%0 Journal Article
%A Katsouri, Loukia
%A Parr, Callum
%A Bogdanovic, Nenad
%A Willem, Michael
%A Sastre, Magdalena
%T PPARγ co-activator-1α (PGC-1α) reduces amyloid-β generation through a PPARγ-dependent mechanism.
%J Journal of Alzheimer's disease
%V 25
%N 1
%@ 1875-8908
%C Amsterdam
%I IOS Press
%M DZNE-2020-02591
%P 151-162
%D 2011
%X 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.
%K Aged
%K Aged, 80 and over
%K Alzheimer Disease: metabolism
%K Alzheimer Disease: pathology
%K Amyloid beta-Peptides: antagonists & inhibitors
%K Amyloid beta-Peptides: biosynthesis
%K Animals
%K Cell Line, Tumor
%K Down-Regulation: physiology
%K Female
%K Heat-Shock Proteins: antagonists & inhibitors
%K Heat-Shock Proteins: physiology
%K Humans
%K Male
%K Mice
%K Middle Aged
%K PPAR gamma: physiology
%K Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
%K Transcription Factors: antagonists & inhibitors
%K Transcription Factors: physiology
%K Amyloid beta-Peptides (NLM Chemicals)
%K Heat-Shock Proteins (NLM Chemicals)
%K PPAR gamma (NLM Chemicals)
%K PPARGC1A protein, human (NLM Chemicals)
%K Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (NLM Chemicals)
%K Transcription Factors (NLM Chemicals)
%F PUB:(DE-HGF)16
%9 Journal Article
%$ pmid:21358044
%R 10.3233/JAD-2011-101356
%U https://pub.dzne.de/record/136269