CN115791988A - Alzheimer's disease biomarker taurine and application thereof - Google Patents
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Abstract
The invention relates to an Alzheimer's disease biomarker taurine and application thereof. The biomarker of Alzheimer's disease is taurine. The method for detecting the Alzheimer's disease in the urine sample of the patient is used for the first time, the taurine level in the urine sample is obviously higher than that of a normal feces sample, the taurine in the feces is used as an Alzheimer's disease biomarker, early diagnosis of the Alzheimer's disease can be assisted by detecting the taurine level in the feces, noninvasive and rapid detection is facilitated, and the method has the characteristics of timeliness, convenience, high specificity and high sensitivity.
Description
Technical Field
The invention belongs to the technical field of biology, and relates to an Alzheimer's disease biomarker taurine and application thereof.
Background
Alzheimer Disease (AD), also known as senile dementia, is a progressive degenerative disease of the central nervous system occurring in the elderly, characterized by progressive memory impairment, cognitive decline and loss of daily life, accompanied by neuropsychiatric symptoms such as personality changes, which seriously affect social and life functions. Because the pathogenesis of the Alzheimer's disease is not completely clear, and the early symptoms of the Alzheimer's disease are more secret, patients with the Alzheimer's disease are easy to miss diagnosis or misdiagnose, the current diagnosis of the AD mainly depends on the level detection of pathological indexes such as memory scale, PET, cerebrospinal fluid, abeta in blood, phosphorylated tau protein and the like, however, the detection results of the diagnosis indexes in clinic still have a certain dispute, and effective detection evidence is lacked for the early symptoms of the AD, so the development of a new marker for the early diagnosis of the AD is one of important research directions in the field of AD diagnosis and treatment.
CN106062563A discloses a biomarker and method for early diagnosis of alzheimer's disease, said AD biomarker is at least four biomarkers selected from the group consisting of brain-derived neurotrophic factor (BDNF), insulin-like growth factor-1 (IGF-1), tumor growth factor β 1 (TGF- β 1), vascular Endothelial Growth Factor (VEGF), interleukin 18 (IL-18) and monocyte chemoattractant protein-1 (MCP-1), and by analyzing its expression level, it can assist in early diagnosis of AD.
Researches find that various neuropsychiatric diseases such as Parkinson, depression, autism and the like are related to intestinal flora imbalance, and more than 80 percent of AD patients have the phenomenon of intestinal flora imbalance, which indicates that the intestinal flora stability is closely related to the pathogenesis of neurodegenerative diseases such as AD and the like. A large amount of metabolites are generated by a host and intestinal flora in the process of metabolizing food substances, the variety and abundance change of the intestinal flora can generate important influence on the types and concentrations of small molecular metabolites in organisms, data show that the composition of the intestinal flora of AD patients is different from that of healthy people of the same age, more and more evidences show that the disturbance of various metabolic pathways can mediate the pathological occurrence and development of AD, flora imbalance in AD can be importantly related to the occurrence of metabolic disturbance of the organisms, and the change of the peripheral metabolism of the organisms can further cause the metabolic disturbance of the central nervous system through blood circulation.
In conclusion, the relationship between the intestinal flora metabolic homeostasis and the onset of AD is researched, a new AD biomarker is screened, the judgment basis of AD early diagnosis is expanded, the AD biomarker can be combined with other marker detection, the AD diagnosis accuracy is improved, and early warning, pathological typing, prediction and evaluation of development stages and the like of diseases are facilitated.
Disclosure of Invention
Aiming at the defects and actual requirements of the prior art, the invention provides taurine as a biomarker of Alzheimer's disease and application thereof.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides an alzheimer's disease biomarker, which is Taurine (Taurine).
Taurine is a sulfur-containing amino acid with simple structure, chemical name of 2-aminoethanesulfonic acid, and molecular formula of C 2 H 7 NO 3 S, molecular weight is 125.15, odorless, slightly acidic, its diluted solution is neutral, stable to heat, and can be combined with cholic acid in human bile and animal bile, and can be existed in combined form, and can be existed in brain, ovary, heart, liver, milk, pineal body, pituitary, retina and adrenal gland, etc. in free form, but does not participate in protein synthesis, taurine is essential amino acid for human body, and can be used for making fetusThe taurine can be widely applied to the fields of medicines, food additives, fluorescent whitening agents, organic synthesis and the like, and can also be used as biochemical reagents, wetting agents, pH buffering agents and the like.
