PPARγ co-activator-1α (PGC-1α) reduces amyloid-β generation through a PPARγ-dependent mechanism

Katsouri, L; Parr, C; Bogdanovic, N; Willem, M; Sastre, M

Journal article

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.

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Katsouri, L., Parr, C., Bogdanovic, N., Willem, M., & Sastre, M. (2011). PPARγ co-activator-1α (PGC-1α) reduces amyloid-β generation through a PPARγ-dependent mechanism. Journal of Alzheimer's Disease, 25(1), 151–162.

MLA Style

Katsouri, L., et al. “PPARγ Co-Activator-1α (PGC-1α) Reduces Amyloid-β Generation through a PPARγ-Dependent Mechanism.” Journal of Alzheimer's Disease, vol. 25, no. 1, IOS Press, 2011, pp. 151–62.

Chicago Style

Katsouri, L, C Parr, N Bogdanovic, M Willem, and M Sastre. 2011. “PPARγ Co-Activator-1α (PGC-1α) Reduces Amyloid-β Generation through a PPARγ-Dependent Mechanism.” Journal of Alzheimer's Disease 25 (1): 151–62.
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