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WO1992006376A1 - PROCEDE DE DETECTION DE LA PROTEINE β-AMYLOIDE PAR LIAISON NON SPECIFIQUE D'OLIGONUCLEOTIDES - Google Patents

PROCEDE DE DETECTION DE LA PROTEINE β-AMYLOIDE PAR LIAISON NON SPECIFIQUE D'OLIGONUCLEOTIDES Download PDF

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Publication number
WO1992006376A1
WO1992006376A1 PCT/FI1991/000300 FI9100300W WO9206376A1 WO 1992006376 A1 WO1992006376 A1 WO 1992006376A1 FI 9100300 W FI9100300 W FI 9100300W WO 9206376 A1 WO9206376 A1 WO 9206376A1
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WIPO (PCT)
Prior art keywords
amyloid
oligonucleotides
amyloid protein
precursor
detection
Prior art date
Application number
PCT/FI1991/000300
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English (en)
Inventor
Stina SYRJÄNEN
Kari SYRJÄNEN
Outi Heinonen
Paavo Riekkinen
Original Assignee
Locus-Genex Oy
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 Locus-Genex Oy filed Critical Locus-Genex Oy
Priority to FI922392A priority Critical patent/FI922392L/fi
Publication of WO1992006376A1 publication Critical patent/WO1992006376A1/fr

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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
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/28—Neurological disorders
    • G01N2800/2814—Dementia; Cognitive disorders
    • G01N2800/2821—Alzheimer

Definitions

  • the invention relates to the detection of proteins by means of oligonucleotides.
  • the invention may be utilized especially in diagnostics.
  • Alzheimer's disease is a disease resulting in a difficult dementia, in which the risk of falling ill increases along with aging. Symptoms of Alzheimer's disease are the progressive deterioration of memory, perception and other higher brain functions, which finally results in the patient's complete feeblemindedness.
  • the pathological changes caused by it are fairly well-known.
  • the most typical changes are the extracellular accumulation of amyloid protein on the walls of the cerebral membranes and blood vessels as well as as senile plaques.
  • the cyto-skelenton components of neurons aggregate intracellularly as so-called neurofi- brillary tangles.
  • the filamentary proteins may completely change the structure of the neuron, which finally results in the dystrophy and cell death of the neurons.
  • the number of amyloid plaques correlates fairly well with the deterioration of cognitive functions, the neuron loss and the decrease in neurotransmitters (Tanzi et al. 1989) .
  • Senile or neuritic plaques consist of an amyloid core, which is surrounded by a periphery comprised of dystrophic neurites and extracellular material.
  • the plaques may be dense, so-called classic plaques or diffuse concentrations formed of loosely interconnected material. Diffuse plaques have in fact been assumed to be pre-stages of denser formations, which may form during several years without first causing neurologic symptons (Joachim et al. 1989, Tanzi 1989) .
  • amyloid in the senile plaques forms of 6-10 nm stranded ⁇ -amyloid protein, whose identical subunits are arranged antiparallelly into a beta-structure.
  • This hydrofobic protein of ca. 4.2-4.5 kDa is synthesized most likely in neurons as part of a longer ⁇ -amyloid precursor protein.
  • the gene coding for the precursor protein is localized in the chromosome 21 (Goldgaber et al. 1978, Tanzi 1987) .
  • the ⁇ -amyloid precursor is a receptor-like, transmembranal glycosylated protein, in which two thirds are located in the extracellular state (Kang et al. 1987) .
  • the ⁇ -amyloid dipeptide is in turn located partly in the transmembranal area so that its proteolytic release from the precursor occurs either before the precursor*s loosening onto or after loosening from cellular membrane (Tanzi 1989) .
  • ⁇ -amyloid gene codes for at least three transcripts acting as models for polypeptides with 695, 751 and 770 amino acids.
  • the two longer polypep- tides contain an extra sequence with 56 the amino acid, which is 50% homogenous with the enzymes belonging to the so-called Kuniz's serine protease inhibitor family.
  • protease inhibitor sequence in the aggregation of the ⁇ -amyloid Two contradictory hypotheses corcerning the possible share of the protease inhibitor sequence in the aggregation of the ⁇ -amyloid have been presented: 1) it may prevent the cumulation of amyloid by inhibiting proteases which release ⁇ -peptide from the precursor, or 2 ) the protease inhibitor may advance the cumulation of amyloid by preventing specific proteinases from purifying the tissue from ⁇ -amyloid.
  • the function of the protease inhibitor sequence of the ⁇ -amyloid precursor protein and also its release from the precursor into an active enzyme are thus not known for certain.
  • the invention is based on the surprising discovery that oligonucleotides bind to the ⁇ -amyloid protein or its precursor.
  • the ⁇ -amyloid protein or its precursor thus binds DNA.
  • the binding occurs especially in the ⁇ -amyloid protein or its precursor present in a peripheral tissue (e.g. skin, mucous membrane) .
  • the phenomenon may be utilized especially in diagnostic tests (e.g. Alzheimer's disease, Down's syndrome, dementias, old persons).
  • the object of our examination was the expression of ⁇ - a yloid on the frontal cortex and hippocampus of Alzheimer patients.
  • the RNA in situ hybridization and as a specific tester was a cocktail formed by three short oligonucleotides corresponding to different areas of the ⁇ -amyloid sequence.
  • the oligonuc ⁇ leotides were labelled at the 3'-end with biotin.
  • antisense-RNA-oligonucleotides were synthesized complementary sense-RNA-oligonucleotides, which were labelled in the same way as the antisense probes.
  • the in situ hybridization was performed by using the routine methods of our laboratory (a hybridized biotinylated intron is allowed to bind to a streptavidine-alkaline phosphatase complex, which is in turn detected by means of a substrate reaction) .
  • the brain samples of 3 different Alzheimer patients as well as two normal samples were examined. As a result could be observed strong signals in the area of the cortex and hippocampus corresponding both by their location and shape to senile plaques.
  • a positive colouring was seen in the walls of blood vessels, as described in connection with the ⁇ -amyloid protein.
  • the sense probe we could to our surprise see the same result as when using the antisense probe.
  • the in situ hybridization was repeated several times to preclude a possible false positive reaction caused by endogenic biotin or alkaline phosphatase.
  • the in situ hybridization was repeated by using a radioactive label or other enzymes for the detection of a biotinylized hybrid (e.g. peroxidase) .
  • a biotinylized hybrid e.g. peroxidase
  • the results were always the same.
  • other oligonucleotides were tested, which deviated from the published sequence of ⁇ -amyloid (e.g. erb cancer gene or 18 and 16 of human papilloma virus (HPV) .
  • HPV human papilloma virus
  • the location of senile plaques and amyloid was additional ⁇ ly ensured by using conventional stainings: kongo, Bielschowski.
  • the samples were additionally stained also immunohistochemically by using as a primary antibody an antibody made against a commercial ⁇ -amyloid protein. These stainings gave considerably weaker signals, but the positive areas were the same.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Chemical & Material Sciences (AREA)
  • Urology & Nephrology (AREA)
  • Molecular Biology (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Analytical Chemistry (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Neurosurgery (AREA)
  • Neurology (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Cell Biology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
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Abstract

