CN111721859A - Early Alzheimer disease mouse lipidomics analysis method based on ultra-high performance liquid phase tandem high-resolution mass spectrometry and application - Google Patents
Early Alzheimer disease mouse lipidomics analysis method based on ultra-high performance liquid phase tandem high-resolution mass spectrometry and application Download PDFInfo
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Abstract
The invention discloses a lipidomics-based method for representing biomarkers of plasma and brain lipids of mice in different stages of early Alzheimer's disease, which comprises the following steps: extracting early Alzheimer disease mouse plasma and brain tissue homogenate by a specific solvent, performing ultrasonic treatment, centrifuging, performing vacuum drying, re-dissolving by an acetonitrile-water solution, injecting a sample, separating by an UPLC chromatographic column (C18), eluting by using an A and B mobile phase consisting of acetonitrile, ammonium acetate, isopropanol and water, detecting by using a QTOF high-resolution mass spectrometer in a full-scanning mode under a positive and negative ion mode respectively, collecting secondary fragment ions, and screening and identifying the measured data according to the chemical formula, the accurate molecular weight, the secondary fragment and the abundance ratio of a target molecule. The method has the advantages of sensitivity, accuracy, high throughput and independence of standard compounds, represents the biomarkers of plasma and brain lipids of mice in the early stage of the Alzheimer's disease, and is suitable for the lipidomics analysis of the mice with the Alzheimer's disease.
Description
Technical Field
The invention relates to a lipidomics-based method for representing lipid biomarkers of different stages of early-stage Alzheimer's disease of mice, belonging to the technical field of lipidomics analysis.
Background
Alzheimer's Disease (AD) is a neurodegenerative chronic fatal disease of the brain. According to the report of the international organization for Alzheimer's disease in 2018, about 5000 million patients with senile dementia worldwide are reported, and 1.52 hundred million patients are reached by 2050. The number of AD patients in China is over ten million people and is the first in the world.
The pathological mechanism of AD remains unclear, with the main hypotheses being abnormal deposition of β -amyloid, entanglement of Tau protein, inflammatory cascade, invasion of viruses, bacteria and fungi into the brain leading to inflammation and neurotoxicity. The later period of AD can not be cured and is difficult to prevent, so that the excavation of early AD biomarkers provides possibility for early diagnosis and intervention of AD.
Clinically, the AD biomarkers are mainly proteins, the small molecular biomarkers are few, and the current biomarkers in the early stage of AD are not well known, especially the research on lipid biomarkers in the early stage of AD is lack of attention, and no clinical biomarkers for early diagnosis of AD are available. Lipidomics is an emerging omics technology that plays an increasingly important role in biological research because it can reveal unique lipid chemical fingerprints characteristic of body cell metabolism. Lipidomics as a research method of lipid small molecule metabolites provides possibility for discovering more AD biomarkers. There is increasing evidence that the processes of AD development and progression lead to lipid abnormalities.
Disclosure of Invention
The invention aims to provide an early Alzheimer disease mouse lipidomics analysis method based on ultra-high performance liquid chromatography-tandem high resolution mass spectrometry, which can realize sensitive, accurate and high-throughput analysis on early Alzheimer disease mouse lipid potential biomarkers without a standard substance.
In order to achieve the aim, the invention provides an early Alzheimer disease mouse lipidomics analysis method based on ultra-high performance liquid chromatography-tandem high resolution mass spectrometry, which comprises the following steps: step 1, extracting collected rat plasma/serum and brain tissue with butanol-methanol, n-heptane-ethyl acetate and water to obtain an upper organic solution; step 2, drying the organic solvent of the upper layer in vacuum, concentrating the sample, further re-dissolving the concentrated sample by using an acetonitrile-water solution, and obtaining a supernatant sample to be detected after high-speed centrifugation; and 3, eluting the sample to be detected by a mobile phase in the UPLC chromatographic column, separating, detecting by using a quadrupole time-of-flight high-resolution mass spectrometer in a positive ion mode and a negative ion mode, comparing detection data with the chemical formula, the accurate molecular weight, the secondary fragment and the abundance ratio of the target phospholipid molecules, and identifying to obtain the rat plasma and various brain phospholipid molecules in different early stages of the Alzheimer disease. And 4, constructing a metabolic pathway of the biomarker by using a lipidomics related database and analysis software, and analyzing.