The method is used for carrying out qualitative and quantitative analysis on the fecal metabolites based on a high-resolution non-targeted metabonomics analysis technology, detecting that the taurine level in the fecal samples of the Alzheimer's disease is obviously higher than that of normal fecal samples, taking the taurine in the fecal as a biomarker of the Alzheimer's disease, and assisting early diagnosis of the Alzheimer's disease by detecting the taurine level in the fecal.
In a second aspect, the present invention provides the use of the biomarker for alzheimer's disease as described in the first aspect in constructing an early diagnosis model for alzheimer's disease and/or in preparing an early diagnosis device for alzheimer's disease.
In a third aspect, the present invention provides an early diagnosis model of alzheimer's disease, wherein the input variables of the early diagnosis model of alzheimer's disease comprise peak intensity values of taurine mass spectra as described in the first aspect.
Preferably, the output variables of the model for early diagnosis of alzheimer's disease comprise fold differential expression, and the calculation formula of the fold differential expression is shown in equation (1):
preferably, the positive judgment standard of the Alzheimer's disease is that the differential expression fold is more than or equal to 8.51.
According to the invention, the peak intensity values of the taurine mass spectra in the normal excrement sample and the AD excrement sample are fully compared and analyzed, and rational design is carried out, so that the model for early diagnosis of the Alzheimer's disease is constructed, the model takes the peak intensity value of the taurine mass spectra as an input variable, takes the differential expression multiple as an output variable, can rapidly output a result, and fully represents the sample with abnormal taurine level, thereby assisting the early diagnosis of the Alzheimer's disease.
In a fourth aspect, the present invention provides an apparatus for early diagnosis of alzheimer's disease, comprising:
a sample preparation unit: preparing a sample to be detected into a sample solution to be detected which can be used for the separation of a liquid chromatograph;
a detection unit: separating the sample solution to be detected by using the liquid chromatograph, performing data processing on the separated sample by using a mass spectrometer, and determining the peak intensity value of the taurine mass spectrum in the sample on the first aspect;
an analysis unit: inputting the peak intensity value of the detected taurine mass spectrum into the model for early diagnosis of Alzheimer's disease for data analysis;
an evaluation unit: and outputting the differential expression multiple corresponding to the sample, and judging whether the sample is positive for the Alzheimer's disease.
In the device for early diagnosis of Alzheimer's disease, all units are effectively matched, the device is simple and efficient, sample processing, detection and differential expression multiple obtaining can be rapidly completed, positive assessment of Alzheimer's disease is carried out according to a reasonably designed judgment standard, and the device has important significance for early diagnosis of Alzheimer's disease.
Preferably, the sample to be tested comprises a stool sample.
Preferably, the preparation method of the sample solution to be detected comprises the steps of adding a sample to be detected into an acetonitrile aqueous solution, centrifuging and collecting supernatant, so as to obtain the sample solution to be detected.
Preferably, the preparation method of the sample solution to be tested comprises the following steps:
(1) Adding a sample to be detected into a precooled methanol/acetonitrile/water solution, mixing and ultrasonically standing for 5-15 min (such as 26min, 27min, 28min, 29min or 32 min) at-20 to-15 ℃ (such as-19 ℃, -18 ℃, -16 ℃ or-17 ℃), such as 6min, 7min, 8min, 9min, 10min, 12min or 14 min), centrifuging for 15-25 min (such as 16min, 17min, 18min, 19min, 20min, 21min, 22min, 23min or 24 min) at 0-4 ℃ (such as1 ℃, 2 ℃ or 3 ℃), such as 12200 × g, 00 × g, 12600 × g, 12800 × g, 13200 × g, 12600 × g, 15000 × g or 15800 × g), and taking the supernatant to vacuum dry to obtain a pretreated sample;
(2) Adding the pretreated sample into 80-120 mul acetonitrile aqueous solution for redissolving, vortexing, centrifuging at 0-4 ℃ for 10-20 min (for example, 11min, 12min, 13min, 14min, 15min, 16min, 17min, 18min or 19 min) at 12000-16000 Xg (for example, 12200 Xg, 12400 Xg, 12600 Xg, 12800 Xg, 13200 Xg, 12600 Xg, 15000 Xg or 15800 Xg), and taking supernatant to obtain the sample solution to be tested.
