CN1721437A - Polypeptide antigen and antibody related to Tau protein - Google Patents
Polypeptide antigen and antibody related to Tau protein Download PDFInfo
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- CN1721437A CN1721437A CN 200410045033 CN200410045033A CN1721437A CN 1721437 A CN1721437 A CN 1721437A CN 200410045033 CN200410045033 CN 200410045033 CN 200410045033 A CN200410045033 A CN 200410045033A CN 1721437 A CN1721437 A CN 1721437A
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Abstract
The present invention relates to Tau protein relative polypeptide antigen and antibody. The specific polypeptide antigen of the present invention has the amino acid sequence of SEQ ID No. 1, and corresponding polyclonal or monoclonal antibody may be obtained in available method. The antibody of the present invention may be prepared into kit for detecting and diagnosing senile dementia.
Description
Technical field
The present invention relates to Tau albumen relevant polypeptide antigen and antibody.
Technical background
Microtubule system is the neurocyte framework ingredient, mainly participates in the various kinds of cell function.Microtubule is made up of tubulin and microtubule-associated protein, the microtubule-associated protein that Tau albumen is.The normal proteic function of Tau is to combine with tubulin to promote its polymerization to form microtubule; Combine with the microtubule that forms, keep microtubule stability, reduce dissociating of tubulin molecule.It is long-armed that the Tau protein gene is positioned at 17 karyomit(e)s.Owing to Tau protein rna montage mode difference, can give expression at least 6 kinds of abnormal shapes among the normal people.Tau albumen is phosphorous acidic group albumen, and the Tau protein molecular contains 2～3 phosphates in the normal mature brain.The then unusual excessive phosphorylation of AD patient's Tau albumen, per molecule Tau albumen can contain 5～9 phosphates, and loses normal biological function.Protein tau may be from neurocyte death or degradation degeneration in the cerebrospinal fluid.The Protein tau level significantly raises in AD patient's cerebrospinal fluid, is about normal healthy controls group and other nervous system disorders control group 2 times.
The applicant finds that the montage of Tau gene the 6th exon is different from its exon 2 when the montage of research Tau gene the 6th exon, 3, and 4A and 10 montage
[1]Studies confirm that subsequently, the selection utilization of Tau gene the 6th exon splice site will cause the change of its reading frame, and may produce brachymemma, promptly lack the new Tau albumen abnormal shape with tubulin binding domains (C-holds by brachymemma)
[1,2]---the special-shaped 6d of Tau albumen.Whether the special-shaped 6d of this new Tau albumen exists with proteinic form, needs further research.From its mRNA structure, the special-shaped 6d of Tau albumen utilizes alternative splicing site 6d in No. 6 exons of Tau gene and produces, and this montage causes the phase shift mutation of back sequence and runs into termination codon very soon, and 3 ' end has very long non-translational region (see figure 1).Present 3 ' non-translational region of end be generally acknowledge cause the unsettled important factor of mRNA
[3,4]Therefore, whether the special-shaped 6d of albumen exists and can not directly directly reach a conclusion from above-mentioned disclosed document with proteinic form.
Summary of the invention
The objective of the invention is further to obtain its specific polypeptide antigen and antibody, and be used for proteic detection to Tau by affirmation to the special-shaped 6d of Tau albumen.
Specific polypeptide antigen provided by the invention has the aminoacid sequence of SEQ ID No.1.
The applicant has determined specific polypeptide fragment by the analysis to the special-shaped 6d aminoacid sequence of Tau albumen.
Through traditional immunization method, can obtain polyclonal antibody with the above-mentioned specific polypeptide antigen that obtains.
Also can obtain the antigenic monoclonal antibody of aforementioned polypeptides with traditional method.
Polyclonal antibody with above-mentioned acquisition detects and identifies the special-shaped 6d of Tau albumen.The result shows that the special-shaped 6d of the new Tau albumen of A. exists (Fig. 4,5) with proteinic form really; B. prepared 6d antibody is the antibody (Fig. 4,5) of high special
[11]
From Fig. 5 the detected result of B, C, D as can be seen, the antibody of the present invention preparation only produces immune response to the special-shaped 6d of Tau albumen; And other existing antibody do not possess such characteristic.
The memory of hippocampus and humans and animals, intelligence, emotion etc. are closely related.The senile dementia patient, hippocampus is to get involved at first and the heaviest position of pathology, and in normal adult and animal brain, the dentate gyrus of its hippocampus is the neural stem cell concentration zones, think these neural stem cell and brain normal function keep closely related.For understanding expression and the distribution of the special-shaped 6d of new Tau albumen in the normal people hippocampus, through the immunohistochemical methods method normal people's hippocampus is carried out immunostaining with anti--6d antibody, find that the special-shaped 6d positive cell of new Tau albumen mainly concentrates on dentate gyrus and CA1-CA3 district, and locate altogether with neuronic marker protein MAP2, see Fig. 7.
