WO2012081433A1 - アミロイドβ神経障害バイオマーカー - Google Patents
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- WO2012081433A1 WO2012081433A1 PCT/JP2011/078036 JP2011078036W WO2012081433A1 WO 2012081433 A1 WO2012081433 A1 WO 2012081433A1 JP 2011078036 W JP2011078036 W JP 2011078036W WO 2012081433 A1 WO2012081433 A1 WO 2012081433A1
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
- G01N33/6896—Neurological disorders, e.g. Alzheimer's disease
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
- G01N33/6806—Determination of free amino acids
- G01N33/6812—Assays for specific amino acids
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
- G01N2333/4701—Details
- G01N2333/4709—Amyloid plaque core protein
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/28—Neurological disorders
- G01N2800/2814—Dementia; Cognitive disorders
- G01N2800/2821—Alzheimer
Definitions
- the present invention relates to a biomarker for examining amyloid ⁇ neuropathy such as Alzheimer's disease.
- Alzheimer's disease is a progressive neurodegenerative disease characterized by accumulation in the brain of an insoluble fibrous protein called ⁇ -amyloid.
- Various methods have been proposed for diagnosing Alzheimer's disease, including detection of specific proteins in cerebrospinal fluid, detection of specific proteins and lipoproteins in blood, and detection of genetic mutations including genetic polymorphisms. Yes.
- a simple and effective diagnostic method using peripheral blood has not been put into practical use.
- An object of the present invention is to provide a novel biomarker for examining amyloid ⁇ neuropathy such as Alzheimer's disease.
- the present inventors used a magnetic nanoliposome that mimic brain biological membranes, was searching for a group of proteins present in the culture supernatant of mouse primary neuronal cultures dementia model, Ca 2+ dependent manner MFG-E8 was identified as a protein that binds to phosphatidylserine. Furthermore, we found that the level of MFG-E8 protein was elevated in patients with Alzheimer's disease, and found that MFG-E8 could be a biomarker for Alzheimer's disease.
- the present invention is a method for examining Alzheimer's disease, which measures the amount of MFG-E8 protein in a blood, serum or plasma sample obtained from a subject or a test animal, and obtains the obtained measurement value.
- a method characterized by being used as an index for diagnosis of Alzheimer's disease Preferably, Alzheimer's disease is diagnosed at a stage where amyloid ⁇ protein accumulation has not progressed.
- the amount of MFG-E8 protein is measured using an anti-MFG-E8 antibody.
- the present invention also provides a test agent for Alzheimer's disease comprising an anti-MFG-E8 antibody.
- the present invention further provides an Alzheimer's disease test kit comprising an anti-MFG-E8 antibody and a reagent for detecting the MFG-E8 protein bound to the anti-MFG-E8 antibody.
- the present invention provides a method for selecting a candidate substance for a therapeutic agent for Alzheimer's disease.
- This method comprises administering a test substance to a model cell or model animal of Alzheimer's disease, measuring the amount of MFG-E8 protein in a culture solution of the model cell or a sample obtained from the model animal, and When the amount of MFG-E8 protein is lower than when not administered, the test substance is selected as a candidate substance for a therapeutic agent for Alzheimer's disease.
- the onset of Alzheimer's disease can be examined by a simple method.
- FIG. 1 shows the structure of mouse and human MFG-E8.
- FIG. 2 shows the results of SDS-PAGE of fractions that bind to nanoliposomes in a Ca 2+ -dependent manner in the culture supernatant.
- FIG. 3 shows the results of measurement of the expression level of MFG-E8 by Western blot.
- FIG. 4 shows an ROC curve of plasma MFG-E8 concentration in healthy elderly versus AD patients.
- the present invention is characterized by a method of diagnosing Alzheimer's disease by measuring the expression level of MFG-E8 in a test sample such as blood of a subject.