Preferably, the volume ratio of methanol, acetonitrile and water in the methanol/acetonitrile/water solution is (1-2): 1 includes but is not limited to 1.2.
Preferably, the volume ratio of acetonitrile to water in the acetonitrile water solution is (1-2) and includes but not limited to 1.1.
Preferably, the liquid chromatograph comprises an ultra high performance liquid chromatograph.
Preferably, the ultra high performance liquid chromatograph comprises an Agilent1290Infinity LC ultra high performance liquid chromatograph.
Preferably, the mass spectrometer comprises a tandem time-of-flight mass spectrometer.
Preferably, the tandem time-of-flight mass spectrometer comprises an AB Triple TOF 6600 mass spectrometer.
Preferably, the data processing comprises:
and (3) collecting a primary spectrogram and a secondary spectrogram of the separated sample by using a tandem time-of-flight mass spectrometer, converting the primary spectrogram and the secondary spectrogram into an mzXML format, performing peak alignment, retention time correction, peak area extraction and structure identification, and determining the peak intensity value of the taurine mass spectrum on the first aspect in the sample.
Preferably, the alzheimer's disease early diagnosis device includes:
a sample preparation unit: preparing a sample to be detected into a sample solution to be detected which can be used for the separation of a liquid chromatograph;
a detection unit: separating the sample solution to be detected by using the liquid chromatograph, collecting a primary spectrogram and a secondary spectrogram of the separated sample by using a tandem time-of-flight mass spectrometer, converting the primary spectrogram and the secondary spectrogram into an mzXML format, performing peak alignment, retention time correction, peak area extraction and structure identification, and determining the peak intensity value of the taurine mass spectrum of the first aspect in the sample;
an analysis unit: inputting the peak intensity value of the detected taurine mass spectrum into the model for early diagnosis of Alzheimer's disease for data analysis;
an evaluation unit: and outputting the differential expression multiple corresponding to the sample, and judging whether the sample is positive for the Alzheimer's disease.
In the invention, the detection of the taurine level in the excrement sample can be used as a diagnosis basis, and is combined with other detection results to assist the early diagnosis of the Alzheimer's disease, so that the accuracy of the diagnosis of the Alzheimer's disease can be expected to be improved, but the detection cannot be independently used as a diagnosis index capable of 100% diagnosis of the Alzheimer's disease.
In the present invention, taurine was found to belong to the ABC transporters pathway in the Membrane transport pathway (Membrane transport pathway) by KEGG pathway analysis.
In a fifth aspect, the present invention provides a use of the biomarker for alzheimer's disease described in the first aspect in screening a medicament for treating and/or preventing alzheimer's disease.
Namely, the Alzheimer's disease biomarker of the first aspect is used as a target for screening drugs for treating and/or preventing Alzheimer's disease.
Compared with the prior art, the invention has the following beneficial effects:
the invention firstly detects that the taurine level in the excrement sample of the Alzheimer's disease is obviously higher than that of the normal excrement sample, takes the taurine in the excrement as the biomarker of the Alzheimer's disease, provides an early diagnosis model and a device of the Alzheimer's disease, can assist the early diagnosis of the Alzheimer's disease by detecting the taurine level in the excrement, is beneficial to noninvasive and rapid detection, and has the characteristics of timeliness, convenience, high specificity and high sensitivity.
Drawings
FIG. 1 is a graph of taurine levels in fecal samples from AD model mice and wild type mice;
FIG. 2 is a graph of mannose levels in cerebral cortex samples of AD model mice and wild type mice;
FIG. 3 is a graph of the levels of myo-inositol in cortical brain samples from AD model mice and wild type mice;
FIG. 4 is a graph of glycine levels in cerebral cortex samples of AD model mice and wild type mice.
