Aminopeptidase A contributes to the N-terminal truncation of amyloid beta-peptide. - Université Paris Cité Accéder directement au contenu
Article Dans Une Revue Journal of Neurochemistry Année : 2009

Aminopeptidase A contributes to the N-terminal truncation of amyloid beta-peptide.

Résumé

Several lines of data previously indicated that N-terminally truncated forms of amyloid-beta (Abeta) peptides are likely the earliest and more abundant species immunohistochemically detectable in Alzheimer's disease-affected brains. It is noteworthy that the free N-terminal residue of full-length Abeta (fl-Abeta) is an aspartyl residue, suggesting that Abeta could be susceptible to exopeptidasic attack by aminopeptidase A (APA)-like proteases. In this context, we have examined whether APA could target Abeta peptides in both cell-free and cellular models. We first show that the general aminopeptidase inhibitor amastatin as well as two distinct aminopeptidase A inhibitors EC33 and pl302 both significantly increase the recovery of genuine fl-Abeta peptides generated by cells over-expressing Swedish-mutated beta amyloid precursor protein (APP) while the aminopeptidase N blocker pl250 did not modify fl-Abeta recovery. In agreement with this observation, we establish that over-expressed APA drastically reduces, in a calcium dependent manner, fl-Abeta but not APP IntraCellular Domain in a cell-free model of Abeta production. In agreement with the above data, we show that recombinant APA degrades fl-Abeta in a pl302-sensitive manner. Interestingly, we also show that EC33 and pl302 lower staurosporine-stimulated activation of caspase-3 in wild-type fibroblasts but not in betaAPP/beta-amyloid precursor protein-like protein 2 (APLP2) double knockout fibroblasts, suggesting that protecting endogenous fl-Abeta physiological production triggers neuroprotective phenotype. By contrast, EC33 does not modify staurosporine-induced caspase-3 activation in wild-type and Swedish-mutated betaAPP-HEK293 expressing cells that display exacerbated production of Abeta. Overall, our data establish that APA contributes to the N-terminal truncation of Abeta and suggest that this cleavage is likely abrogating a protective function associated with physiological but not supraphysiological levels of genuine fl-Abeta peptides.

Dates et versions

hal-00418760 , version 1 (21-09-2009)

Identifiants

Citer

Jean Sevalle, Audrey Amoyel, Philippe Robert, Marie-Claude Fournié-Zaluski, Bernard P. Roques, et al.. Aminopeptidase A contributes to the N-terminal truncation of amyloid beta-peptide.. Journal of Neurochemistry, 2009, 109 (1), pp.248-56. ⟨10.1111/j.1471-4159.2009.05950.x⟩. ⟨hal-00418760⟩
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