WO2004019045A2 - Method for the diagnosis of alzheimer disease - Google Patents

Method for the diagnosis of alzheimer disease Download PDF

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Publication number
WO2004019045A2
WO2004019045A2 PCT/EP2003/009300 EP0309300W WO2004019045A2 WO 2004019045 A2 WO2004019045 A2 WO 2004019045A2 EP 0309300 W EP0309300 W EP 0309300W WO 2004019045 A2 WO2004019045 A2 WO 2004019045A2
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WO
WIPO (PCT)
Prior art keywords
neuregulin
kda
diagnosis
alzheimer disease
forms
Prior art date
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PCT/EP2003/009300
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French (fr)
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WO2004019045A3 (en
Inventor
André SCHRATTENHOLZ
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Proteosys Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Proteosys Ag filed Critical Proteosys Ag
Priority to AU2003266302A priority Critical patent/AU2003266302A1/en
Publication of WO2004019045A2 publication Critical patent/WO2004019045A2/en
Publication of WO2004019045A3 publication Critical patent/WO2004019045A3/en

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Classifications

    • 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
    • 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
    • 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 invention relates to a method for the diagnosis of Alzheimer disease in a body fluid comprising determining the presence and/or amount of specific forms of neuregulin- ?.
  • Neuregulins also ARIA, neurogenic differentiation factors, heregulins and DDF
  • ARIA neurogenic differentiation factors
  • DDF DDF
  • PCT/EP01 /01 424 discloses a neuregulin- ⁇ isoform having an isoelectric point of ⁇ pH 7, particularly from pH 4.3 to pH 5.0 and more particularly from pH 4.5 to pH 4.7.
  • This neuregulin- ⁇ isoform was obtained from hippocampal primary cultures from pre- or neonatal rats and characterized as indicator or target, respectively, for neuronal processes. Further, neuregulin- ⁇ could be identified as target in case of Morbus Alzheimer.
  • Several novel neuregulin- ? isoforms are disclosed in USSN 60/341 ,809.
  • a Western blot analysis of liquor (cerebrospinal fluid) samples from human patients suffering from Alzheimer disease with anti-neuregulin- ? antibodies show the presence of four different neuregulin-y? cleavage products and/or neuregulin- ⁇ isoforms having molecular weights (SDS-PAGE) of about 28 kDa, 55 kDa, 65 kDa and 80 kDa. Higher concentrations of these neuregulin- ⁇ forms are found in Alzheimer patients compared to non- Alzheimer patients. This is particularly true for the 65 kDa and 28 kDa neuregulin forms. Particularly, in the most cases, the 65 kDa neuregulin form cannot be detected in non-Alzheimer patients.
  • a subject-matter of the present invention for the diagnosis of Alzheimer disease in a sample, particularly in a body fluid, more particularly in liquor (cerebrospinal fluid), comprising determining the presence and/or amount of at least one neuregulin- ? form having a molecular weight (SDS- PAGE) of about 28 kDa, 55kDa, 65 kDa and 80 kDa.
  • SDS- PAGE molecular weight
  • the method comprises determining at least two, e.g. two, three or four of said neuregulin- ? forms. Determination of the 28 kDa form and/or the 65 kDa form is particularly preferred.
  • the sample may be obtained from body fluids or tissue, particularly neuronal fluids, more particularly liquor (cerebrospinal fluid) or neuronal tissue.
  • the diagnostic method preferably comprises detection on the protein level, e.g. by immunological methods using neuregulin-/? antibodies or antibody fragments. Such diagnostic methods are well known.
