CN102279270A - Method for monitoring beta amyloid protein aggregation process by aggregation-induced emission - Google Patents
Method for monitoring beta amyloid protein aggregation process by aggregation-induced emission Download PDFInfo
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Abstract
本发明公开了一种利用聚集诱导发光监测β淀粉样蛋白聚集过程的方法，属于生物医学研究和临床检测技术领域。该方法利用马来酰亚胺与半胱氨酸上巯基的高亲和性，将β淀粉样蛋白特异性地结合在聚集诱导荧光探针上。基于聚集诱导发光增强现象监测β淀粉样蛋白的聚集过程。该方法具有高灵敏、高选择性、稳定性好，易控制，制作成本低廉等优点。可以监测微摩尔甚至纳摩尔的Aβ42和Aβ40含量，且检测速度比利用ANS（8-苯胺-1-萘磺酸）等探针的监测方法提高15倍。可以定性或定量地监测β淀粉样蛋白聚集过程，将用其于潜伏期老年性痴呆患者的病理诊断，具有很好的应用前景。The invention discloses a method for monitoring the aggregation process of beta amyloid protein by using aggregation-induced luminescence, and belongs to the technical field of biomedical research and clinical detection. This method utilizes the high affinity between maleimide and the sulfhydryl group on cysteine to specifically bind β-amyloid to the aggregation-inducing fluorescent probe. Monitoring the aggregation process of β-amyloid based on the phenomenon of aggregation-induced luminescence enhancement. The method has the advantages of high sensitivity, high selectivity, good stability, easy control, low production cost and the like. The content of Aβ42 and Aβ40 in micromolar or even nanomolar can be monitored, and the detection speed is 15 times higher than the monitoring method using ANS (8-aniline-1-naphthalenesulfonic acid) and other probes. It can qualitatively or quantitatively monitor the aggregation process of β-amyloid protein, and it will be used in the pathological diagnosis of patients with latent senile dementia, which has a good application prospect.
Description
Technical field
The present invention relates to the monitoring method of amyloid beta accumulation process, relate in particular to the method for utilizing aggregation inducing luminescence method monitoring amyloid beta accumulation process, belong to biomedical research and clinical detection technique field.
Background technology
Alzheimer's disease (Alzheimer ' s Disease is to cause the modal a kind of disease of senile dementia AD).At present, AD is elderly population relaying cardiovascular and cerebrovascular diseases, cancer, apoplexy the fourth-largest killer afterwards.The pathological characteristics of AD is to observe old and feeble patch in extracellular and intracellular NFT in patient's brain, this is can form the small peptide aggregation that neuronal cell is had toxic action because amyloid-beta (amyloid β-protein, A β) is coalescent unusually inside and outside cell.Modal A β is A β 40 and A β 42(A β 42 easier gatherings in blood plasma, celiolymph and small peptide aggregation, and toxicity is stronger), they are cut and produce through β and gamma-secretase fixed point enzyme successively by amyloid protein precursor.Current to AD patient's diagnosis mainly is to lose according to the part of its memory and behavior, and patient's pathological diagnosis is a world's advanced subject with challenge meaning for latent period.
Show that according to the medical science related data in the existing 2,400 ten thousand senile dementia patients in the whole world, China accounts for 1/4, and with annual 1000000 speed increase.Current, the most frequently used technology of asymptomatic AD patient's detection there is magnetic resonance imaging (magnetic resonance Imaging, MRI), positron emission imaging (positron emission tomography, PET) and optical imagery (optical imaging), surface-enhanced Raman (surface enhanced Raman spectroscopy, SERS) spectrum, scan-type electrochemical microscope (scanning electrical microscopy, SEM) technology and electrochemical method etc.The sensitivity of MRI is lower, is difficult to effective utilization at clinical medicine; The PET price is too high, and alternative isotope-labeled PET probe is less at present, and these have limited its widespread use greatly.Electrochemical method needs complicated electrode production process.The document that endogenous fluorescence method detects the amyloid beta aggregation also has report, but the excitation wavelength and the emission wavelength of tryptophane, lysine and the phenylalanine of sending out fluorescence endogenous all are in the ultraviolet region, are difficult to direct imaging and observe, and quantum yield is lower, and detection sensitivity is lower.Fluorescence probe can adsorb or be covalently bound on the protein, causes its fluorescent characteristic (emission wavelength, fluorescence intensity, fluorescence polarization degree etc.) to change, and then can carry out qualitative and quantitative examination to protein.At present, in the fluoroscopic examination of A β the most frequently used fluorescence probe have thioflavin (Thioflavin, ThT), Congo red (Congo Red, CR) and 8-phenylamino-1-naphthalene sulfonic aicd (8-Anilino-1-naphthalenesulfonic acid, ANS) etc.These probes all are to combine by hydrophobic effect and protein, cause the variation of fluorescence probe fluorescent characteristic, so specificity is very poor; In addition, the detection repeatability of these probes is all very poor; These probes also can't detect some intermediates that occur in the amyloplaste forming process.Add, amyloid beta content in body fluid is low, aggregation velocity is slower, so, synthetic hypersensitive actuator and the sensor that can monitor the amyloid beta accumulation process of design, develop medical kit, can make that a lot of early stage patients are early found, early treatment, significantly reduce patient's body misery and financial burden senile dementia patient early diagnosis.