Affiliations: [a] Centre for Neuroscience, Division of Experimental Medicine, Imperial College London, London, UK | [b] Department for Neurobiology, Caring Science and Society Division of Clinical Geriatrics Karolinska Institutet, Stockholm, Sweden | [c] German Center for Neurodegenerative Diseases (DZNE) & Adolf-Butenandt-Institute, Biochemistry, Ludwig-Maximilians-University Munich, Munich, Germany
Correspondence:
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Correspondence to: Magdalena Sastre, Centre for Neuroscience, Division of Experimental Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK. Tel.: +44 2075946673; Fax: +44 2075946548; E-mail: [email protected].
Note: [1] These authors contributed equally to this work.
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.
