*For medical professionals only
I bet five cents, as the clinical/scientific/worker who opened this article, you must have a caffeinated drink on your desk, or even more than one bottle. Whether it is coffee, tea or functional drinks, in order to maintain a good state of study or work, concentrate without getting sleepy, and even brush books violently before the final exam, most people will choose to consume caffeine sprint deadline. Even many people have developed the habit of long-term intake of coffee, coming for a cup in the morning and not dozing off during the day.
I believe that many people will think about this problem in their minds, drinking coffee like this every day, can my brain withstand it? In other words, through what mechanisms does caffeine affect the brain over the course of this long-term process?
Recently, scientists published a paper in the Journal of Clinical Research (JCI)[1] that brings a new answer to this question. Combining the epigenetic, metabolomics, and proteomics results of mouse hippocampal tissue, as well as changes in the level of gene transcription in mice during learning, they found that a set of combination punches down, and hippocampal neurons from gene expression to metabolic processes have "become caffeine shapes" and work efficiency is much higher.
Note! The concentration of the following letters is too high, and I don't know how to do it like last week, I can read the conclusion directly!
Paiva et al. divided mice into a caffeine group and a blank control group. The effect of long-term caffeine intake on epigenetic omics of hippocampal tissue was first observed. They selected two histone acetylation modifications H3K27ac, H3K9/K14ac, associated with chromatin transcriptional activity. The results showed that long-term intake of caffeine significantly reduced the acetylation level of histones in multiple gene sites (histone acetylation increased gene expression).
In caffeine-ingested mice, the acetylatation level of H3K9/14ac in 778 gene regions decreased, with elevations occurring in only 3 regions (left in the figure below). The results of the H3K27ac analysis were even more striking, with 2105 regions in the caffeine group having decreased acetylation levels and only 4 regions experiencing elevations (right in the figure below).
Figure 1: Changes in acetylation levels of different histone markers in both groups
What exactly do these genes do?
Through gene total analysis and pathway analysis of KEGG in the GREAT database, the above-mentioned acetylated reduction regions are closely associated with various metabolic processes. The insulin signaling pathway is associated with both H3K9/14 and H3K27ac, while the glucagon signaling pathway is associated with H3K9/14 (left in the figure below). Using the STRING database, the protein interaction analysis of the above insulin and glucagon-related genes can see a clear correlation (right in the figure below).
In summary, long-term caffeine intake can regulate protein translation, lipid metabolism, and glucagon/insulin-related metabolic processes through epigenetic regulation.
Figure 2: KeGG database and STRING database results show that the above genes are closely related to metabolism
Following the metabolism of this vine, Paiva and the others continued to touch the melon. Comparing the metabolomics results of the two groups, they found that the main differences were in the biochemical classification, with metabolite-related 27%, lipid-related accounting for 32%, and the other 41% not clearly classified (below left).
In addition, 92% of the above molecules were reduced in the caffeine group, and only 8% of the molecules were elevated (in the figure below). It can be seen from mass spectrometry imaging that caffeine has significantly altered the metabolic processes of hippocampal tissue (right in the figure below).
Figure 3: Significant changes in metabolomics in the caffeine group compared to the control group
The proteomics results further corroborate their findings. Compared with the control group, the caffeine group had elevated levels of 130 proteins and decreased levels of 49 proteins (Figure A below). Consistent with metabolomics results, 49 reduced proteins were also metabolically correlated. The above three omics methods hammered out the effect of caffeine on the metabolic processes of the mouse hippocampus.
Figure 4: Proteomics changes in the caffeine group
Wait, what about those elevated proteins? That's right, it's about improving the efficiency of nerve cells!
After ontology analysis of these 130 proteins, it was found that most of them were related to synapse formation and signaling (below). Taken together, proteomics suggests that long-term caffeine intake can inhibit the expression of metabolically related proteins while upregulating synapse-associated protein levels.
Figure 5: Results of gene ontology analysis of elevated proteins in the caffeine group
So do these effects really make the brain perform better? OK!
Paiva et al. used the Morris water maze experiment to compare the learning of mice in the caffeine group and the control group. The swimming speed of the two groups of mice was essentially the same, but on the third day of training, the caffeine group mice needed to reach the platform at a shorter distance (figure below). The above results show that caffeine can enhance learning to some extent.
Figure 6: Results of the water maze experiment
They then used RNA sequencing to compare the changes in gene expression between the two groups after learning. It was found that only a small number of genes changed in both groups at the same time (left in the figure below), and most of the gene expression changes only occurred in the case of caffeine + learning. Moreover, both the up-and-down adjustment were significantly different from the control group (right in the figure below).
In addition, combined with previous gene analyses, Paiva et al. also found that of the 720 genes in the caffeine group that were upregulated, 121 were deacylated in the non-learning caffeine group (below, left), and the gene ontology analysis using the STRING database showed that these 121 genes were significantly correlated with multiple metabolic processes (below J).
In summary, in the hippocampal tissue of mice, long-term intake of caffeine enhances the inducibility of these genes in the learning process by regulating the acetylation of metabolism-related genes, regulates transcription levels, affects tissue metabolism, increases synaptic-related protein levels, and enhances learning effects.
Previous studies have confirmed that long-term caffeine intake can inhibit tau protein deposition in early Alzheimer's disease (AD), which can prevent spatial memory impairment in mice to some extent[2]; It is also possible to inhibit the deposition of Aβ protein by lowering β-secretase and Presenilin 1, which protects cognitive function in mice [3].
After reading this article, are you looking forward to caffeine, then let's do this cup together, work hard, and let the boss live a better life!
Friends who have purchased courses,
Directly enter the mini program to listen to the addition of food Oh ~
Resources:
1.Paiva, I. et al. J. Clin. Invest. https://doi.org/10.1172/JCI149371 (2022).
2. Laurent， C.， et al.， Beneficial effects of caffeine in a transgenic model of Alzheimer's disease-like tau pathology. Neurobiol Aging， 2014. 35(9): p. 2079-90.
3. Arendash， G.W.， et al.， Caffeine protects Alzheimer's mice against cognitive impairment and reduces brain beta-amyloid production. Neuroscience， 2006. 142(4): p. 941-52.
The author of this article 丨 Liu Qingrui
Responsible editor 丨dai siyu