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Article type: Research Article
Authors: Espuny-Camacho, Iraa; b | Dominguez, Dianaa; b | Merchiers, Pascalc | Rompaey, Luc Vanc | Selkoe, Dennisd | Strooper, Bart Dea; b; *
Affiliations: [a] Center for Human Genetics, KU Leuven, Leuven, Belgium | [b] Department of Developmental and Molecular Genetics, VIB, Leuven, Belgium | [c] Galapagos Genomics NV, Mechelen, Belgium | [d] Department of Neurology, Harvard Medical School and Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, MA, USA
Correspondence: [*] Correspondence to: Bart De Strooper, KU Leuven, Leuven, Belgium. Tel.: +3216346227; Fax: +321634718; E-mail: [email protected].
Abstract: Peroxisome proliferator-activated receptor gamma (PPARγ) activation results in an increased rate of amyloid-β (Aβ) clearance from the media of diverse cells in culture, including primary neurons and glial cells. Here, we further investigate the mechanism for Aβ clearance and found that PPARγ activation modulates a cell surface metalloprotease that can be inhibited by metalloprotease inhibitors, like EDTA and phenanthroline, and also by the peptide hormones insulin and glucagon. The metalloprotease profile of the Aβ-degrading mechanism is surprisingly similar to insulin-degrading enzyme (IDE). This mechanism is maintained in hippocampal and glia primary cultures from IDE loss-of-function mice. We conclude that PPARγ activates an IDE-like Aβ degrading activity. Our work suggests a drugable pathway that can clear Aβ peptide from the brain.
Keywords: Amyloid-β (Aβ) clearance, insulin-degrading enzyme (IDE), metalloprotease, peroxisome proliferator-activated receptor gamma (PPARγ)
DOI: 10.3233/JAD-2010-091633
Journal: Journal of Alzheimer's Disease, vol. 20, no. 4, pp. 1119-1132, 2010
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