In a preferred embodiment, in step 1, murine plasma/serum and brain tissue (10/group) collected from 2, 3 and 7 month old APP/PS1 mice and corresponding healthy mice are extracted with butanol-methanol, n-heptane-ethyl acetate and water to give an upper organic solution.
In a preferred embodiment, in step 1, the ratio of butanol to methanol and butanol to n-heptane-ethyl acetate in the extract: methanol: n-heptane: ethyl acetate: the volume ratio of the ammonium acetate aqueous solution is (0.1-0.3): 0.05-0.2): 0.15-0.3): 0.05-0.2): 0.2-0.5. Wherein the concentration of ammonium acetate water is 40-60 mM. The ultrasonic power is 200W, 60Hz, and the ultrasonic time is 10 min; vortex 60 seconds, frequency 200 Hz.
In a preferred embodiment, in step 2, the rotation speed of the centrifuge is 12000-15000rpm in step 2.
In a preferred embodiment, in step 2, the ratio of acetonitrile in the acetonitrile-water solution of the reconstituted concentrated sample is: the volume ratio of water is (3-4) to (2-3), and the usage volume is 45-55 μ L.
In a preferred embodiment, in step 3, the UPLC column is a C18 column, the C18 column having an inner diameter of 2.1mm and a length of 100mm, and the stationary phase particles therein have a particle size of 1.7 μm. Wherein the UPLC chromatographic column is an ACQUITYUPLC CSH C18 chromatographic column.
In a preferred implementation, in step 3, the sample to be tested is eluted by the mobile phase in the chromatographic column by using mobile phase a and mobile phase B; wherein the mobile phase A comprises acetonitrile and ammonium acetate, the acetonitrile is 100%, and the concentration of the ammonium acetate is 4.0-6.0 mM; the mobile phase B comprises isopropanol, acetonitrile and ammonium acetate, wherein the ratio of isopropanol: the volume ratio of the acetonitrile is (8-15): (85-92), and the concentration of the ammonium acetate is 4.0-6.0 mM.
In a preferred embodiment, the chromatographic column is used under the following conditions: setting the sample introduction volume of the sample to be detected to be 5 mu l, the column temperature to be 55 ℃ and the flow rate to be 0.4 mL/min; the gradient elution procedure is specified as follows: 0-2min, 40% -43% of mobile phase B; 2-4.1min, 43% -45% of mobile phase B; 4.1-12min, 45% -48% of mobile phase B; 12-12.1min, 48% -60% of mobile phase B; 12.1-18min, 60% -100% of mobile phase B; 18-18.1min, 80% -40% of mobile phase B; 18.1-20min, 40% mobile phase B.
In a preferred embodiment, the mass spectrometry conditions for the measurement using a quadrupole time-of-flight high resolution mass spectrometer are: the electrospray ion source successively adopts a positive and negative ionization mode to collect data, and the positive and negative ionization mode is as follows: the capillary voltage is-3.5 kV, the declustering voltage is-2.0 kV, the ion source temperature is 250 ℃, the spraying pressure is 2.0bar, the flow rate of the drying gas is 6L/min, and the collision energy is 70 eV; in positive ion mode: the capillary voltage is 4.5kV, the declustering voltage is 2.0kV, the ion source temperature is 250 ℃, the spraying pressure is 2.0bar, the flow rate of the drying gas is 7L/min, and the collision energy is 70 eV.
The invention also provides application of the early Alzheimer disease mouse lipidomics analysis method based on the ultra-high performance liquid chromatography-tandem high resolution mass spectrometry in high-throughput detection of different mouse lipid molecules.
Compared with the prior art, the invention has the following advantages:
(1) the invention applies the high performance liquid chromatography-quadrupole time-of-flight mass spectrometry detection method in series connection to the identification of early Alzheimer's disease mouse lipid molecules for the first time, and can complete the rapid, sensitive and accurate lipidomics analysis of the mouse;
(2) the method does not need a standard compound, has high sample determination and analysis efficiency and good repeatability, is suitable for high-throughput analysis of a large number of samples, and can distinguish the early-stage Alzheimer disease mouse lipid group.
