Tripchlorolide Attenuates [beta]-amyloid Generation via Suppressing PPAR[gamma]-Regulated BACE1 Activity in N2a/APP695 Cells

• Published in: Molecular neurobiology 2016-11, Vol.53 (9), p.6397
• Main Authors: Lin, Nan, Chen, Li-min, Pan, Xiao-dong, Zhu, Yuan-gui, Zhang, Jing, Shi, Yan-qing, Chen, Xiao-chun
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Cytoplasm; Neurobiology; Proteins; Transcription factors
• ISSN: 0893-7648; 1559-1182
• DOI: 10.1007/s12035-015-9542-2

Due to its apparent rate-limiting function, BACE1 ([beta]-secretase) appears to be a prime target for prevention of amyloid-[beta] (A[beta]) generation in brains with Alzheimer's disease (AD). The activity of BACE1 is regulated by peroxisome proliferator-activated receptor-γ (PPARγ), a transcription factor binding site of the BACE1 promoter, indicating that PPARγ may be a potential target for AD treatment. Several studies have demonstrated that PPARγ activation is involved in the immunostimulation of amyloid-[beta] precursor protein processing by nonsteroidal anti-inflammatory drugs (NSAIDs). The present study found that tripchlorolide (T4), with a similar chemical structure to that of NSAIDs, decreased the levels of A[beta] secreted in N2a-APP695 cells. T4 treatment reduced the mRNA and protein levels of BACE1 and the protein level of sAPP[beta], a cleaved N-terminal fragment of APP by BACE1. The treatment also translocated PPARγ from cytoplasm to nuclear. Intriguingly, T4, like pioglitazone (a PPARγ agonist), suppressed the BACE1 activity in N2a-APP695 cells, which was attenuated by GW9662 (a PPARγ antagonist). These results indicate that T4 may be a PPARγ agonist to enhance the binding of nuclear PPARγ to the BACE1 promoter, which may in turn inhibit the transcription and translation of BACE1, suppress the activity of BACE1, and ultimately attenuate the generation of A[beta]. Due to its capability to alter A[beta] generation and to protect central neural system against the neurotoxicity of A[beta], T4 may serve as a promising agent in modulating A[beta]-related pathology in Alzheimer's disease.