The Alzheimer's amyloid beta-peptide (Abeta) binds a specific DNA Abeta-interacting domain (AbetaID) in the APP, BACE1, and APOE promoters in a sequence-specific manner: characterizing a new regulatory motif.

摘要

Deposition of extracellular plaques, primarily consisting of amyloid beta peptide (Abeta), in the brain is the confirmatory diagnostic of Alzheimer's disease (AD); however, the physiological and pathological role of Abeta is not fully understood. Herein, we demonstrate novel Abeta activity as a putative transcription factor upon AD-associated genes. We used oligomers from 5'-flanking regions of the apolipoprotein E (APOE), Abeta-precursor protein (APP) and beta-amyloid site cleaving enzyme-1 (BACE1) genes for electrophoretic mobility shift assay (EMSA) with different fragments of the Abeta peptide. Our results suggest that Abeta bound to an Abeta-interacting domain (AbetaID) with a consensus of "KGGRKTGGGG". This peptide-DNA interaction was sequence specific, and mutation of the first "G" of the decamer's terminal "GGGG" eliminated peptide-DNA interaction. Furthermore, the cytotoxic Abeta25-35 fragment had greatest DNA affinity. Such specificity of binding suggests that the AbetaID is worth of further investigation as a site wherein the Abeta peptide may act as a transcription factor.