Potential of transcriptional coordination of nine genes associated with Alzheimer's disease

A comparative analysis of transcription factor- (TF-) DNA binding consensus sequences, DNA sequence characteristics, nuclear scaffold/matrix attachmen t regions (S/MARs) and related transcription initiator elements was underta ken within the immediate promoters of 9 genes implicated in the pathogenesi s of Alzheimer's disease (AD). Human-specific gene promoter sequences were analyzed for the early onset familial AD (FAD) genes beta-amyloid precursor protein (beta APP), presenilin-1 (PS1), presenilin-2 (PS2), the late onset FAD gene apolipoprotein E (apoE), the sporadic AD (SAD) genes neurofilamen t light chain (NFL), synaptobrevin (SYNb), synaptophysin (SYNp), synapsin ( SYNs) and the inducible neuroinflammatory (NIF) and oxidoreductase gene cyc looxygenase-2 (COX-2) from -1100 bp to +100 bp past the major start of tran scription at +1. All genes implicated in early or late onset FAD, SAD or NI F mechanisms originate from a diverse set of chromosomes and represent both inducible, TATA-box-containing and G+C-rich housekeeping gene promoters. D isease linkage to diverse chromosomal elements in all AD genes currently kn own strengthens the idea that the molecular basis for AD pathogenesis is ge netically heterogeneous. However, the data presented here suggests certain underlying conformities as to the nature of the control of expression of al l AD-associated genes. Firstly, and except for PS2 RNA message (half-life > >12 hr) and the internal control alpha-tubulin RNA message (half-life >>32 hr), mRNAs encoded by the AD genes have relatively short-to-medium half-liv es ranging from 1-8 hr, indicating a potentially rapid rate of information signaling. All 9 genes studied encode membrane-integral or membrane-associa ted proteins and are implicated in various aspects of synaptic plasticity ( SP); at least 3 (PS1, PS2 and COX-2) are potentially hypoxia sensitive and contain multiple hypoxia inducible factor- (HIF-) DNA binding sites; 2 syna ptosomal SAD genes are X-chromosome linked. All 9 FAD, SAD and NIF gene 5' regulatory regions studies are related by the fact that each possess common activator/stimulatory protein AP1, AP1-like or STAT-1 (GAS) DNA binding si tes; 8 of the 9 AD promoters contain AP2 or NF-kappa B recognition sites, 6 of the 9 contain at least one SP1-DNA binding site and 4 of the 9 contain DNA sequences homologous to the synaptophysin-neurofilament-nerve growth fa ctor (SNN) consensus, a brain-specific regulatory element. The human TFs AP 1, NF-kappa B and STAT-1 (GAS) have been implicated in the activation and p roliferation of a brain-specific inflammatory response. Brain gene promoter s containing AP1, AP1-like, AP2, HIF, NF-kappa B, SP1, STAT-1(GAS) and/or S NN consensus sequences may represent a family of related gene regulatory el ements targeted for dysfunction during AD pathogenesis.