Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, 15219, PA, USA.
Sanford Burnham Prebys Medical Discovery Institute, Orlando, 32827, FL, USA.
Sci Rep. 2017 Jun 27;7(1):4307. doi: 10.1038/s41598-017-04412-2.
We examined the effect of chronic high fat diet (HFD) on amyloid deposition and cognition of 12-months old APP23 mice, and correlated the phenotype to brain transcriptome and lipidome. HFD significantly increased amyloid plaques and worsened cognitive performance compared to mice on normal diet (ND). RNA-seq results revealed that in HFD mice there was an increased expression of genes related to immune response, such as Trem2 and Tyrobp. We found a significant increase of TREM2 immunoreactivity in the cortex in response to HFD, most pronounced in female mice that correlated to the amyloid pathology. Down-regulated by HFD were genes related to neuron projections and synaptic transmission in agreement to the significantly deteriorated neurite morphology and cognition in these mice. To examine the effect of the diet on the brain lipidome, we performed Shotgun Lipidomics. While there was no difference in the total amounts of phospholipids of each class, we revealed that the levels of 24 lipid sub-species in the brain were significantly modulated by HFD. Network visualization of correlated lipids demonstrated overall imbalance with most prominent effect on cardiolipin molecular sub-species. This integrative approach demonstrates that HFD elicits a complex response at molecular, cellular and system levels in the CNS.
我们研究了慢性高脂肪饮食（HFD）对 12 个月大的 APP23 小鼠淀粉样蛋白沉积和认知的影响，并将表型与大脑转录组和脂质组相关联。与正常饮食（ND）组的小鼠相比，HFD 显著增加了淀粉样斑块并恶化了认知表现。RNA-seq 结果表明，在 HFD 小鼠中，与免疫反应相关的基因（如 Trem2 和 Tyrobp）表达增加。我们发现，HFD 引起大脑皮层中 TREM2 免疫反应显著增加，在雌性小鼠中最为明显，这与淀粉样蛋白病理学相关。HFD 下调了与神经元突起和突触传递相关的基因，这与这些小鼠明显恶化的神经突形态和认知一致。为了研究饮食对大脑脂质组的影响，我们进行了 Shotgun 脂质组学分析。虽然每种磷脂类别的总含量没有差异，但我们发现 24 种脂质亚类在大脑中的水平因 HFD 而显著调节。相关脂质的网络可视化显示整体失衡，对心磷脂分子亚类的影响最为明显。这种综合方法表明，HFD 在中枢神经系统的分子、细胞和系统水平上引发了复杂的反应。
