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  • Title: Pituitary adenylate cyclase-activating polypeptide inhibits caspase-3 activity but does not protect cerebellar granule neurons against beta-amyloid (25-35)-induced apoptosis.
    Author: Vaudry D, Cottet-Rousselle C, Basille M, Falluel-Morel A, Fournier A, Vaudry H, Gonzalez BJ.
    Journal: Regul Pept; 2004 Dec 15; 123(1-3):43-9. PubMed ID: 15518892.
    Abstract:
    The beta-amyloid (Abeta) peptide Abeta25-35 provokes apoptosis of cerebellar granule cells through activation of caspase-3 while the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) promotes granule cell survival by inhibiting caspase-3 activation through the intrinsic apoptotic pathway. The aim of the present study was to determine whether PACAP could prevent Abeta25-35 neurotoxicity by inhibiting caspase-3 activity. A 24-h exposure of cultured cerebellar granule cells to Abeta25-35 induced shrinkage of cell bodies, neurite retraction and alteration of mitochondrial activity. Administration of graded concentrations (10-80 microM) of Abeta25-35 induced a dose-related decrease of the number of living cells, and the neurotoxic effect was highly significant after a 24-h exposure to 80 microM Abeta25-35. Exposure of cerebellar granule cells to Abeta25-35 markedly enhanced caspase-3 but not caspase-9 activity. Co-incubation with 1 microM PACAP significantly reduced Abeta25-35-evoked caspase-3 activation. In contrast, PACAP did not prevent the deleterious effects of Abeta25-35 on mitochondrial potential and granule cell survival. Taken together, these data suggest that caspase-3 activation is not the main pathway activated by Abeta25-35 that leads to granule cell death. The results also demonstrate that PACAP cannot be considered as a potent neuroprotective factor against Abeta25-35-induced apoptosis in cerebellar granule neurons.
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