TMP21 regulates Aβ production but does not affect caspase-3, p53, and neprilysin

Abstract

The presenilin (PS)-dependent γ-secretase activity refers to a high molecular mass-complex including, besides PS1 or PS2, three other proteins recently identified, namely nicastrin, Aph-1, and Pen-2. This proteolytic complex has been shown to contribute to both γ- and ε-cleavages of the β-amyloid precursor protein (βAPP), thereby generating β-amyloid peptides (Aβ) and the APP intracellular domain (AICD), respectively. TMP21, a member of the p24 cargo protein family, was recently shown to interact with PS complexes. Interestingly, TMP21 modulates γ-secretase-mediated Aβ production but does not regulate ε-secretase-derived AICD formation [F. Chen, H. Hasegawa, G. Schmitt-ulms, T. Kawarai, C. Bohm, T. Katayama, Y. Gu, N. Sanjo, M. Glista, E. Rogaeva, Y. Wakutami, R. Pardossi-Piquard, X. Ruan, A. Tandon, F. Checler, P. Marambaud, K. Hansen, D. Westaway, P. St. George-Hyslop, P. Fraser, TMP21 is a presenilin complex component that modulates γ- but not ε-secretase activities, Nature 440 (2006) 1208–1212]. Here we investigate the functional incidence of the over-expression or depletion of TMP21 on both intracellular and secreted Aβ recoveries and AICD-associated phenotypes. First we confirm that TMP21 depletion yields increased levels of secreted Aβ40. However, we demonstrate that both staurosporine-stimulated caspase-3 activation, p53 and neprilysin expression and activity were not affected by TMP21 over-expression or depletion. Overall, our functional data further reinforce the view that TMP21 behaves as a regulator of γ- but not ε-cleavages generated by PS-dependent γ-secretase complex.