title: PPARγ co-activator-1α (PGC-1α) reduces amyloid-β generation through a PPARγ-dependent mechanism.
abstract: We have previously reported that the nuclear receptor peroxisome proliferator activated receptor-γ (PPARγ) regulates the transcription of β-secretase (BACE1), a key enzyme involved in amyloid-β (Aβ) generation. Here, we aimed to investigate the role of PPARγ coactivator-1α (PGC-1α), which controls major metabolic functions through the co-activation of PPARγ and other transcription factors. Western blotting experiments with nuclear extracts from brain cortex of AD cases and controls showed a reduction in the levels of PGC-1α in AD patients. PGC-1α overexpression in N2a neuroblastoma cells induced a decrease in the levels of secreted Aβ and an increase in the levels of non-amyloidogenic soluble AβPPα. The decrease in Aβ after exogenous expression of PGC-1α was a consequence of reduced BACE1 expression and transcription, together with a decrease in BACE1 promoter activity. In addition, we detected a significant reduction in β-secretase activity by measuring the levels of β-carboxy terminus fragment (β-CTFs) and by using a commercial assay for β-secretase. In contrast, down-regulation of PGC-1α levels by transfection with PGC-1α siRNA increased BACE1 expression. These effects appeared to be dependent on PPARγ, because PGC-1α did not affect Aβ and BACE1 levels in N2a cells transfected with PPARγ siRNA or in PPARγ knockout fibroblasts. In conclusion, since PGC-1α appears to decrease Aβ generation, therapeutic modulation of PGC-1α could have real potential as a treatment for AD.
authors.affiliation: Centre for Neuroscience, Division of Experimental Medicine, Imperial College London, London, UK.
authors.forename: Loukia
authors.initials: L
authors.lastname: Katsouri
authors.forename: Callum
authors.initials: C
authors.lastname: Parr
authors.forename: Nenad
authors.initials: N
authors.lastname: Bogdanovic
authors.forename: Michael
authors.initials: M
authors.lastname: Willem
authors.forename: Magdalena
authors.initials: M
authors.lastname: Sastre
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D000818:Animals; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000502:physiology; D005260:Female; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D047495:PPAR gamma / Q000502:physiology*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D016229:Amyloid beta-Peptides; D006360:Heat-Shock Proteins; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors