Role of peroxisome proliferator-activated receptor gamma in amyloid precursor protein processing and amyloid beta-mediated cell death.
Recent data indicate that PPARgamma (peroxisome proliferator-activated receptor gamma) could be involved in the modulation of the amyloid cascade causing Alzheimer's disease. In the present study we show that PPARgamma overexpression in cultured cells dramatically reduced Abeta (amyloid-beta) secretion, affecting the expression of the APP (Abeta precursor protein) at a post-transcriptional level. APP down-regulation did not involve the pathway of the secretases and correlated with a significant induction of APP ubiquitination. Additionally, we demonstrate that PPARgamma was able to protect the cells from H(2)O(2)-induced necrosis by decreasing Abeta secretion. Taken together, our results indicate a novel mechanism at the basis of the neuroprotection shown by PPARgamma agonists and an additional pathogenic role for Abeta accumulation.
d'Abramo
Cristina
C
Department of Experimental Medicine, University of Genoa, 16132 Genoa, Italy.
Massone
Sara
S
Zingg
Jean-Marc
JM
Pizzuti
Antonio
A
Marambaud
Philippe
P
Dalla Piccola
Bruno
B
Azzi
Angelo
A
Marinari
Umberto M
UM
Pronzato
Maria A
MA
Ricciarelli
Roberta
R
D000544:Alzheimer Disease / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation; D006801:Humans; D006861:Hydrogen Peroxide; D009336:Necrosis; D047495:PPAR gamma / Q000819:agonists / Q000378:metabolism*; D011499:Protein Processing, Post-Translational; D034622:RNA Interference
D016564:Amyloid beta-Protein Precursor; D047495:PPAR gamma; D006861:Hydrogen Peroxide