Alzheimer's disease (AD) is characterized neuropathologically by the extracellular deposition of the 4 kDa b-amyloid peptide (Ab), a 39-43 amino acid peptide that is neurotoxic (Borchelt et al. 1996) and accumulates in neuritic plaques and in cerebral and meningeal microvessels (Wahrle et al. 2002). Amyloid precursor protein (APP) is the precursor of Ab and can be processed via alternative pathways. A nonamyloidogenic secretory pathway includes cleavage of APP to soluble APP (sAPPa) by a-secretases from the a disintegrin and metalloprotease (ADAM) family of proteases within the Ab peptide sequence, thus precluding the formation of Ab. In contrast, the formation of the amyloidogenic Ab peptides is regulated by the sequential action of b-and c-secretases (Checler 1995;Nunan and Small 2000). A primary strategy proposed to treat AD is to prevent the formation of Ab peptides, and their deposition as senile plaques in the brain. Recently, Postina et al. (2004) showed that activation of a-secretase significantly reduces AD-like pathology in an animal model of AD. This raises the possibility that a pharmacological approach to increase a-secretase activity and sAPPa levels, and thus reduce Ab formation may be suitable for AD treatment (Bandyopadhyay et al. 2007).This approach is consistent with the observation that profound changes occur in APP processing with aging and the development of AD. In particular, a reduction in the activity of the non-amyloidogenic pathway leading to Received February 7, 2008; revised manuscript received March 6, 2008; accepted March 28, 2008. Address correspondence and reprint requests to Laurent Désiré, Department of Neurology, Exonhit Therapeutics, 63 Bd Massena, 75013 Paris, France. E-mail: laurent.desire@exonhit.comAbbreviations used: Ab, beta amyloid; ADAM, a disintegrin and metalloprotease; AD, Alzheimer's Disease; APP, amyloid precursor protein; BACE, beta-site APP-cleaving enzyme; DAPT, N-[N-(3,5-difluorophenacetyl-L-alanyl)]-S-phenylglycine t-butyl ester; IP, immunoprecipitation; LTP, long-term potentiation; PDE4, phosphodiesterase 4; PTX, picrotoxin; sAPPa, soluble APP ectodomain; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel electrophoresis; TAPI-1, TNF-a Protease Inhibitor-1.
AbstractPharmacological modulation of the GABA A receptor has gained increasing attention as a potential treatment for central processes affected in Alzheimer disease (AD), including neuronal survival and cognition. The proteolytic cleavage of the amyloid precursor protein (APP) through the a-secretase pathway decreases in AD, concurrent with cognitive impairment. This APP cleavage occurs within the b-amyloid peptide (Ab) sequence, precluding formation of amyloidogenic peptides and leading to the release of the soluble N-terminal APP fragment (sAPPa) which is neurotrophic and procognitive. In this study, we show that at nanomolar-low micromolar concentrations, etazolate, a selective GABA A receptor modulator, stimulates sAPPa production in rat cortical neurons and in guinea pig brains. Etazolate (20 ...