- MFG-E8 (Milk fat globule EGF factor 8) is a secreted protein also called lactadherin; P47; Mfgm; SED1 (GenBank No. NP — 032620.2, IPI No. IPI00788387.1) , Has two functional domains (EGF domain at the N-terminus and C2 domain at the C-terminus). This has L-form (72 kDa, 61 kDa) and S-form (56 kDa, 48 kDa) isoforms, and the L form is reported to be a secretory type (FIG. 1).
- MFG-E8 contributes to phagocytosing apoptotic cells in many tissues.
- MFG-E8 is an important regulator of apoptotic cell phagocytosis by transmitting the apoptotic cell eat-me signal to macrophages in peripheral blood, promoting macrophage phagocytosis, and competitively inhibiting phagocytosis by excessive amounts It is known.
- MFG-E8 is known to promote cell-cell interactions, promoting sperm-egg binding, epididymal epithelial maintenance, intestinal epithelial repair, glandular branching, angiogenesis, dendriticity It is involved in the promotion of exosome function of cells.
- the present inventors confirmed that immunostaining did not confirm any accumulation of A ⁇ and MFG-E8 in the normal mouse brain (12 months old), and A ⁇ accumulation in the Alzheimer model mouse brain (12 months old). It was found that MFG-E8 accumulated in accordance with the site. Fuller et al., Boddaert et al. And the inventors obtained completely opposite results, but the cause of this may be due to differences in the antibodies used, but details are unknown. Prior to this discovery, the inventors found that the level of MFG-E8 in peripheral blood was also significantly high in patients with Alzheimer's disease, as specifically shown in the following examples, and completed the present invention. .
- MFG-E8 in the peripheral blood
- the MFG-E8 accumulated in accordance with the A ⁇ accumulation site may be leaked and observed.
- the transmission of is completely unknown. Therefore, it is unlikely that MFG-E8 as observed at the A ⁇ accumulation site directly affects the concentration of MFG-E8 in the blood across the blood brain barrier.
- the detailed mechanism of the correlation between elevated levels of MFG-E8 and Alzheimer's disease found in the present invention is currently unknown.
- test sample whose amount of MFG-E8 protein is to be measured
- body fluid, blood, serum, plasma or the like obtained from a subject or a test animal can be used.
- cerebrospinal fluid is not suitable as a sample for the reasons described above.
- the amount of MFG-E8 protein in a sample obtained from a subject can be measured by using an immunological measurement method well known in the art using an anti-MFG-E8 antibody.
- the anti-MFG-E8 antibody may be a polyclonal antibody or a monoclonal antibody.
- Various anti-MFG-E8 polyclonal antibodies and monoclonal antibodies are commercially available, and any of these antibodies can be used in the present invention. Alternatively, antibodies may be made by methods well known in the art.
- MFG-E8 protein in the sample obtained from the subject or test animal by immunological methods.
- the measurement may be qualitative or quantitative.
- the immunological measurement of the expression of MFG-E8 obtained from the subject can be performed using, for example, radioimmunoassay, ELISA, immunochromatography, immunoprecipitation, immunoagglutination, Western blot, and the like.
- a biosensor using the surface plasmon resonance phenomenon may be used.
- a sandwich ELISA can be performed as follows. Plasma is prepared by collecting the peripheral blood of the subject, and this is added to the plate or chip on which the anti-MFG-E8 antibody is immobilized, and incubated for an appropriate time. After washing the plate or chip to remove unbound components, add another anti-MFG-E8 antibody.
- This antibody can be labeled so that it can be detected by an enzyme, a fluorescent dye, a chemiluminescent substance, biotin, a radiation compound, or the like. After incubation for an appropriate time, the plate or chip is washed, and the label is detected by measuring fluorescence, luminescence, radioactivity, and the like.
- a secondary antibody eg, goat anti-mouse antibody
- the secondary antibody can be labeled so as to be detectable with an enzyme, a fluorescent dye, a chemiluminescent substance, biotin, a radiation compound, or the like. In this way, the amount of MFG-E8 protein in plasma obtained from a subject can be measured.