Detailed Description
To further illustrate the technical means adopted by the present invention and the effects thereof, the present invention is further described below with reference to the embodiments and the accompanying drawings. It is to be understood that the specific embodiments described herein are merely illustrative of the invention and are not limiting of the invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or apparatus used are conventional products commercially available from normal sources, not indicated by the manufacturer.
Example 1
This example provides qualitative and quantitative metabolite analysis of fecal samples from 9-month-old AD model mice (APP/PS 1 transgenic mice, provided by the university of Nanjing model animal research institute) and wild-type (WT) mice.
Respectively collecting the excrement of 10 AD model mice and 10 wild type mice cultured under the same condition, sequentially numbering the samples of the wild type mice as FWT-1-FWT-1-10 and the samples of the AD model mice as FTG-1-FTG-1-10, and detecting the taurine level in the samples by adopting ultra-high performance liquid chromatography-tandem flight time mass spectrometry, wherein the concrete method comprises the following steps:
(1) Adding a pre-cooled methanol/acetonitrile/water solution (volume ratio is 2;
(2) Adding the pretreated sample into 100 mu L acetonitrile aqueous solution (volume ratio is acetonitrile: water = 1) for redissolution, vortexing, centrifuging at 4 ℃ and 14000 Xg for 15min, taking supernatant, injecting and analyzing, and separating by using an Agilent1290Infinity LC ultra-performance liquid chromatography system (UHPLC) HILIC chromatographic column with the column temperature of 25 ℃; the flow rate is 0.5mL/min; the sample size is 2 mu L; the mobile phase composition comprises: phase A: ammonium acetate and aqueous ammonia mixed aqueous solution (ammonium acetate and aqueous ammonia both at 25mM final concentration), phase B: acetonitrile; the gradient elution procedure was as follows: 0 to 0.5min,95% of phase B; 0.5-7min, phase B changing linearly from 95% to 65%; 7-8min, wherein the phase B is linearly changed from 65% to 40%; maintaining the phase B at 40% within 8-9min; 9-9.1min, the phase B changes from 40% to 95% linearly; 9.1-12min, and maintaining the phase B at 95%; the sample is placed in an automatic sample injector at 4 ℃ in the whole analysis process;
(3) And (3) adopting an AB Triple TOF 6600 mass spectrometer to collect primary and secondary spectrograms of the sample separated by the ultra performance liquid chromatography system in the step (2), wherein ESI source conditions are as follows: ion Source Gas Gas1 (Gas 1): 60, ion Source Gas2 (Gas2): 60, curtain gas (CUR): 30, source temperature:600 ℃, ionSapary Voltage flowing (ISVF) + -5500V (positive and negative modes); TOF MS scan m/z range:60-1000Da, product ion scan m/z range:25-1000Da, TOF MS scan accumulation time 0.20s/spectra, product scan accumulation time 0.05s/spectra; secondary mass spectra were acquired using Information Dependent Acquisition (IDA) and high sensitivity mode, clustering potential (DP): ± 60V (positive and negative modes), precision Energy: 35. + -.15eV, IDA the following extract isotopes with 4Da, candidates ions to monitor per cycle:10, converting acquired raw data in a Wiff format into an mzXML format through a proteo wizard, performing peak alignment, retention time correction and peak area extraction by using an XCMS software, performing metabolite structure identification on the data extracted by the XCMS, analyzing the taurine level in a sample, and performing Fold variation analysis (FCAnalysis), principal Component Analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA) and T-test (Student's T-test) by using an R language tool (rpacks), wherein the results are shown in fig. 1 and table 1, and the taurine level in the feces sample of the AD model mouse is significantly higher than that of a wild type mouse, which shows that the taurine in the feces can be used as an alzheimer's disease biomarker, and early diagnosis of alzheimer's disease can be assisted by detecting the taurine level in the feces.
TABLE 1
| Metabolites | VIP | Fold differential expression | pvalue | Significance of | |
| AD model mouse vs wild type mouse | Taurine | 10.18 | 8.51 | 0.013 | * |
Note: * P <0.05.
