Upregulation of Presenilin-2 (PS2) Gene Expression in Kainic Acid (KA) Induced Epileptogenesis in Adult Rats
Abstract number :
1.026
Submission category :
Year :
2000
Submission ID :
3143
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Nicolas G Bazan, Evgeny I Rogaev, Walter J Lukiw, LSU Neuroscience Ctr, New Orelans, LA; Molecular Brain Research Ctr, Acad of Medical Science, Moscow, Russia; Louisiana State Univ Neuroscience Ctr, New Orleans, LA.
RATIONALE: The presenilin-2 (PS2; AD4; chr1q42.1) and related homologue presenilin-1 (PS1; AD3, chr14q24.3) genes encode polytopic integral transmembrane proteins whose expression are associated with a very aggressive form of Alzheimer's disease (age of onset <70 yr). Delayed PS1 gene expression can be induced in animal retinal models of glaucoma and hypoxia triggered neovascularization, in brain hippocampus after a single electroconvulsive stimulus (ECS) or KA treatment and in IL-1 and NMDA induced human neural cells in primary culture; the role of PS2 expression in brain injury is not well understood. In this study PS2 gene expression was analyzed over a time course of 1 hr to 8 wk at the level of transcription during a KA induced epileptogenesis in adult rat hippocampus. METHODS: 1200 bp of the PS1 and PS2 gene promoters (GenBank L76518 and U50871) were computer analyzed using a DNASIS v2.6 sequence analysis package. Transcription factor (TF)-DNA binding for AP1, AP2 , STAT1, SP1, TFIID and the hypoxia inducible factor-1 (HIF-1) were analyzed using a modified gel-shift assay (Lukiw et al., PNAS 95:3914,1998). PS2 and -actin RNA abundance were analyzed by an integrated RT-PCR (Lukiw et al., JBC 274:8630, 1999). RESULTS: The PS2 promoter (-1100 to +100 bp for the primary PS2 transcript) contains abundant TF-DNA binding sites for the developmentally regulated AP2 (N=9) and HIF-1 (N=6). AP2 -DNA binding increased 6-fold at 1-3 hr and again at 72 hr and HIF-DNA binding increased 8-fold after 72 hr after KA treatment in contrast to SP1-DNA binding which showed no significant change. PS2 RNA abundance showed a sustained 13-fold increase over controls at 7 da - 8 wk post KA. CONCLUSIONS: Current evidence supports a role for PS1 expression in intercellular signaling during CNS development, apoptosis, cell fate determination, intracellular calcium homeostasis and increased PS1 expression may be a marker for the onset of neurodegenerative disease processes. Our current finding of delayed PS2 gene induction in the hippocampus of KA injected rats may represent a component of a novel signaling pathway during epileptogenesis (Supported by NIH NS23002).