  • the proteins in the sample are preferably subjected to a separation procedure according to their molecular weight and/or charge.
  • the separation procedure is preferably a gel electrophoresis such as SDS-PAGE or an equivalent method.
  • determination may also comprise chromatographic separation procedures such as HPLC and/or molecular weight exclusion chromatography.
  • a quantitative or semi- quantitative determination of the amount of the individual neuregulin- / -? forms is carried out.
  • This quantitative or semi-quantitative determination may comprise the use of labelled detection reagents such as neuregulin-/? antibodies and quantitatively or semi-quantitatively determining the amount of label bound to a respective neuregulin- ? form in a sample.
  • the method additionally comprises a determination of an internal standard, e.g. a reference protein, which allows quantification of the neuregulin- ? forms to be determined.
  • the internal standard is recognized by the same antibody which is used for determining the relevant neuregulin- ? forms.
  • the reference protein exhibits characteristics, e.g. a molecular weight, which allows a differentiation from the neuregulin- ⁇ forms to be determined, particularly after electrophoretic separation of the sample.
  • the reference protein may be selected from biological extracts, which contain predetermined amounts of recombinant or native neuregulin- /?, purified or partially purified native neuregulin-/? proteins from biologic material, e.g. 42 kDa protein from rat hippocampus cell line HK3, purified recombinant protein, e.g. a full-length or truncated neuregulin-/? protein or a hybrid protein containing relevant neuregulin-/? epitopes as a "tag" coupled to a suitable carrier.
  • a particularly preferred reference protein is a recombinant neuregulin-/? protein from E.coli comprising the extracellular domain and having a molecular weight of about 30 kDa (Neomarkers) .
  • the invention relates to the use of a region kit, comprising neuregulin- ⁇ antibodies for the diagnosis of Alzheimer disease, particularly in a method as described above. Further, the present invention shall be explained in more detail by the following Figure and Example.
  • Figure 1 Neuregulin-R Western blot from liquor (cerbrospinal fluid) samples obtained from Alzheimer patients (A) and non-Alzheimer patients (B).
  • the membranes were blocked in 0.1 % TBS-T buffer (20 mmol/l Tris pH 7.4, 175 mmol/l NaCI, 3.5 mmol/l KCI, 0.1 % Tween 20) and 4% Bovine Serum Albumin for 90 min. Then, the membrane was incubated overnight at 4°C with a primary antibody (neuregulin Ab-2, rabbit polyclonal antibody, Neomarkers; 1 :5000 diluted in blocking buffer) .
  • a primary antibody neutraliser Ab-2, rabbit polyclonal antibody, Neomarkers; 1 :5000 diluted in blocking buffer
  • the membrane was washed 4 x 10 min in 0.05% TBS-T buffer (20 mmol/l Tris pH 7.4, 175 mmol/l NaCI, 3.5 mmol/l KCI, 0.05% Tween 20) incubated for 1 h with a secondary antibody (anti-rabbit IgG -Peroxidase- conjugate, Sigma; 1 : 10 000 diluted in blocking buffer). After this incubation, the membrane was washed 4 x 1 0 min in 0.05% TBS-T buffer. Then, an electro-chemiluminescence determination (Super Signal West Dura Kit, Pierce) was carried out according to the manufacturer's instructions. The DIANA-chemiluminescence detection system (Raytest) was used.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
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  • Urology & Nephrology (AREA)
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  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
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Abstract