(α-synuclein) is modified at after quantum dot (Qdot 605) goes up with sisters' protein alpha-same nucleoprotein of A β in discoveries such as Roberti, form a nucleating centre that can promote that α-synuclein assembles, this method can be studied the accumulation process of α-synuclein in living cells fast, delicately.Jovin etc. pass through covalent bond coupling maleimide (maleimide) on the fluorescent material pyrene, alanine mutation with inertia on α-synuclein is the halfcystine ((Cysteine that contains hydroxyl, Cys)), utilize the high-affinity of maleimide and sulfydryl, on three kinds of mutant of α-synuclein mark the pyrene molecule.Utilize pyrene to assemble the back and form the gathering that the emission peak that produces behind the excimer (excimer) detects α-synuclein.Although the pyrene molecule can form excimer, because excimer is less at the fluorescence peak at 470 nm places, so, can only illustrate qualitatively to have formed aggregation, aggregation extent can't quantitatively be described exactly.
Aggregation inducing fluorescence strengthens that (aggregation induced emission enhancement, AIEE) the type compound is a research focus of fluorescence probe aspect in recent years.Because its specific molecule structure, its fluorescence in organic solvent is very weak even not luminous, if the solvent environment polarity of its existence increases, when perhaps compound exists with aggregation or solid form, some substituting group rotations that can rotate freely originally in the molecule are obstructed, the non-radiative inactivation that has suppressed fluorescence molecule so consumingly causes the fluorescence of AIEE type compound to strengthen greatly.If at a kind of AIEE type compound molecule on the mark specifically on A β 42 or the A β 40, the gathering of A β 42 or A β 40 molecules must cause the gathering of AIEE type compound, fluorescence strengthens.Can monitor the amyloid beta accumulation process qualitative or quantitatively, will have good application prospects, yet there are no the pertinent literature report with its pathological diagnosis in senile dementia patient in latent period.
Summary of the invention
The object of the invention provide a kind of can be highly sensitive, the luminous new method of aggregation inducing of highly selective monitoring amyloid beta accumulation process, for the early diagnosis of diseases such as senile dementia provides useful information.
For realizing the object of the invention, the present invention utilizes the high-affinity of sulfydryl on maleimide and the halfcystine, amyloid beta is combined on the aggregation inducing fluorescence probe specifically, based on the luminous enhancing phenomenon of aggregation inducing, highly sensitive, highly selective monitoring amyloid beta accumulation process, thereby the qualitative or interior amyloid beta variation of monitoring human quantitatively.
Concrete technical scheme: at first synthetic fluorescence probe with the luminous enhancement effect of aggregation inducing, utilize covalent bond coupling maleimide on the aggregation inducing fluorescent probe molecule, the 2nd glycine mutation on amyloid beta 42 molecules is become halfcystine, utilize the high-affinity of sulfydryl on maleimide and the halfcystine, amyloid beta is combined on the aggregation inducing fluorescence probe specifically, with the accumulation process of the luminous enhancing method monitoring of aggregation inducing amyloid beta.
Specifically realize by following steps:
1) become the amyloid-beta of halfcystine to be dissolved in the phosphate buffered solution the 2nd glycine mutation on A β 42 molecules;
2) add the fluorescence probe with the luminous enhancement effect of aggregation inducing of following structure then:
Fluorescence probe 1
Or
Fluorescence probe 2
Or
Fluorescence probe 3;
3) in the solution that step (2) makes, add the amyloid beta testing sample, monitor its fluorescence intensity, utilize the accumulation process of the luminous enhancing monitoring of aggregation inducing amyloid beta.
Described phosphate buffered solution is phosphate 0.2 M, pH 7.4 buffer solution.
