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Prog Neurobiol. 2006 Jun;79(2):95-111. Epub 2006 Aug 14.

Transcriptional and translational regulation of BACE1 expression--implications for Alzheimer's disease.

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  • 1Paul Flechsig Institute for Brain Research, Department of Neurochemistry, University of Leipzig, Jahnallee 59, 04109 Leipzig, Germany. rossn@medizin.uni-leipzig.de <rossn@medizin.uni-leipzig.de>

Abstract

The proteolytical processing of the amyloid precursor protein (APP) gives rise to beta-amyloid peptides, which accumulate in brains of Alzheimer's disease (AD) patients. Different soluble or insoluble higher molecular weight forms of beta-amyloid peptides have been postulated to trigger a complex pathological cascade that may cause synaptic dysfunction, inflammatory processes, neuronal loss, cognitive impairment, and finally the onset of the disease. The generation of beta-amyloid peptides requires the proteolytical cleavage of APP by an aspartyl protease named beta-site APP-cleaving enzyme 1 (BACE1). The expression and enzymatic activity of BACE1 are increased in brains of AD patients. Here we discuss the importance of a number of recently identified transcription factors as well as post-transcriptional modifications and activation of intracellular signaling molecules for the regulation of BACE1 expression in brain. Importantly, some of these factors are known to be involved in the inflammatory and chronic stress responses of the brain, which are compromised during aging. Moreover, recent evidence indicates that beneficial effects of non-steriodal anti-inflammatory drugs on the progression of AD are mediated--at least in part--by effects on the peroxisome proliferator-activated receptor-gamma response element present in the BACE1 promoter. The identification of the cell type-specific expression and activation of NF-kappaB, Sp1 and YY1 transcription factors may provide a basis to specifically interfere with BACE1 expression and, thereby, to lower the concentrations of beta-amyloid peptides, which may prevent neuronal cell loss and cognitive decline in AD patients.

PMID:
16904810
[PubMed - indexed for MEDLINE]
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