Therefore, antibody provided by the invention can be prepared into test kit, is used for detection and diagnoses senile dementia to cause a disease.
Description of drawings
The special-shaped reading frame structure iron of the alternative splicing of No. 6 exons of Fig. 1 .Tau gene.On: be Tau/6
+Montage abnormal shape (Tau/6
+) cDNA and aminoacid sequence.In: the cDNA and the aminoacid sequence of Tau/6p montage abnormal shape (Tau/6p).Down: the cDNA and the aminoacid sequence of Tau/6d montage abnormal shape (Tau/6d).The arrow mark of last figure part optionally splice site of two of 6p and 6d, and the terminator of StuI, Tau/6p and Tau/6d (TAA, tga) with setting-out sign down, * represents the non-translational region of 3 '-end, flanking sequence is a lower case.
The chromatogram result of Fig. 2 institute synthetic specific polypeptide;
The mass spectrum result of Fig. 3 institute synthetic specific polypeptide;
The antibody that Fig. 4 purifying is later;
Fig. 5 uses the anti--6d polyclonal antibody that is obtained to detect the FLAG-Tau/6d of vivoexpression through Western Blotting.
(A) the special-shaped expression vector structure diagram of Tau albumen of constructed FLAG-fusion.
(B-D) Western Blotting detects the Tau albumen abnormal shape of the FLAG-fusion of transient expression in the SY5Y cell.Each 30 μ g of the SY5Y cell lysate of FAT/6-and FFT/6-transfection, each 50 μ g of the SY5Y cell lysate of FAT/6d and FFT/6d transfection separate through 10%SDS-PAGE, and the right side is a protein molecular weight standard; (B) detect expressed Tau albumen abnormal shape with anti-FLAG (M2) monoclonal antibody.; (C) will use the polyclonal antibody of anti-6d to detect expressed Tau albumen abnormal shape behind the membrane elution of (B) again; (D) detect expressed Tau albumen abnormal shape with the 5A6 monoclonal antibody, the result is consistent with (B).(E) FAT/6d and FFT/6d molecular weight behind dephosphorylation drops to predicated value;
The spatial and temporal distributions of the special-shaped 6d of endogenous Tau albumen in Fig. 6 human brain tissue.Used antibody is marked in the left side, and protein molecular weight standard is listed in the right side.(A-C) detect endogenous Tau albumen abnormal shape in 100 each sample of μ g with the 5A6 monoclonal antibody through WesternBlotting, (A) the above traditional Tau of 49kD, (B) the following special-shaped 6d of Tau albumen of 36KD.(C) with behind (A) and the membrane elution (B), the polyclonal antibody with anti-6d detects again, only detects the signal of 25-36Kd scope, and is similar to (B).(D-F) carry out quantitatively
The distribution of the special-shaped 6d of Fig. 7 endogenous Tau albumen in the adult hippocampus is with the common location of MAP2.
(A-D) the special-shaped 6d of Tau albumen distributes, and one anti-ly is the 6d polyclonal antibody, and two anti-ly are the goat anti-rabbit igg of FITC mark; (A-D) scale is 500 μ m.(E-G) special-shaped 6d of Tau albumen and the common location situation of MAP2 in hippocampus.(E) distribution of the special-shaped 6d of Tau albumen, antibody and Fig. 4 (A-D) are together; (F) distribution of MAP2 in hippocampus, one anti-is the MAP2 monoclonal antibody, two anti-ly are the sheep anti-mouse igg of Cy3 mark; (G) be 4E and 4F the stack after image.
Specific embodiment
Embodiment 1
The preparation of polypeptide antigen
Polypeptide antigen provided by the invention has the described aminoacid sequence of SEQ ID No.1, i.e. FWSKGDETQGG.Can be synthetic by commercial company.This polypeptide antigen, purifying synthetic by Zymed company among the application, freeze-drying the results are shown in Figure 2,3.