The invention relates to a method for the diagnosis of Alzheimer disease in a body fluid comprising determining the presence and/or amount of specific forms of neuregulin-,β.

Description

Method for the diagnosis of Alzheimer disease
Specification
The invention relates to a method for the diagnosis of Alzheimer disease in a body fluid comprising determining the presence and/or amount of specific forms of neuregulin- ?.
Neuregulins (also ARIA, neurogenic differentiation factors, heregulins and DDF) belong to a family of wide-spread and known growth and differentiation factors. For example in publication Ozaka M. et al., Nature 1 997, Dec 10-25, 390(6661 ): 691 -4 the inducing influence of neuregulin-R on the expression of the NR2C subunit of the NMDA receptor is described.
PCT/EP01 /01 424 discloses a neuregulin-β isoform having an isoelectric point of < pH 7, particularly from pH 4.3 to pH 5.0 and more particularly from pH 4.5 to pH 4.7. This neuregulin-β isoform was obtained from hippocampal primary cultures from pre- or neonatal rats and characterized as indicator or target, respectively, for neuronal processes. Further, neuregulin-β could be identified as target in case of Morbus Alzheimer. Several novel neuregulin- ? isoforms are disclosed in USSN 60/341 ,809.
A Western blot analysis of liquor (cerebrospinal fluid) samples from human patients suffering from Alzheimer disease with anti-neuregulin- ? antibodies show the presence of four different neuregulin-y? cleavage products and/or neuregulin-β isoforms having molecular weights (SDS-PAGE) of about 28 kDa, 55 kDa, 65 kDa and 80 kDa. Higher concentrations of these neuregulin-β forms are found in Alzheimer patients compared to non- Alzheimer patients. This is particularly true for the 65 kDa and 28 kDa neuregulin forms. Particularly, in the most cases, the 65 kDa neuregulin form cannot be detected in non-Alzheimer patients.
Thus, a subject-matter of the present invention for the diagnosis of Alzheimer disease in a sample, particularly in a body fluid, more particularly in liquor (cerebrospinal fluid), comprising determining the presence and/or amount of at least one neuregulin- ? form having a molecular weight (SDS- PAGE) of about 28 kDa, 55kDa, 65 kDa and 80 kDa.
Preferably, the method comprises determining at least two, e.g. two, three or four of said neuregulin- ? forms. Determination of the 28 kDa form and/or the 65 kDa form is particularly preferred.
The sample may be obtained from body fluids or tissue, particularly neuronal fluids, more particularly liquor (cerebrospinal fluid) or neuronal tissue. The diagnostic method preferably comprises detection on the protein level, e.g. by immunological methods using neuregulin-/? antibodies or antibody fragments. Such diagnostic methods are well known.
In order to differentiate between different neuregulin forms, the proteins in the sample are preferably subjected to a separation procedure according to their molecular weight and/or charge. The separation procedure is preferably a gel electrophoresis such as SDS-PAGE or an equivalent method. Furthermore, determination may also comprise chromatographic separation procedures such as HPLC and/or molecular weight exclusion chromatography.
In a preferred embodiment of the invention, a quantitative or semi- quantitative determination of the amount of the individual neuregulin-/-? forms is carried out. This quantitative or semi-quantitative determination may comprise the use of labelled detection reagents such as neuregulin-/? antibodies and quantitatively or semi-quantitatively determining the amount of label bound to a respective neuregulin- ? form in a sample. In some cases, it is preferred that the method additionally comprises a determination of an internal standard, e.g. a reference protein, which allows quantification of the neuregulin- ? forms to be determined. In a preferred embodiment, the internal standard is recognized by the same antibody which is used for determining the relevant neuregulin- ? forms. Further, the reference protein exhibits characteristics, e.g. a molecular weight, which allows a differentiation from the neuregulin-β forms to be determined, particularly after electrophoretic separation of the sample. For example, the reference protein may be selected from biological extracts, which contain predetermined amounts of recombinant or native neuregulin- /?, purified or partially purified native neuregulin-/? proteins from biologic material, e.g. 42 kDa protein from rat hippocampus cell line HK3, purified recombinant protein, e.g. a full-length or truncated neuregulin-/? protein or a hybrid protein containing relevant neuregulin-/? epitopes as a "tag" coupled to a suitable carrier. A particularly preferred reference protein is a recombinant neuregulin-/? protein from E.coli comprising the extracellular domain and having a molecular weight of about 30 kDa (Neomarkers) .
Furthermore, the invention relates to the use of a region kit, comprising neuregulin-^ antibodies for the diagnosis of Alzheimer disease, particularly in a method as described above. Further, the present invention shall be explained in more detail by the following Figure and Example.
Figure 1 : Neuregulin-R Western blot from liquor (cerbrospinal fluid) samples obtained from Alzheimer patients (A) and non-Alzheimer patients (B).
Example
1 5 μg protein from liquor was separated by SDS-PAGE (9% polyacrylamide) and subsequently blotted on a nitrocellulose membrane (Optitran BA-S83, Reinforced NC, Schleicher & Schuell) . The blot procedure was carried out in a semi-dry blotter for 1 20 min with 1 mA/cm2 gel surface. As transfer buffers, the following were used: Anode buffer I (0.3 mol/l Tris pH 10.4, 10% methanol), anode buffer II (25 mmol/l Tris pH 10.4, 10% methanol) and cathode buffer (25 mmol/l Tris pH 9.4, 40 mmol/l 6-amino-n-caproic acid, 20% methanol) .
After the blotting, the membranes were blocked in 0.1 % TBS-T buffer (20 mmol/l Tris pH 7.4, 175 mmol/l NaCI, 3.5 mmol/l KCI, 0.1 % Tween 20) and 4% Bovine Serum Albumin for 90 min. Then, the membrane was incubated overnight at 4°C with a primary antibody (neuregulin Ab-2, rabbit polyclonal antibody, Neomarkers; 1 :5000 diluted in blocking buffer) . Then, the membrane was washed 4 x 10 min in 0.05% TBS-T buffer (20 mmol/l Tris pH 7.4, 175 mmol/l NaCI, 3.5 mmol/l KCI, 0.05% Tween 20) incubated for 1 h with a secondary antibody (anti-rabbit IgG -Peroxidase- conjugate, Sigma; 1 : 10 000 diluted in blocking buffer). After this incubation, the membrane was washed 4 x 1 0 min in 0.05% TBS-T buffer. Then, an electro-chemiluminescence determination (Super Signal West Dura Kit, Pierce) was carried out according to the manufacturer's instructions. The DIANA-chemiluminescence detection system (Raytest) was used.