- the MFG-E8 protein can be detected using a detection method utilizing an agglutination reaction.
- MFG-E8 can be detected using a carrier to which an anti-MFG-E8 antibody is bound, for example, latex particles.
- a carrier to which an anti-MFG-E8 antibody is bound for example, latex particles.
- latex particles bound with anti-MFG-E8 antibody are mixed with the sample and incubated for a certain period of time, the particles will aggregate if the sample contains MFG-E8.
- MFG-E8 in the sample can be detected by observing the degree of aggregation with the naked eye or by quantifying with a spectrophotometer.
- the present invention also provides an Alzheimer's disease test drug comprising an anti-MFG-E8 antibody.
- the Alzheimer's disease test agent of the present invention can be provided in the form of a test kit.
- the test kit contains a reagent for detection of MFG-E8, for example, an anti-MFG-E8 antibody as an active ingredient.
- the kit may further contain appropriate reagents necessary for the measurement, such as a buffer solution, a diluting solution, a reaction stopping solution, a washing solution, and a control sample.
- Alzheimer's disease can be examined using the amount of MFG-E8 protein thus measured as an index. Specifically, the amount of MFG-E8 protein in a sample obtained from a subject or test animal is measured, and the obtained measurement value is compared with the measurement value of a healthy control. If the measured value is higher, the subject or test animal is diagnosed as having a high probability of having Alzheimer's disease. Further, the progress of Alzheimer's disease may be monitored using the method of the present invention. Measure the amount of MFG-E8 protein in samples obtained from subjects or test animals at multiple time points, and the increase in measured values over time indicates the progression of Alzheimer's disease, which is decreasing This indicates an improvement in Alzheimer's disease. The progress of treatment may be monitored by this method to determine the therapeutic effect.
- Alzheimer's disease can be diagnosed using MFG-E8 protein in blood as a marker without collecting cerebrospinal fluid.
- the expression level of MFG-E8 in plasma in patients with Alzheimer's disease is significantly increased compared to healthy controls.
- the test method of the present invention includes, for example, early diagnosis of Alzheimer's disease (early diagnosis at a stage where accumulation of amyloid ⁇ protein has not progressed), definite diagnosis of onset, monitoring of the course of disease, determination of therapeutic effect, And is useful for predicting prognosis.
- Alzheimer's disease model cell or animal models for example, A [beta] 42 peptide test substance to the mouse primary nerve cell cultures or TG mice fed cytotoxic administered, the model cell culture or sample in obtained from a model animal This is done by measuring the amount of MFG-E8 protein.
- test substance various synthetic chemical substances and antibodies can be used.
- the test substance can be obtained from libraries such as various synthetic or natural compound libraries, combinatorial libraries, oligonucleotide libraries, peptide libraries, and the like.
- test substance from natural products, such as bacteria, fungi, algae, a plant, and an animal, or its partially purified product as a test substance. If the amount of MFG-E8 protein is low compared to when the test substance is administered and not administered, the test substance can be selected as a candidate substance for the treatment of Alzheimer's disease. That is, the test method of the present invention provides a platform for developing a new treatment method for Alzheimer's disease.
- amyloid beta nerve Disorder biomarker candidates were searched.
- a [beta] 42 is amyloid precursor protein: is one of among APP final product can be cut at three enzymes from (150 KD), most cells are highly toxic, it is what is used in many studies.
- mice telencephalon primary culture cells (5x10 6/10 ml dish) were stimulated for 24 hours with A [beta] 42 (0.1 [mu] M).
- a [beta] 42 0.1 [mu] M
- a low concentration was set for a short time in order to suppress cell damage mildly and also assumed an early stage of Alzheimer's. That is, the concentration at which cell necrosis or apoptosis does not occur was selected to be 0.1 ⁇ M and the time was 24 hours.
- Cell culture supernatants were treated with EGTA (final concentration 5 mM), then pooled in a certain amount, and concentrated from 10 ml to 1 ml by ultrafiltration using Amicon Ultra 153000NMWL.