Embodiment 2
The preparation of the specific polyclonal antibody (6d) of the special-shaped 6d of Tau albumen:
Above-mentioned antigen that obtains and KLH coupling
[5]After, immune animal (rabbit)
[6,7]The preparation antiserum(antisera), the purifying antiserum(antisera) obtains 6d antibody
[8,9], the 6d antibody of purifying separates with 10%SDS-PAGE after Coomassi dyeing detects (Fig. 4)
[10]
(1) immune animal (rabbit)
[6,7]The preparation antiserum(antisera):
Add the equivalent Freund's complete adjuvant in 1ml polypeptide antigen solution (1mg/ml is dissolved in PBS), (Thomas Scientific 345OD46) carries out emulsification with two-tube miniature emulsification pin.Strike off the rabbit back hair, 70% alcohol disinfecting.Carry out intradermal injection with 3ml syringe (24-G) syringe needle to be 30 ° of angles with skin, divide 24 points to inject, each injection point is injected 25 μ l, altogether 3 rabbits of immunity.Carry out booster immunization respectively at the freshly prepared antigen of injection 0.5ml-Freund's complete adjuvant emulsion in the two back leg leg muscles of rabbit after 6 weeks, the same every 2 all booster immunizations 1 time, blood sampling in 10 days detects antibody through ELISA and produces level behind booster immunization, booster immunization 3 times, serum is collected in the heart blood sampling after the aggegation.
(2) the purifying antiserum(antisera) obtains 6d antibody
[8,9]:
A. the saturated ammonium sulphate method precipitates IgG
Slowly in serum, add the saturated ammonium sulphate of 1/2 volume in 4C ° with dropper, continue to stir 4h, 12, the centrifugal 20min precipitation of 000Xg IgG is resuspended in throw out 33% saturated ammonium sulphate to former serum volume, centrifuge washing.Heavily wash 1 time.Throw out is dissolved in PBS to 10% of former serum volume in 4C ° of slow vibration, and 4C ° of dialysis 48h changes dialysis buffer liquid 3 times, removes all ammonium sulfate.
B. carry out purifying with antigen-Sepharose through immunoaffinity chromatography
1) preparation antigen-Sepharose post:
With the expanded CNBr-Sepharose 4B of 1mM HCl, in succession with 1mM HCl 300ml and coupling buffer (pH8.3,0.125M Na
2HPO
4) the expanded CNBr-Sepharose 4B of 300ml washing, adding synthetic 6d polypeptide antigen is 2mg/ml to final concentration, and 4C ° of vibration spent the night, and the centrifugal 10min of 250Xg adds coupling buffer, the centrifugal 10min of 250Xg.Hatch 5h with 1M thanomin (pH8.0) at 4C °, the centrifugal 10min of 250Xg, behind the PBS centrifuge washing, the dress post is also used the PBS balance.
2) application of sample: sample 1-5ml/min is added to antigen-Sepharose post, with the unconjugated composition of 30ml PBS wash-out.
3) composition of elution of bound: the hydrochloric acid-glycine buffer (2-3 times of column volume) with pH2.3 carries out wash-out.
4) collect elutriant, concentrate the antibody that obtains with centrifugal filter device.
Embodiment 3
6d antibody is used for detecting and identifies whether the special-shaped 6d of Tau albumen exists with proteinic form: with 6d is one anti-, through Western Blotting, detects expression level and the spatial and temporal distributions of endogenous Tau albumen abnormal shape 6d in the cerebral tissue of different sites; Clone the special-shaped 6d gene of Tau albumen simultaneously and import COS cell etc. and carry out vivoexpression, through Western Blotting the special-shaped 6d of exogenous Tau albumen is detected evaluation, the result shows that the special-shaped 6d of the new Tau albumen of A. exists (Fig. 5,6) with proteinic form really;
B. prepared 6d antibody is the antibody (Fig. 5,6) of high special
[11]
Embodiment 4
Through the immunohistochemical methods method to the special-shaped 6d of Tau albumen Position Research in cerebral tissue and spinal cord:
The method that frozen spinal cord, fresh preceding hippocampus and hippocampal tissue (Harvard Brain Tissue ResourceCenter in Boston and Brain and Tissue Bank for Developmental Disorders inBaltimore) are pressed Jones
[12]Carry out antifreeze processing: will fill stationary liquid (with 6% Paraformaldehyde 96 of PBS preparation, 20% sucrose, 20% ethanol, 20% ethylene glycol, 10% glycerine) container immerse another be equipped with 100% ethanol and also all around in the container of dry ice rapidly the refrigeration, begin hardening (pact-60C °) up to stationary liquid.Tissue block is put into stationary liquid, forwards to then-20C °, shook gently once in per 8 hours, kept like this 7 days, go to 4C ° and continue to shake again, up to the temperature equilibrium of tissue block and stationary liquid to 4C °.