Drawings
The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate an embodiment of the invention and, together with the description, serve to explain the invention and not to limit the invention. In the drawings:
figure 1 shows a total ion flowsheet of AD mouse plasma and brain in positive and negative ion mode of a mass spectrometer.
Fig. 2 shows profile plots of Principal Component Analysis (PCA) of data obtained from the detection of rat plasma lipid extracts of 2-, 3-and 7-month-old AD groups and corresponding healthy groups in negative (a) and positive (B) ion modes, respectively, of a mass spectrometer.
Fig. 3 shows principal component analysis profiles of data obtained from the detection of lipid extracts from rat brain tissue of 2, 3 and 7 month old AD groups and corresponding healthy groups in negative (a) and positive (B) ion modes of a mass spectrometer, respectively.
Figure 4 shows the fluctuating changes in potential lipid biomarkers in plasma of 2, 3 and 7 month old AD mice.
Figure 5 shows the fluctuating changes in potential lipid biomarkers in the brains of AD mice at 2, 3 and 7 months of age.
Detailed Description
The following detailed description of the present invention is provided in conjunction with the accompanying drawings, but it should be understood that the scope of the present invention is not limited to the specific embodiments.
Throughout the specification and claims, unless explicitly stated otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or component but not the exclusion of any other element or component.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
The embodiment of the invention applies an ultra-high performance liquid chromatography combined tandem high-resolution mass spectrometry technology to detect lipid metabolites of plasma and brain tissue samples and find potential biomarkers for distinguishing the mouse lipid in the early stage of the Alzheimer's disease. The specific preference includes:
2, 3 and 7 month old APP/PS1 mice and corresponding healthy mice were collected with 10-14 plasma samples per group and 8-10 brain tissue samples per group. After being processed, the sample is detected by an ultra-high performance liquid chromatography-tandem high resolution mass spectrometer, and the difference of lipid metabolism spectra of early Alzheimer disease mice in different stages and between healthy controls is visually distinguished by establishing a multi-dimensional statistical model, so that the difference lipid metabolites are obtained.
The determination method can comprehensively and comprehensively reflect the change conditions of the lipid metabolites between different stages of early Alzheimer's disease mice and healthy controls, find out the potential lipid biomarkers for distinguishing the different stages of the early Alzheimer's disease mice, and provide favorable technical support for diagnosis of the early Alzheimer's disease biomarkers.
Test material and test method
1. Plasma and brain tissue sample collection
After fasting for 12 hours, the method of orbital blood collection is adopted to obtain about 0.4mL of whole blood, the whole blood is placed into a heparinized 1.5mL Eppendorf tube, 5000rmp is carried out, centrifugation is carried out for 10min, and plasma is obtained and placed in a refrigerator at the temperature of 80 ℃ below zero for standby. Taking out brain tissue immediately after mouse is dislocated and killed, cleaning with ice normal saline, drying with filter paper, weighing, adding ice normal saline according to the proportion of 5:1(v/g), homogenizing with a tissue homogenizer at the frequency of 60Hz for 60s, taking out brain tissue homogenate, and placing in a refrigerator at-80 ℃ for later use.
2. Plasma and brain homogenate sample pretreatment
The plasma and brain homogenate samples were subjected to the same pretreatment method, i.e., 20. mu.L of plasma/brain homogenate was added with 10. mu.L of 30mM2, 6-di-tert-butyl-p-cresol (antioxidant), 200. mu.L of butanol-methanol (2:1, v/v), vortexed for 60s, then 200. mu.L of n-heptane-ethyl acetate (3:1, v/v), vortexed for 60s, sonicated in ice water for 5min, added with 200. mu.L of 50mM ammonium acetate solution (induced stratification), vortexed for 60s, centrifuged at 4 ℃ and 6000rpm for 10min, the upper organic phase was collected, vacuum dried, re-dissolved with 50. mu.L of acetonitrile-water (4:3, v/v) solution, vortexed for 60s, 12000rpm, centrifuged at 4 ℃ for 10min, and the supernatant was injected into a sample with a volume of 5. mu.L.