The present invention has set up a kind of luminous new method of aggregation inducing of monitoring the amyloid beta accumulation process, choosing coupling has three kinds of fluorescent probe molecules with aggregation inducing luminescent effect of maleimide base group, the 2nd glycine mutation on A β 42 molecules is become halfcystine, utilize the high-affinity of sulfydryl on maleimide and the halfcystine, amyloid beta is combined on the aggregation inducing fluorescence probe specifically.The gathering of amyloid beta can cause that the environment hydrophobicity that mark aggregation inducing fluorescent probe molecule thereon exists increases, and fluorescence strengthens, can be highly sensitive, the accumulation process of highly selective monitoring amyloid beta.Have the following advantages:
1) the aggregation inducing luminescence method of monitoring amyloid beta has very low fluorescence background, and sensitivity improves widely;
2) the 2nd glycine mutation on A β 42 (amyloid beta 42) molecule is become the amyloid beta 42 of halfcystine, described variation position can be marked at fluorescence probe the gathering behavior that is unlikely to change A β 42 molecules on amyloid beta 42 molecules again effectively.Utilize the high-affinity of sulfydryl on maleimide and the halfcystine, improved the selectivity of monitoring method;
3) preparation method is simple, control easily, and cost of manufacture is cheap, and is simple efficient; The monitoring method good stability, favorable reproducibility;
4) applied range can connect other protein or utilize the structural change of the luminous enhancing phenomenon of aggregation inducing research protein molecule or dna molecular on the aggregation inducing fluorescence probe.
5), can monitor the A β 42 and A β 40 content of micromole even nanomole, and detection speed Billy is with ANS(8-aniline-1-naphthalene sulfonic aicd by the luminous enhancing phenomenon of aggregation inducing) wait 15 times of the monitoring method raisings of probe.
Embodiment
For the present invention is better illustrated, as follows for embodiment:
Embodiment one usefulness coupling has the accumulation process of the fluorescence probe 1 monitoring amyloid beta 42 of maleimide, realizes by following steps:
1, synthesis of coupling has maleimide fluorescence probe 1,, this probe is water miscible.Synthetic route is as follows.
2, buy the A β 42 that the 2nd glycine mutation becomes halfcystine, it is dissolved in (0.2 M, pH 7.4) in the phosphate buffered solution.
3, adding coupling in above-mentioned steps 2 has maleimide fluorescence probe 1, utilizes the specificity covalent bond that forms between the sulfydryl on maleimide and the halfcystine that amyloid beta is combined on the aggregation inducing fluorescence probe specifically.
4, utilize the accumulation process of the luminous enhancing monitoring of aggregation inducing amyloid beta: the above-mentioned probe for preparing is put into contained 50 nM A β 42 and 400 times of complement C3, complement C4, IGA, IGM, IGG, IGD, IGE, fibroblast growth factor, epidermal growth factor, PDGF, 200 times of seralbumins, beta lipoprotein, α-1 acidoglycoprotein, the anti-tryptose of α-1, alpha-fetoprotein, haptoglobin, CER, α-2 macroglobulin, α-2 lipoprotein, transferrins, 100 times α-1 globulin, α-2 globulin, betaglobulin, in the gamma globulin sample, the discovery amyloid beta is assembled, the gathering of amyloid beta causes that the environment hydrophobicity that mark aggregation inducing fluorescent probe molecule 1 thereon exists increases, and fluorescence strengthens.With the accumulation process of the luminous enhancing monitoring of aggregation inducing amyloid beta, the range of linearity is 4-100 nM (R=0.9958), detects to be limited to 0.5 nM(3 σ), sensitivity is preferably arranged.And above-mentioned chaff interference does not all disturb the mensuration (relative standard deviation is controlled in 5%) of amyloid beta, has selectivity preferably.Detection in 30 minutes finishes.
Coupling has fluorescence probe 1 synthetic route of maleimide
Compound 1 and 2 is at NaH and Ph
3Reaction generates intermediate product 3 under the condition of P, and intermediate product 3 is at CHCl
3With under the condition of NaOAc and maleic anhydride reacting generating compound 4, compound 4 and BBr
3Reacting generating compound 5, compound 5 in the NaOH environment and ethylene dibromide reaction generate intermediate 6, intermediate 6 generates target product 7 in the mixed solvent of tetrahydrofuran and water and the triethylamine effect.
The coupling of embodiment dual-purpose has the accumulation process of imido fluorescence probe 2 monitoring amyloid betas 42, realizes by following steps:
1, synthesis of coupling has maleimide fluorescence probe 2, and this probe is water miscible.Synthetic route is as follows.
2, buy the A β 42 that the 2nd glycine mutation becomes halfcystine, it is dissolved in (0.2 M, pH 7.4) in the phosphate buffered solution.
3, adding coupling in above-mentioned steps 2 has maleimide fluorescence probe 2, utilizes the specificity covalent bond that forms between the sulfydryl on maleimide and the halfcystine that amyloid beta is combined on the aggregation inducing fluorescence probe specifically.
