Centre for Neuroscience, Division of Experimental Medicine, Imperial College London, London, UK.
J Alzheimers Dis. 2011;25(1):151-62. doi: 10.3233/JAD-2011-101356.
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.
我们之前曾报道过，过氧化物酶体增殖物激活受体-γ（PPARγ）核受体调节β-分泌酶（BACE1）的转录，BACE1 是参与淀粉样蛋白-β（Aβ）生成的关键酶。在此，我们旨在研究过氧化物酶体增殖物激活受体-γ共激活因子-1α（PGC-1α）的作用，它通过 PPARγ 和其他转录因子的共激活来控制主要的代谢功能。用 AD 病例和对照的大脑皮质核提取物进行 Western blot 实验表明，AD 患者的 PGC-1α 水平降低。PGC-1α 在 N2a 神经母细胞瘤细胞中的过表达诱导分泌的 Aβ 水平降低和非淀粉样可溶性 AβPPα 水平升高。外源性表达 PGC-1α 后 Aβ 减少是由于 BACE1 表达和转录减少，以及 BACE1 启动子活性降低所致。此外，通过测量β-羧基末端片段（β-CTFs）的水平并使用商业β-分泌酶测定法，我们检测到β-分泌酶活性显著降低。相比之下，用 PGC-1α siRNA 转染下调 PGC-1α 水平会增加 BACE1 的表达。这些影响似乎依赖于 PPARγ，因为 PGC-1α 不会影响转染了 PPARγ siRNA 的 N2a 细胞或 PPARγ 敲除成纤维细胞中的 Aβ 和 BACE1 水平。总之，由于 PGC-1α 似乎可降低 Aβ 的产生，因此对 PGC-1α 的治疗性调节可能具有治疗 AD 的实际潜力。
