Journal Article

DZNE-2020-02591

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png PPARγ co-activator-1α (PGC-1α) reduces amyloid-β generation through a PPARγ-dependent mechanism.

Katsouri, L. ; Parr, C. ; Bogdanovic, N. ; Willem, M.DZNE* ; Sastre, M. (Corresponding author)

2011
IOS Press Amsterdam

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Please use a persistent id in citations: doi:10.3233/JAD-2011-101356

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.

Keyword(s): Aged (MeSH) ; Aged, 80 and over (MeSH) ; Alzheimer Disease: metabolism (MeSH) ; Alzheimer Disease: pathology (MeSH) ; Amyloid beta-Peptides: antagonists & inhibitors (MeSH) ; Amyloid beta-Peptides: biosynthesis (MeSH) ; Animals (MeSH) ; Cell Line, Tumor (MeSH) ; Down-Regulation: physiology (MeSH) ; Female (MeSH) ; Heat-Shock Proteins: antagonists & inhibitors (MeSH) ; Heat-Shock Proteins: physiology (MeSH) ; Humans (MeSH) ; Male (MeSH) ; Mice (MeSH) ; Middle Aged (MeSH) ; PPAR gamma: physiology (MeSH) ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha (MeSH) ; Transcription Factors: antagonists & inhibitors (MeSH) ; Transcription Factors: physiology (MeSH) ; Amyloid beta-Peptides ; Heat-Shock Proteins ; PPAR gamma ; PPARGC1A protein, human ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha ; Transcription Factors

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Contributing Institute(s):

1. Ext Ludwig-Maximilians-University (Ext LMU)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2011

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF < 5 ; JCR ; NCBI Molecular Biology Database ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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