3. Analytical instrumentation test
Liquid phase conditions: the mobile phase A is an acetonitrile solution containing 5mM of amine acetate, and the mobile phase B is an isopropanol solution containing 5mM of amine acetate and 10% of acetonitrile; the mobile phase gradient was: 0-2min, 40% -43% of mobile phase B; 2-4.1min, 43% -45% of mobile phase B; 4.1-12min, 45% -48% of mobile phase B; 12-12.1min, 48% -60% of mobile phase B; 12.1-18min, 60% -100% of mobile phase B; 18-18.1min, 80% -40% of mobile phase B; 18.1-20min, 40% mobile phase B. The flow rate was 0.4 mL/min. The column was ACQUITY UPLC CSH C18(2.1 mm. times.100 mm,1.7 μm) and the column operating temperature was 55 ℃.
Mass spectrum conditions: adopting Bruker TIMSTF high-resolution mass spectrum, under the negative ion mode: the capillary voltage is-3.5 kV, the declustering voltage is-2.0 kV, the ion source temperature is 250 ℃, the spraying pressure is 2.0bar, the flow rate of the drying gas is 6L/min, and the collision energy is 70 eV; in positive ion mode: the capillary voltage is 4.5kV, the declustering voltage is 2.0kV, the ion source temperature is 250 ℃, the spraying pressure is 2.0bar, the flow rate of the drying gas is 7L/min, and the collision energy is 70 eV. Nitrogen was used as the atomizing drying gas and argon was used as the collision gas. The Auto-MS/MS mode is used to further break up the lipid molecules of interest to obtain secondary fragment ions.
Second, data statistical analysis
The plasma and brain homogenate samples of all early Alzheimer disease mice in different stages and healthy control groups are subjected to UPLC-QTOF/MS full-scan detection to obtain mass spectrum data under positive and negative modes respectively, the plasma and brain total ion flow diagram is shown in figure 1, the obtained data is subjected to Principal Component Analysis (PCA) and cross-bias minimum variance discriminant analysis (OPLS/PLS-DA), and AD mice of 2, 3 and 7 months are distinguished, as shown in figures 2 and 3, so that corresponding potential lipid biomarkers are obtained. The multidimensional OPLS-DA model provides selection criteria for lipid molecules with significantly different variable weights (conditions: VIP value >1, anova (p) <0.05 (significant difference), qValue (false positive rate) <0.05, CV (coefficient of variation) < 30%). According to this criterion, under positive and negative spectral detection, a total of 45 potential lipid biomarkers were identified in plasma and 21 potential lipid biomarkers in brain tissue. Metabolic pathway enrichment analysis is performed on the differential metabolites by using a Metabionalyst online website, and metabolic pathways related to the differential lipid metabolites between an experimental group and a control group comprise glycerophospholipid metabolism, glycerolipid metabolism, unsaturated fatty acid synthesis, fatty acid biosynthesis, linoleic acid metabolism and the like, as shown in tables 1 and 2. The fluctuation of potential lipid biomarkers in these AD mice at different ages of the month (2, 3 and 7 months), as shown in fig. 4 and 5, is predictive of the metamorphosis and disease progression in the early AD mouse lipidome at different ages of the month.
TABLE 1 Effect of early AD on plasma lipid metabolism pathways in mice
TABLE 2 Effect of early AD on the brain lipid metabolism pathway in mice
Claims (10)
1. A lipidomics analysis method of early Alzheimer disease model mice based on ultra-high performance liquid chromatography tandem high resolution mass spectrometry is characterized by comprising the following steps:
step 1, extracting collected plasma/serum and/or animal brain tissue of an Alzheimer disease model mouse by using butanol-methanol, n-heptane-ethyl acetate and ammonium acetate aqueous solution, and performing vortex and centrifugation to obtain an upper organic solution;
step 2, drying the organic solvent of the upper layer in vacuum, concentrating the sample, further re-dissolving the concentrated sample by using an acetonitrile-water solution, and obtaining a supernatant sample to be detected after high-speed centrifugation;
and 3, eluting the sample to be detected by a mobile phase in the UPLC chromatographic column, separating, detecting by using a quadrupole time-of-flight high-resolution mass spectrometer in a positive ion mode and a negative ion mode, comparing detection data with the chemical formula, the accurate molecular weight, the secondary fragment and the abundance ratio of the target phospholipid molecules, and identifying to obtain the rat plasma and various brain phospholipid molecules in different early stages of the Alzheimer disease.