Claims

Claims
1 . A method for the diagnosis of Alzheimer disease in a sample comprising determining the presence and/or amount of at least one neuregulin-β form having a molecular weight (SDS-PAGE) of about 28 kDa, 55 kDa, 65 kDa or 80 kDa.
2. The method of claim 1 comprising determining at least two of said neuregulin-β forms.
3. The method of claims 1 or 2 wherein the 28 kDa neuregulin-β form is determined.
4. The method of any one of claims 1 -3 wherein the 65 kDa neuregulin-β form is determined.
5. The method of any one of claims 1 -4 wherein the sample is liquor.
6. The method of any one of claims 1 -5 wherein proteins in the sample are subjected to a separation procedure according to their molecular weight and/or charge.
7. The method of claim 6 wherein the separation procedure comprises SDS-PAGE.
8. The method of any one of claims 1 -7 wherein the neuregulin-β forms are determined immunologically.
9. Use of a reagent kit comprising neuregulin-β antibodies for the diagnosis of Alzheimer disease in a method of any one of claims 1 -8.
PCT/EP2003/009300 2002-08-23 2003-08-21 Method for the diagnosis of alzheimer disease WO2004019045A2 (en)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2010084150A1 (en) * 2009-01-23 2010-07-29 Proteosys Ag Diagnostic method for detecting neurodegenerative diseases
US9062101B2 (en) 2010-08-14 2015-06-23 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
US9822171B2 (en) 2010-04-15 2017-11-21 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
US9951125B2 (en) 2006-11-30 2018-04-24 Abbvie Inc. Aβ conformer selective anti-Aβ globulomer monoclonal antibodies
US10208109B2 (en) 2005-11-30 2019-02-19 Abbvie Inc. Monoclonal antibodies against amyloid beta protein and uses thereof
US10464976B2 (en) 2003-01-31 2019-11-05 AbbVie Deutschland GmbH & Co. KG Amyloid β(1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof
US10538581B2 (en) 2005-11-30 2020-01-21 Abbvie Inc. Anti-Aβ globulomer 4D10 antibodies

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100311767A1 (en) 2007-02-27 2010-12-09 Abbott Gmbh & Co. Kg Method for the treatment of amyloidoses

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004919A1 (en) * 1996-07-25 1998-02-05 The Mclean Hospital Corporation Use of presenilin-1 for diagnosis of alzheimer's disease
WO2001026607A2 (en) * 1999-10-08 2001-04-19 Uab Research Foundation Smdf and ggf neuregulin splice variant isoforms and uses thereof
WO2001058948A2 (en) * 2000-02-11 2001-08-16 Proteosys Ag USE OF NEUREGULIN-β AS AN INDICATOR AND/OR TARGET
WO2003014156A2 (en) * 2001-08-06 2003-02-20 Proteosys Ag NEUREGULIN-β ISOFORMS ASSOCIATED WITH NEURONAL PROCESSES

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004919A1 (en) * 1996-07-25 1998-02-05 The Mclean Hospital Corporation Use of presenilin-1 for diagnosis of alzheimer's disease
WO2001026607A2 (en) * 1999-10-08 2001-04-19 Uab Research Foundation Smdf and ggf neuregulin splice variant isoforms and uses thereof
WO2001058948A2 (en) * 2000-02-11 2001-08-16 Proteosys Ag USE OF NEUREGULIN-β AS AN INDICATOR AND/OR TARGET
WO2003014156A2 (en) * 2001-08-06 2003-02-20 Proteosys Ag NEUREGULIN-β ISOFORMS ASSOCIATED WITH NEURONAL PROCESSES

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FALLS DOUGLAS L: "Neuregulins: Functions, forms, and signaling strategies" EXPERIMENTAL CELL RESEARCH, SAN DIEGO, CA, US, vol. 284, no. 1, 10 March 2003 (2003-03-10), pages 14-30, XP002262024 ISSN: 0014-4827 *
LU HSIENG S ET AL: "Studies on the structure and function of glycosylated and nonglycosylated neu differentiation factors: Similarities and differences of the alpha and beta isoforms" JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 270, no. 9, 1995, pages 4784-4791, XP002266596 ISSN: 0021-9258 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10464976B2 (en) 2003-01-31 2019-11-05 AbbVie Deutschland GmbH & Co. KG Amyloid β(1-42) oligomers, derivatives thereof and antibodies thereto, methods of preparation thereof and use thereof
US10208109B2 (en) 2005-11-30 2019-02-19 Abbvie Inc. Monoclonal antibodies against amyloid beta protein and uses thereof
US10323084B2 (en) 2005-11-30 2019-06-18 Abbvie Inc. Monoclonal antibodies against amyloid beta protein and uses thereof
US10538581B2 (en) 2005-11-30 2020-01-21 Abbvie Inc. Anti-Aβ globulomer 4D10 antibodies
US9951125B2 (en) 2006-11-30 2018-04-24 Abbvie Inc. Aβ conformer selective anti-Aβ globulomer monoclonal antibodies
WO2010084150A1 (en) * 2009-01-23 2010-07-29 Proteosys Ag Diagnostic method for detecting neurodegenerative diseases
US9822171B2 (en) 2010-04-15 2017-11-21 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
US9062101B2 (en) 2010-08-14 2015-06-23 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins
US10047121B2 (en) 2010-08-14 2018-08-14 AbbVie Deutschland GmbH & Co. KG Amyloid-beta binding proteins

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