- Nanoliposomes are magnetic fine particles whose surface is modified with a temperature-responsive polymer and phospholipid, and can form liposome-like structures in an aqueous solution.
- the principle and structure of nanoliposomes are described in detail in JP2010-066200.
- phosphatidylserine was used as the phospholipid.
- Phosphatidylserine is one of the lipids that make up the cell membrane, but it usually exists inside the cell membrane and is exposed outside the cell when the cell undergoes apoptosis. Therefore, if a protein that binds to phosphatidylserine is screened, apoptosis-related proteins can be screened.
- the gel was divided into 10 fractions at the position of the arrow in FIG. 2, and the peptide was recovered by digestion in the gel with trypsin and analyzed by mass spectrometry.
- MFG-E8 milk fat globule-EGF factor 8 protein isoform 1
- a PS100% nanoliposome-binding fraction obtained from a culture supernatant of a lot different from that used for mass spectrometry analysis was used. After electrophoresis (Bio RadReady Gel (5-15%)), it was transferred to a PVDF membrane (9 V, 16.5 hours (about 150 Vhr). 1 ⁇ g / ml hamster anti-mouse MFG-E8 antibody (MBL) was used as the primary antibody. Was reacted for 2 hours (room temperature) with HRP-conjugated goat anti-hamster IgG (Santa Cruz) as a secondary antibody at 1000-fold diluted concentration for 1 hour (room temperature). The exposure time was 3 minutes.
- FIG. 3 shows the results.
- the obtained signal is considered to be MFG-E8 long form (isoform 1) from its molecular weight. From the fact that the MFG-E8 band darker than the control (no stimulation) was detected in the lane of the sample stimulated with A ⁇ 42 (0.1 ⁇ M0.1), it was confirmed that there was a significant difference in the protein level.
- MFG-E8 concentration in plasma of Alzheimer's disease patients MLF-E8 concentration in plasma of Alzheimer's disease (AD) patients and age-matched healthy elderly was measured by ELISA.
- Plasma was prepared from 20 healthy elderly people and 20 AD patients, and ELISA was performed using anti-MFG-E8 antibody by ELISA ⁇ Kit for Human Milk Fat Globule EGF Factor 8 (USCN) according to the instructions of the kit. went. The sample was diluted 10-fold. After concentration measurement, JMP statistical analysis was performed.
- Fig. 4 shows an ROC curve (conducting AD as positive) of MFG-E8 concentration in plasma of healthy elderly versus AD patients.
- the area under the ROC curve was 0.72000, indicating a significant difference.
- MFG-E8 was present in mouse brain nerve cell cultures stimulated with A ⁇ 42 and was detected more in AD patient plasma than in healthy individuals.
- the present invention is useful for diagnosis of Alzheimer's disease.