And 4, constructing a metabolic pathway of the biomarker by using a lipidomics related database and analysis software, and analyzing.
2. The early stage Alzheimer's disease mice of claim 1 are Alzheimer's disease mice APP/PS1 double transgenic mice and mice aged 2, 3 and 7 months old, respectively.
3. The method for performing murine lipidomics analysis of early stage alzheimer's disease based on hplc-tandem high resolution mass spectrometry according to claim 1, wherein in step 1, the ratio of butanol-methanol and n-heptane-ethyl acetate in the extract solution is butanol: methanol: n-heptane: ethyl acetate: the volume ratio of the ammonium acetate aqueous solution is (0.1-0.3): 0.05-0.2): 0.15-0.3): 0.05-0.2): 0.2-0.5. Wherein the concentration of ammonium acetate water is 40-60 mM.
4. The method for performing murine lipidomics analysis of early stage alzheimer's disease based on hplc-tandem high resolution mass spectrometry according to claim 1, wherein in step 1, the vortex time is 60 seconds, and the frequency is 100 HZ; the ultrasonic frequency is 60HZ, the power is 200W, and the ultrasonic time is 10 min.
5. The method for performing murine lipidomics analysis of early stage alzheimer's disease based on hplc-tandem high resolution mass spectrometry according to claim 1, wherein in step 2, the centrifuge rotation speed is 12000-15000 rpm.
6. The method for performing murine lipidomics analysis of early stage alzheimer's disease based on hplc-tandem high resolution mass spectrometry according to claim 1, wherein in step 2, the acetonitrile in the acetonitrile-water solution of the concentrated sample is redissolved: the volume ratio of water is (3-4) to (2-3), and the usage volume is 45-55 μ L.
7. The method for performing murine lipidomics analysis of early stage alzheimer's disease based on hplc-tandem high resolution mass spectrometry according to claim 1, wherein in step 3, said UPLC chromatography column is an acquire UPLC CSH C18 chromatography column.
8. The lipidomics analysis method according to claim 1, characterized in that in step 3, the sample to be tested is eluted by means of mobile phase in a chromatographic column by means of mobile phase a and mobile phase B;
wherein the mobile phase A comprises acetonitrile and ammonium acetate, the acetonitrile is 100%, and the concentration of the ammonium acetate is 4.0-6.0 mM;
the mobile phase B comprises isopropanol, acetonitrile and ammonium acetate, wherein the ratio of isopropanol: the volume ratio of the acetonitrile is (8-15): (85-92), and the concentration of the ammonium acetate is 4.0-6.0 mM.
9. The mobile phase elution mode of claim 8 wherein the chromatographic column is used under the following conditions: setting the sample introduction volume of the sample to be detected to be 5 mu l, the column temperature to be 55 ℃ and the flow rate to be 0.4 mL/min; the gradient elution procedure is specified as follows: 0-2min, 40% -43% B; 2-4.1min, 43% -45% B; 4.1-12min, 45% -48% B; 12-12.1min, 48% -60% B; 12.1-18min, 60% -100% B; 18-18.1min, 80% -40% B; 18.1-20min, 40% B.
10. The method for performing murine lipidomics analysis of early stage alzheimer's disease based on hplc-tandem high resolution mass spectrometry according to claim 1, wherein the mass spectrometry conditions for the determination using a quadrupole time-of-flight high resolution mass spectrometer are as follows: the electrospray ion source successively adopts a positive and negative ionization mode to collect data, and the positive and negative ionization mode is as follows: capillary voltage is-3.5 kV, declustering voltage is-2.0 kV, ion source temperature is 250 ℃, spray pressure is 2.0bar, flow rate of drying gas is 6L/min, and collision energy is 20-70 eV; in positive ion mode: the capillary voltage is 4.5kV, the declustering voltage is 2.0kV, the ion source temperature is 250 ℃, the spraying pressure is 2.0bar, the flow rate of the drying gas is 7L/min, and the collision energy is 70 eV.
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