L'invention se rapporte à un procédé de détection de la protéine β-amyloïde à partir d'un échantillon, au moyen de la réaction dudit échantillon avec un oligonucléotide. Ce procédé s'adresse particulièrement à la détection d'une amyloÏdose apparentée, par exemple, à la maladie d'Alzheimer.
PCT/FI1991/000300 1990-09-27 1991-09-27 PROCEDE DE DETECTION DE LA PROTEINE β-AMYLOIDE PAR LIAISON NON SPECIFIQUE D'OLIGONUCLEOTIDES WO1992006376A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
FI922392A FI922392L (fi) 1990-09-27 1991-09-27 Foerfarande foer detektering av b-amyloidprotein genom anvaendning av ospecifik bindning av oligonukleotider.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FI904766A FI904766A7 (fi) 1990-09-27 1990-09-27 Foerfarande foer detektering av protein.
FI904766 1990-09-27

Publications (1)

Publication Number Publication Date
WO1992006376A1 true WO1992006376A1 (fr) 1992-04-16

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/FI1991/000300 WO1992006376A1 (fr) 1990-09-27 1991-09-27 PROCEDE DE DETECTION DE LA PROTEINE β-AMYLOIDE PAR LIAISON NON SPECIFIQUE D'OLIGONUCLEOTIDES

Country Status (5)

Country Link
EP (1) EP0503022A1 (fr)
JP (1) JPH05502512A (fr)
CA (1) CA2069731A1 (fr)
FI (1) FI904766A7 (fr)
WO (1) WO1992006376A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2256642A (en) * 1991-06-13 1992-12-16 Ici Plc Nucleotide sequences for detecting alzheimer's disease

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988003951A1 (fr) * 1986-11-17 1988-06-02 California Biotechnology, Inc. Proteine amyloide recombinante relative a la maladie d'alzheimer

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1988003951A1 (fr) * 1986-11-17 1988-06-02 California Biotechnology, Inc. Proteine amyloide recombinante relative a la maladie d'alzheimer

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Dialog Information Services, File 155, Medline, Dialog accession No. 07192545, M.R. PALMERT et al., "The beta amyloid protein precursor: mRNAs, membrane-associated forms, and soluble derivatives", Prog Clin Biol Res 1989, 317, p 971-84. *
Dialog Information Services, File 73, Embase, Dialog accession No. 8232571, S. SYRJANEN et al.: "Short biotinylated oligonucleotides bind non-specifically to senile plaques of Alzheimer's disease", Neurosci, Lett. (Ireland); 1991, 130/1 (89-91). *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2256642A (en) * 1991-06-13 1992-12-16 Ici Plc Nucleotide sequences for detecting alzheimer's disease
GB2256642B (en) * 1991-06-13 1995-12-06 Ici Plc Yeast artificial chromosomes comprising nucleotide sequences for the detection of disease alleles

Also Published As

Publication number Publication date
FI904766A7 (fi) 1992-03-28
JPH05502512A (ja) 1993-04-28
EP0503022A1 (fr) 1992-09-16
FI904766A0 (fi) 1990-09-27
CA2069731A1 (fr) 1992-03-28

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