Tissue block after the antifreeze processing changes in the 30% sucrose liquid with PBS preparation, shakes 24 hours in 4C °, changes sucrose solution once after interim 12 hours.Then tissue block can be frozen in-70C ° or be cut into 50 μ m slabs.Section is washed 3 times with the 50mM PBS (pH7.4) of precooling, each 10 minutes; 100mMPBS (pH7.4) washes 2 times, each 10 minutes; The PBS that contains 1%BSA and 0.3%Triton X-100 sealed 30 minutes; One resists in 4C ° of dyeing and spends the night; Wash 4 times each 15 minutes with the PBS that contains 0.02%Triton X-100; Two anti-room temperature dyeing 2 hours are washed 4 times each 15 minutes with PBS; Section is laid on the slide glass, does the back mounting and observation under fluorescent microscope.
Used antibody: one anti-has: the polyclonal antibody of anti--6d, dilution in 1: 200; The Tau5 monoclonal antibody, dilution in 1: 500; MAP2 monoclonal antibody (Zymed) dilution in 1: 200.Two anti-have: FITC-goat anti-rabbit igg (Zymed), dilution in 1: 500; Cy3-sheep anti-mouse igg (Zymed), 1: 1,000 dilution.(Fig. 7)
Embodiment 5
ELISA detected result (seeing Table 1) with the special-shaped 6d of Tau albumen in the antibody test people spinal fluid provided by the invention.The result shows that proteic detection has specificity to Tau with antibody provided by the invention.
Table 1
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | |
| A | 2.573 | 2.330 | 0.005 | 1.863 | 2.774 | 1.359 | 2.030 | 1.453 | 2.034 | 1.746 | 0.000 | 0.000 |
| B | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 |
| C | 2.467 | 1.561 | 0.992 | 2.841 | 1.348 | 1.555 | 2.389 | 0.035 | 1.439 | 1.025 | 0.000 | 0.000 |
| D | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 |
| E | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 |
| F | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 |
| G | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 |
| H | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 |
| 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | |
| A | 0.003 | 0.080 | 0.059 | 0.044 | 0.002 | 0.032 | 0.151 | 0.067 | 0.209 | 0.013 | 0.000 | 0.000 |
| B | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 |
| C | 0.009 | 0.016 | 0.000 | 0.003 | 0.003 | 0.074 | 0.095 | 0.016 | 0.005 | 0.060 | 0.000 | 0.000 |
| D | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 |
| E | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 |
| F | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 |
| G | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 |
| H | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 | 0.000 |
The first half is that Lower Half is a control group to the detected result of patient's group in the table.Wherein, have only A3 and C8 to be negative in 20 routine patient's groups, all the other 18 positive.
Reference
1.Wei ML，Andreadis A.Splicing of a regulated exon reveals additional complexity in theaxonal microtubule-associated protein tau.J Neurochem 1998 Apr；70(4)：1346-56
2.Wei ML，Memmott J，Screaton G，Andreadis A.The splicing determinants of a regulatedexon in the axonal MAP tau reside within the exon and in its upstream intron.Brain ResMol Brain Res.2000 Sep 15；80(2)：207-18.
3.Oliveira CC，McCarthy JE.The relationship between eukaryotic translation and mRNAstability.A short upstream open reading frame strongly inhibits translational initiation andgreatly accelerates mRNA degradation in the yeast Saccharomyces cerevisiae.J Biol Chem1995；270：8936-8943.
4.Frischmeyer PA.Dietz HC.Nonsense-mediated mRNA decay in health and disease.HumMol Genet 1999；8：1893-1900.
The gold winter wild goose, Li Mengfeng translates.Molecular cloning experiment guide second edition. the P856-857. in 1998 of Science Press
The gold winter wild goose, Li Mengfeng translates.Molecular cloning experiment guide second edition. the P854-855. in 1998 of Science Press
7.Current Protocols of Immunology，Chapter 11.12--Preparation of polyclpnal antisera.
8.Current Protocols of Immunology，Chapter 10.11--Immunoaffinity chromatography
9.Current Protocols of Immunology，Chapter 10.13--Purification if IgG fraction fromantiserum，ascites fluid，or hybridoma supernatent
10.Current Protocols of Immunology，(HPLC)
Claims (4)
1, a peptide species has SEQ ID No.1 aminoacid sequence.
2, the antibody of the described polypeptide of a kind of anti-claim 1.
3, a kind of test kit contains the described antibody of claim 2.
4, a kind of method that detects Tau albumen 6d in the cerebrospinal fluid is characterized in that detecting with the antibody of the described polypeptide of anti-claim 1.
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