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Abstract
Description
factor 8)は,lactadherin;P47;Mfgm;SED1などとも呼称される分泌タンパク質であり(GenBank No. NP_032620.2,IPI No. IPI00788387.1)
,2つの機能的ドメインを持つ(N末端にEGFドメイン,C末端にC2ドメイン)。これはL型(72kDa,61kDa)とS型(56kDa,48kDa)のアイソフォームを持ち,L型が分泌タイプであると報告されている(図1)。
Pharmacol (2008) 3:246-256)は,ミクログリア由来細胞株を用いてMFG-E8の動態を調べ,脳内においてはミクログリア細胞がMFG-E8を産生し,MFG-E8がアポトーシスを起こした神経芽腫細胞を認識して,貪食において役割を果たす可能性を報告している。これは,末梢血においてマクロファージがMFG-E8を産生し,MFG-E8がアポトーシスを起こした細胞を認識してこれをマクロファージに伝える機能と対応するものと考えられる。一方,Fullerらはさらに実験を重ねた結果,ヒト家族性アルツハイマー病のAPP遺伝子を有するTGマウス(アルツハイマーモデルマウス)では,正常マウスと比較して脳内のMFG-E8のレベルが低下していることを見いだした。このことに関しては,MFG-E8の制御の乱れがアルツハイマー病の進行に何らかの役割を果たしているのではないかと解釈している。同様に,Boddaert Jら(Am J Pathol (2007) 170:921-929)も,アルツハイマー病の脳において同年齢の脳に比べMFG-E8のmRNA発現が低下している事実を示している。
認知症のモデルとして,Aβ42ペプチドで細胞障害を与えたマウス初代神経培養細胞を用い,脳生体膜を模倣した磁性ナノリポソームを用いて,アミロイドβ神経障害バイオマーカー候補を探索した。Aβ42はアミロイドプリカーサプロテイン:APP(150KD)から3種類の酵素で切断されてできる最終産物のなかの一つであり,最も細胞毒性が強く,多くの研究で使用されているものである。
isoform 1)が同定された。
次に,ウエスタンブロットにてタンパク質レベルでのMFG-E8の発現量の差を確認した。
アルツハイマー病(AD)患者および年齢の対応した健常老人の血漿中のMFG-E8濃度を,ELISAにより測定した。
Claims (6)
- アルツハイマー病を検査するための方法であって,被験者または被検動物から得た血液,血清または血漿試料中のMFG-E8蛋白質の量を測定し,得られた測定値をアルツハイマー病の診断の指標とすることを特徴とする方法。
- アミロイドβ蛋白質の蓄積が進行していない段階でアルツハイマー病が診断される,請求項1記載の方法。
- MFG-E8蛋白質の量が抗MFG-E8抗体を用いて測定される,請求項1に記載の方法。
- 抗MFG-E8抗体を含むアルツハイマー病の検査薬。
- 抗MFG-E8抗体と,抗MFG-E8抗体と結合したMFG-E8蛋白質を検出するための試薬とを含むアルツハイマー病の検査キット。
- アルツハイマー病の治療薬の候補物質を選択する方法であって,
アルツハイマー病のモデル細胞またはモデル動物に試験物質を投与し,
前記モデル細胞の培養液中または前記モデル動物から得た試料中のMFG-E8蛋白質の量を測定し,そして,
試験物質を投与したときに投与していないときと比較してMFG-E8蛋白質の量が低い場合に,その試験物質をアルツハイマー病の治療薬の候補物質として選択する,
の各工程を含む方法。
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US13/994,313 US20130302838A1 (en) | 2010-12-16 | 2011-12-05 | Biomarker for amyloid-b-related neurological disorders |
JP2012548738A JP5907563B2 (ja) | 2010-12-16 | 2011-12-05 | アミロイドβ神経障害バイオマーカー |
ES11849353.5T ES2625529T3 (es) | 2010-12-16 | 2011-12-05 | Biomarcador para trastornos neurológicos asociados a beta-amiloide |
EP11849353.5A EP2653872B1 (en) | 2010-12-16 | 2011-12-05 | Biomarker for amyloid-beta -related neurological disorders |
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JP2008020383A (ja) | 2006-07-14 | 2008-01-31 | Sapporo Medical Univ | リポソームをリガンドとして用いた体液タンパク質の解析方法及び体液タンパク質の調製方法 |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2020085547A1 (ko) * | 2018-10-25 | 2020-04-30 | (주)넥셀 | 알츠하이머병 예방 또는 치료용 재조합 단백질 및 이를 포함하는 알츠하이머병 예방 또는 치료용 조성물 |
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EP2653872B1 (en) | 2017-02-22 |
US20130302838A1 (en) | 2013-11-14 |
EP2653872A1 (en) | 2013-10-23 |
ES2625529T3 (es) | 2017-07-19 |
JP5907563B2 (ja) | 2016-04-26 |
JPWO2012081433A1 (ja) | 2014-05-22 |
EP2653872A4 (en) | 2014-12-24 |
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