Regulation of BACE1 promoter activity by nuclear factor-kappaB\r\n



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The brains of Alzheimer’s disease (AD) patients display cerebrovascular and parenchymal deposits of beta-amyloid peptides, which are derived by proteolytic processing of the amyloid precursor protein (APP). The beta-site APP-cleaving enzyme 1 (BACE1) is required for the generation of beta-amyloid peptides. The NF-kappaB binding DNA consensus sequence in the BACE1 promoter upstream of the gene’s transcription start site suggests a role for NF-kappaB in the expression of neuronal brain BACE1. Failure of activation of NF-kappaB responses to stress in the aged and disregulation of NF-kappaB in the AD brain may result in part in altered NF-kappaB regulation of BACE1 and alterations in cell specific BACE1 transcription and beta-amyloid protein processing.\r\n We identified a number of putative NF-kappaB transcription factor binding sites on the rat BACE1 promoter. The effects of NF-kappaB binding to the “primary” NF-kappaB binding site of the BACE1 promoter were stimulatory for activated astrocytic cells and repressive for neuronal cells. Age-associated perturbations of NF-kappaB activation may result in increasingly aberrant regulation of beta-amyloid processing by BACE1 via changes in the cellular levels of different NF-kappaB protein subunits and cumulative increases in astrocytically-derived beta-amyloid. We confirmed the observation that in PC12 cells the overall activity of NF-kappaB and BACE1 was significantly different depending on the apoptotic initiators: H2O2 or beta-amyloid. Our results are consistent with feedback mechanisms involving beta-amyloid exposure overriding NF-kappaB regulation of BACE1 over time, a source of negative feedback, consistent with observed neuropathologies. It is also likely that a series of transcription factor binding events determine which NF-kappaB binding sites are operant and this may explain the observed cell specificity of BACE1 regulation. Our observation that BACE1 expression was affected by both soluble and aggregated insulin, coupled with our previous observations that both aggregated Abeta1-42 and Abeta42-1 affected BACE1 expression, strongly suggest that the process of protein aggregation displayed by proteins sharing specific structural characteristics (i.e. zinc stabilized hexamers) may have pathological significance. It is tempting to hypothesize that insulin, and/or other similarly structured proteins, have effects on BACE1 activity that may play a role in the establishment and/or progression of Alzheimer’s disease. \r\n



nuclear gactor-kappaB, BACE1, Alzheimer's disease