In addition, further through KEGG pathway annotation and analysis, taurine is found to belong to the ABC transporters pathway in Membrane transport pathway, ABC transporters (ABC transporters), i.e., ATP-binding cassette transporters (ABC), which are a class of ATP-driven pumps, consisting of two transmembrane domains and two cytosolic ATP-binding domains. Under normal physiological conditions, ABC transporters are transporters of sugar, amino acid, phospholipid and peptide on the plasma membrane of bacteria, transporters of phospholipid, lipophilic drugs, cholesterol and other small molecules on the plasma membrane of mammalian cells, are abundantly distributed on the plasma membrane of the cells of organs such as liver, small intestine, kidney and the like, and can discharge natural poisons and metabolic wastes out of the body.
Example 2
This example provides qualitative and quantitative analysis of metabolites in cerebral cortex samples from 9-month-old AD model mice and Wild Type (WT) mice.
Respectively collecting cerebral cortex samples of 10 AD model mice and 10 wild type mice cultured under the same condition, sequentially numbering the wild type cerebral cortex samples as CWT-1-CWT-1-10, sequentially numbering the cerebral cortex samples of the AD model mice as CTG-1-CTG-1-10, and performing qualitative and quantitative analysis on metabolites by adopting an ultra-performance liquid chromatography-tandem flight time mass spectrometer, wherein the specific method comprises the following steps of:
(1) Cutting open the brain shell of a mouse by using a surgical scissors after the neck of the mouse is cut off, exposing the brain, cutting the brain into two halves along the middle brain seam, respectively removing the cerebellum, the brainstem, the thalamus, the hypocortex and the hippocampus, leaving the cerebral cortex, collecting the complete cerebral cortex on the left and right sides as a sample, adding precooled methanol/acetonitrile/water solution (volume ratio is 2;
(2) Adding the pretreated sample into 100 mu L of acetonitrile aqueous solution (volume ratio is acetonitrile: water = 1) for redissolution, vortexing, centrifuging at 4 ℃ and 14000 Xg for 15min, taking supernatant, injecting and analyzing, and separating by using an Agilent1290Infinity LC ultra-performance liquid chromatography system (UHPLC) HILIC chromatographic column under the same conditions as in example 1;
(3) Sample primary and secondary spectrograms are acquired by using an AB Triple TOF 6600 mass spectrometer on a sample separated by the ultra high performance liquid chromatography system in the step (2), the acquired raw data in the Wiff format is converted into an mzXML format through ProteWizard under the same conditions as in the example 1, peak alignment, retention time correction and peak area extraction are carried out by using XCMS software, metabolite structure identification is carried out on the data extracted by XCMS, and then univariate statistical analysis, multidimensional statistical analysis, differential metabolite screening, differential metabolite correlation analysis and KEGG pathway analysis are carried out, wherein Variable weight Values (VIP) obtained by an OPLS-DA model can be used for measuring the influence strength and the interpretation capacity of the expression mode of each metabolite on classification of each group of samples, differential molecules with biological significance are mined, the VIP value and p-value are comprehensively considered for screening the significant differential metabolites, the results are shown in a graph 2-4 and a Table 2, the model of a rat cortex shows that the feces-AD (rat tissue of a mouse tissue belongs to the change of the metabolism pathway of the wild Mannose, and the metabolic pathway of the rat metabolism of the rat is related to the metabolism of the wild rat, and the metabolism of the rat is shown in the rat metabolism pathway of the rat.
TABLE 2
| Metabolites | VIP | Difference inFold expression | pvalue | Significance of | |
| AD model mouse vs wild type mouse | Mannose | 2.67 | 1.55 | 0.002 | ** |
| AD model mouse vs wild type mouse | Inositol | 10.80 | 1.10 | 0.026 | * |
| AD model mouse vs wild type mouse | Glycine | 1.93 | 1.13 | 0.045 | * |
Note: * P <0.05, p <0.01.
In conclusion, the invention firstly detects that the taurine level in the excrement sample of the Alzheimer's disease is obviously higher than that of the normal excrement sample, takes the taurine in the excrement as the biomarker of the Alzheimer's disease, provides an early diagnosis model and a device of the Alzheimer's disease, can assist the early diagnosis of the Alzheimer's disease by detecting the taurine level in the excrement, is beneficial to noninvasive and rapid detection, and has the characteristics of timeliness, convenience, high specificity and high sensitivity.
