Etazolate, a neuroprotective drug linking GABA(A) receptor pharmacology to amyloid precursor protein processing |
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Authors: | Marcade Maryline Bourdin Jérôme Loiseau Nadia Peillon Hélène Rayer Aurélie Drouin Dominique Schweighoffer Fabien Désiré Laurent |
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Affiliation: | Department of Neurology, ExonHit Therapeutics, Paris, France |
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Abstract: | Pharmacological modulation of the GABAA 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 α-secretase pathway decreases in AD, concurrent with cognitive impairment. This APP cleavage occurs within the β-amyloid peptide (Aβ) sequence, precluding formation of amyloidogenic peptides and leading to the release of the soluble N-terminal APP fragment (sAPPα) which is neurotrophic and procognitive. In this study, we show that at nanomolar-low micromolar concentrations, etazolate, a selective GABAA receptor modulator, stimulates sAPPα production in rat cortical neurons and in guinea pig brains. Etazolate (20 nM–2 μM) dose-dependently protected rat cortical neurons against Aβ-induced toxicity. The neuroprotective effects of etazolate were fully blocked by GABAA receptor antagonists indicating that this neuroprotection was due to GABAA receptor signalling. Baclofen, a GABAB receptor agonist failed to inhibit the Aβ-induced neuronal death. Furthermore, both pharmacological α-secretase pathway inhibition and sAPPα immunoneutralization approaches prevented etazolate neuroprotection against Aβ, indicating that etazolate exerts its neuroprotective effect via sAPPα induction. Our findings therefore indicate a relationship between GABAA receptor signalling, the α-secretase pathway and neuroprotection, documenting a new therapeutic approach for AD treatment. |
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Keywords: | alpha secretase Alzheimer's disease amyloid β protein etazolate GABA soluble APP ectodomain |
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