Abstracts

RATIONALE: Presenilins-1 and -2 (PS1, PS2) represent a discrete class of integral membrane-spanning glycoproteins that transduce intercellular signals associated with neural cell and synapse development. PS1 and PS2 also appear to play a role in the proliferation of synaptic contacts and the expansion of neuronal circuitry and also act as catalytic cofactors for the secretase activities associated with the generation of cytotoxic forms of [beta]-amyloid. These and related pro-inflammatory peptides in turn are key players in inducing neural cellular dysfunction and neuronal degeneration. In the current studies we examined the levels of PS1 and/or PS2 gene transcription, and the transcription factors (TFs) which regulate their expression in a rodent model of epileptogenesis employing kainate (KA) as the epileptogenic trigger.
METHODS: Adult male albino Wistar rats were treated i.p.with 10 mg/kg KA for 0, 1, 3, 6 hours, 1, 3, 7 days and 2, 4 and 8 weeks. Rat hippocampal and cerebrocortical nuclear protein extracts (NPXTs) and total RNA were prepared using established protocols (Lukiw et al., Neuroreport 12:53-57, 2001). Similarly, rat retinal and AD hippocampal NPXTs and total RNA were isolated in parallel studies (Lukiw et al., J. Biol. Chem 274:8630-8638, 1999). TF-DNA binding was analyzed by gel-shift assay and PS1 and/or PS2 levels were quantitated using RT-PCR and immunocytochemistry. Data were analyzed for statistical significance using analysis of variance (ANOVA).
RESULTS: PS1 and PS2 gene transcription and AP2[alpha]- and HIF-1[alpha]-DNA binding increased in parallel in KA triggered rodents. Retinal cells of rodents undergoing a progressive retinopathy after exposure to hypoxia and the hippocampal CA1 and Brodman area 22 association neocortex of Alzheimer[ssquote]s disease (AD)-affected humans showed strikingly similar changes. In each case up-regulation of PS gene expression was accompanied by a parallel induction of the oxygen-sensitive TFs AP2[alpha] and HIF-1[alpha], DNA-binding proteins known to promote PS gene transcription.
CONCLUSIONS: Accelerated changes in PS gene expression which accompany KA-induced epileptogenesis and retinal, hippocampal and neocortical degeneration may be part of a neural genetic program directing cellular fate towards synaptic plasticity changes and intercellular signaling dysfunction.
Support: NIH NS23002, AG18031 and the EENT Foundation.