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.