TY  - JOUR
AU  - Katsouri, Loukia
AU  - Parr, Callum
AU  - Bogdanovic, Nenad
AU  - Willem, Michael
AU  - Sastre, Magdalena
TI  - PPARγ co-activator-1α (PGC-1α) reduces amyloid-β generation through a PPARγ-dependent mechanism.
JO  - Journal of Alzheimer's disease
VL  - 25
IS  - 1
SN  - 1875-8908
CY  - Amsterdam
PB  - IOS Press
M1  - DZNE-2020-02591
SP  - 151-162
PY  - 2011
AB  - 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.
KW  - Aged
KW  - Aged, 80 and over
KW  - Alzheimer Disease: metabolism
KW  - Alzheimer Disease: pathology
KW  - Amyloid beta-Peptides: antagonists & inhibitors
KW  - Amyloid beta-Peptides: biosynthesis
KW  - Animals
KW  - Cell Line, Tumor
KW  - Down-Regulation: physiology
KW  - Female
KW  - Heat-Shock Proteins: antagonists & inhibitors
KW  - Heat-Shock Proteins: physiology
KW  - Humans
KW  - Male
KW  - Mice
KW  - Middle Aged
KW  - PPAR gamma: physiology
KW  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
KW  - Transcription Factors: antagonists & inhibitors
KW  - Transcription Factors: physiology
KW  - Amyloid beta-Peptides (NLM Chemicals)
KW  - Heat-Shock Proteins (NLM Chemicals)
KW  - PPAR gamma (NLM Chemicals)
KW  - PPARGC1A protein, human (NLM Chemicals)
KW  - Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (NLM Chemicals)
KW  - Transcription Factors (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:21358044
DO  - DOI:10.3233/JAD-2011-101356
UR  - https://pub.dzne.de/record/136269
ER  -