Nimodipine selectively stimulates β-amyloid 1–42 secretion by a mechanism independent of calcium influx blockage

Abstract

Several lines of evidence indicate that perturbed cellular Ca 2+ homeostasis may play a prominent role in synaptic dysfunction and neuronal death in Alzheimer's disease (AD), suggesting a potential benefit of drugs capable to stabilize Ca 2+ homeostasis. We here investigated the effects of a panel of L-type Ca 2+ channel antagonists on the secretion of the amyloid β-peptide (Aβ), which abnormally accumulates in the senile plaques of the brain of AD patients. We found that, in primary and immortalized neuronal cells in culture, nimodipine robustly stimulated secretion (up to about four-fold at 30 μM) of the highly amyloidogenic 42-residue isoform of Aβ (Aβ42), while leaving largely unaffected total Aβ secretion. An analogous effect was also observed in vivo , as the administration of a single dose of nimodipine (10 mg/kg i.p.) induced a significant rise of Aβ42 levels in plasma of Tg2576 mice. The effect of nimodipine was independent of blockage of L-type Ca 2+ channels and capacitative calcium entry. Accordingly, nimodipine effect was largely Ca 2+-independent, as neither depletion nor rise of extracellular Ca 2+ abolished it. Hence, by showing that the effect of nimodipine on Aβ42 production is distinct from its ability to block Ca 2+-influx pathways, we provide evidence for a previously uncharacterized effect of this long known molecule also used in clinical practice.