this study we have used a fragment of the β-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 β-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.