The applicant states that the present invention is illustrated by the above examples to show the detailed method of the present invention, but the present invention is not limited to the above detailed method, that is, it does not mean that the present invention must rely on the above detailed method to be carried out. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. An Alzheimer's disease biomarker which is taurine.
2. The use of the biomarker of alzheimer's disease according to claim 1 for constructing an early diagnosis model of alzheimer's disease and/or for preparing an early diagnosis device of alzheimer's disease.
3. An early diagnosis model of alzheimer's disease, wherein the input variables of the early diagnosis model of alzheimer's disease comprise peak intensity values of the taurine mass spectrum of claim 1.
4. The model of claim 3, wherein the output variables of the model comprise fold differential expression, and the formula of the fold differential expression is shown in equation (1):
5. the model for early diagnosis of Alzheimer's disease according to claim 4, wherein the positive judgment criteria for Alzheimer's disease is that the fold of differential expression is not less than 8.51.
6. An early diagnosis device for Alzheimer's disease, comprising:
a sample preparation unit: preparing a sample to be detected into a sample solution to be detected which can be used for the separation of a liquid chromatograph;
a detection unit: separating the sample solution to be detected by using the liquid chromatograph, performing data processing on the separated sample by using a mass spectrometer, and determining the peak intensity value of the taurine mass spectrum of claim 1 in the sample;
an analysis unit: inputting the peak intensity values of the detected taurine mass spectrum into the Alzheimer's disease early diagnosis model of any one of claims 3-5 for data analysis;
an evaluation unit: and outputting the differential expression multiple corresponding to the sample, and judging whether the sample is positive for the Alzheimer's disease.
7. The device of claim 6, wherein the test sample comprises a stool sample.
8. The apparatus of claim 6 or 7, wherein the data processing comprises:
collecting a primary spectrogram and a secondary spectrogram of the separated sample by using a tandem time-of-flight mass spectrometer, converting the primary spectrogram and the secondary spectrogram into an mzXML format, performing peak alignment, retention time correction, peak area extraction and structure identification, and determining the peak intensity value of the taurine mass spectrum of claim 1 in the sample.
9. The device according to any of claims 6-8, characterized in that it comprises the following units:
a sample preparation unit: preparing a sample to be detected into a sample solution to be detected which can be used for the separation of a liquid chromatograph;
a detection unit: separating the sample solution to be detected by using the liquid chromatograph, collecting a primary spectrogram and a secondary spectrogram of the separated sample by using a tandem time-of-flight mass spectrometer, converting the primary spectrogram and the secondary spectrogram into an mzXML format, performing peak alignment, retention time correction, peak area extraction and structure identification, and determining the peak intensity value of the taurine mass spectrum of claim 1 in the sample;
an analysis unit: inputting the peak intensity values of the detected taurine mass spectra into the Alzheimer's disease early diagnosis model of any one of claims 3-5 for data analysis;
an evaluation unit: and outputting the differential expression multiple corresponding to the sample, and judging whether the sample is positive for the Alzheimer's disease.
10. Use of the Alzheimer's disease biomarker of claim 1 for screening of drugs for treatment and/or prevention of Alzheimer's disease.
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| US20160209428A1 (en) * | 2013-08-21 | 2016-07-21 | The Regents Of The University Of California | Diagnostic and predictive metabolite patterns for disorders affecting the brain and nervous system |
| EP3254114A1 (en) * | 2015-02-03 | 2017-12-13 | Pharnext | Diagnostic tools for alzheimer's disease |
| KR102355667B1 (en) * | 2016-07-08 | 2022-01-26 | 아지노모토 가부시키가이샤 | Assessment method for future onset risk of Alzheimer's type dementia |
| US20210293794A1 (en) * | 2017-02-24 | 2021-09-23 | University Of Hawii Cancer Center | Metabolic biomarkers for the identification and characterization of alzheimers disease |
| CN109709235A (en) * | 2019-02-25 | 2019-05-03 | 马红华 | Early diagnosis, prediction biomarker combinations, application and its measuring method of Alzheimer disease or slight old cognitive disorder |
| CN112336860A (en) * | 2019-08-06 | 2021-02-09 | 上海绿谷制药有限公司 | Method for treating alzheimer's disease by modulating gut microbiome |
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