4, utilize the accumulation process of the luminous enhancing method monitoring of aggregation inducing amyloid beta: the above-mentioned probe for preparing is put into A β 42 and the 300 times of complement C3 that contain 30 nM, complement C4, IGA, IGM, IGG, IGD, IGE, fibroblast growth factor, epidermal growth factor, PDGF, 150 times of seralbumins, beta lipoprotein, α-1 acidoglycoprotein, the anti-tryptose of α-1, alpha-fetoprotein, haptoglobin, CER, α-2 macroglobulin, α-2 lipoprotein, transferrins, 50 times α-1 globulin, α-2 globulin, betaglobulin, in the gamma globulin sample, the discovery amyloid beta is assembled, the gathering of amyloid beta causes that the environment hydrophobicity that mark aggregation inducing fluorescent probe molecule 2 thereon exists increases, and fluorescence strengthens.With the accumulation process of the luminous enhancing method monitoring of aggregation inducing amyloid beta, the range of linearity is 5-90 nM (R=0.9975), detects to be limited to 1 nM(3 σ), sensitivity is preferably arranged.And above-mentioned chaff interference does not all disturb the mensuration (relative standard deviation is controlled in 5%) of amyloid beta, has selectivity preferably.Detection in 30 minutes finishes.
Coupling has fluorescence probe 2 synthetic routes of maleimide
Compound 1 is under the NaH condition and Ph
3The P reaction generates intermediate 2, and intermediate 2 and compound 3 reactions generate product 4, product 4 and AgNO
3Reaction generates product 5, and product 5 is at CHCl
3And generate target product 6 with the maleic acid anhydride reactant in the HAc/NaOAc environment.
Embodiment three usefulness couplings have the accumulation process of the fluorescence probe 3 monitoring amyloid betas 42 of maleimide, realize by following steps:
1, synthesis of coupling has maleimide fluorescence probe 3, and this probe is water miscible.Synthetic route is as follows.
2, buy the A β 42 that the 2nd glycine mutation becomes halfcystine, it is dissolved in (0.2 M, pH 7.4) in the phosphate buffered solution.
3, adding coupling in above-mentioned steps 2 has maleimide fluorescence probe 3, utilizes the specificity covalent bond that forms between the sulfydryl on maleimide and the halfcystine that amyloid beta is combined on the aggregation inducing fluorescence probe specifically.
4, utilize the accumulation process of the luminous enhancing method monitoring of aggregation inducing amyloid beta: the above-mentioned probe for preparing is put into contained 50 nMA β 42 and 500 times of complement C3, complement C4, IGA, IGM, IGG, IGD, IGE, fibroblast growth factor, epidermal growth factor, PDGF, 200 times of seralbumins, beta lipoprotein, α-1 acidoglycoprotein, the anti-tryptose of α-1, alpha-fetoprotein, haptoglobin, CER, α-2 macroglobulin, α-2 lipoprotein, transferrins, 150 times α-1 globulin, α-2 globulin, betaglobulin, in the gamma globulin sample, the discovery amyloid beta is assembled, the gathering of amyloid beta causes that the environment hydrophobicity that mark aggregation inducing fluorescent probe molecule 3 thereon exists increases, and fluorescence strengthens.With the accumulation process of the luminous enhancing method monitoring of aggregation inducing amyloid beta, the property scope is 10-150 nM (R=0.9982), detects to be limited to 2 nM(3 σ).Sensitivity is preferably arranged.And above-mentioned chaff interference does not all disturb the mensuration (relative standard deviation is controlled in 5%) of amyloid beta, has selectivity preferably.Detection in 30 minutes finishes.
Coupling has fluorescence probe 3 synthetic routes of maleimide
Compound 1 generates compound 2 with glycol reaction in the p-methyl benzenesulfonic acid environment, compound 2 is at Zn/TiCl
4Following and the compound 3 reaction generation products 4 of catalysis, product 4 is under methenyl choloride and NaOAC condition and maleic anhydride reacting generating compound 5, compound 5 changes into compound 6 in the environment of p-methyl benzenesulfonic acid, compound 6 and reactant 7 reactions generate target product 8.
The present invention is based on the luminous enhancing phenomenon of fluorescence probe aggregation inducing, highly sensitive, highly selective is monitored the accumulation process of amyloid beta, has obtained effect preferably.
Claims (2)
1. method of utilizing the luminous monitoring amyloid beta of aggregation inducing accumulation process, its feature
Be, realize by following steps:
1) become the amyloid-beta of halfcystine to be dissolved in the phosphate buffered solution the 2nd glycine mutation on A β 42 molecules;
2) add the fluorescence probe with the luminous enhancement effect of aggregation inducing of following structure then:
Or
Or
3) in the solution that step (2) makes, add the amyloid beta testing sample, monitor its fluorescence intensity, utilize the accumulation process of the luminous enhancing monitoring of aggregation inducing amyloid beta.
2. a kind of method of utilizing the luminous monitoring amyloid beta of aggregation inducing accumulation process as claimed in claim 1 is characterized in that phosphate buffered solution is 0.2 M, pH 7.4 buffer solution.
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