Role of Alzheimer's Amyloid-P Peptide as a Putative Transcription Factor

摘要

The amyloid plaque invariably deposited in Alzheimer's disease (AD) is mostly composed of a 40-42 amino acid p-amyloid peptide (Aβ) [1]. Our goal is to understand the physiological and pathological function of Aβ, including its interaction with other molecules. While nonpathological function for this peptide is poorly understood, Aβ has been shown to induce an increase in levels of the p53 apoptosis-associated protein (gene name P53). Furthermore, this induction was due to direct action of Aβ upon the P53 promoter, with Aβ binding located to a specific decamer within a known heat shock element (HSE) [2]. We undertook a search for similar sequences in the 5'-flanking sequence of the Aβ precursor protein (APP), apolipoprotein E (APOE), and p-site APP-cleaving enzyme (BACE1) genes, which are intimately involved in pathogenesis of AD [1]. We generated specific oligomers, and investigated interaction with the Aβ1-42 and 1-40 peptides. The sequences of interacting oligomers were used to generate a consensus sequence "GGATKGGGGT" and a similarity matrix. A single-base mutation in one of the Ap-binding APP oligomers markedly reduced binding with the Aβ1-42 and 1-40 peptides. We investigated the regions of the Ap peptide that would bind the DNA decamer and determined that maximum binding was obtained with the cytotoxic Aβ25-35 peptide.