Department of Pharmacology and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
Department of Pharmacology and Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada
J Lipid Res. 2018 Jan;59(1):1-13. doi: 10.1194/jlr.M076703. Epub 2017 Nov 9.
We previously demonstrated that oligomeric amyloid β (oAβ) inhibits the mevalonate pathway impairing cholesterol synthesis and protein prenylation. Enzymes of the mevalonate pathway are regulated by the transcription factor SREBP-2. Here, we show that in several neuronal types challenged with oAβ, SREBP-2 activation is reduced. Moreover, SREBP-2 activation is also decreased in the brain cortex of the Alzheimer's disease (AD) mouse model, TgCRND8, suggesting that SREBP-2 may be affected in vivo early in the disease. We demonstrate that oAβ does not affect enzymatic cleavage of SREBP-2 per se, but may impair SREBP-2 transport from the endoplasmic reticulum (ER) to the Golgi. Trafficking of SREBP-2 from the ER to the Golgi requires protein kinase B (Akt) activation. oAβ significantly reduces Akt phosphorylation and this decrease is responsible for the decline in SREBP-2 activation. Overexpression of constitutively active Akt prevents the effect of oAβ on SREBP-2 and the downstream inhibition of cholesterol synthesis and protein prenylation. Our work provides a novel mechanistic link between Aβ and the mevalonate pathway, which will impact the views on issues related to cholesterol, isoprenoids, and statins in AD. We also identify SREBP-2 as an indirect target of Akt in neurons, which may play a role in the cross-talk between AD and diabetes.
我们之前的研究表明，寡聚态淀粉样蛋白β（oAβ）可抑制甲羟戊酸途径，从而损害胆固醇的合成和蛋白质异戊烯化。甲羟戊酸途径的酶受转录因子 SREBP-2 调节。在这里，我们发现几种受到 oAβ 挑战的神经元类型中 SREBP-2 的激活被减弱。此外，阿尔茨海默病（AD）小鼠模型 TgCRND8 大脑皮质中的 SREBP-2 激活也降低，表明 SREBP-2 可能在疾病早期就受到影响。我们证明 oAβ 本身不会影响 SREBP-2 的酶切，而是可能损害 SREBP-2 从内质网（ER）向高尔基体的运输。SREBP-2 从 ER 向高尔基体的运输需要蛋白激酶 B（Akt）的激活。oAβ 显著降低 Akt 的磷酸化，这种减少是 SREBP-2 激活下降的原因。组成性激活 Akt 的过表达可防止 oAβ 对 SREBP-2 的影响以及胆固醇合成和蛋白质异戊烯化的下游抑制。我们的工作为 Aβ 与甲羟戊酸途径之间提供了一个新的机制联系，这将影响与 AD 相关的胆固醇、异戊烯、司他汀等问题的观点。我们还发现 SREBP-2 是神经元中 Akt 的间接靶点，它可能在 AD 和糖尿病的串扰中发挥作用。
