WO2012136871A1 - Méthode de diagnostic de la maladie d'alzheimer qui utilise le sfrp1 comme biomarqueur - Google Patents

Méthode de diagnostic de la maladie d'alzheimer qui utilise le sfrp1 comme biomarqueur Download PDF

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WO2012136871A1
WO2012136871A1 PCT/ES2012/070226 ES2012070226W WO2012136871A1 WO 2012136871 A1 WO2012136871 A1 WO 2012136871A1 ES 2012070226 W ES2012070226 W ES 2012070226W WO 2012136871 A1 WO2012136871 A1 WO 2012136871A1
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alzheimer
disease
suffering
determination
risk
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PCT/ES2012/070226
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English (en)
Spanish (es)
Inventor
Paola BOVOLENTA NICOLAO
Pilar ESTEVE PASTOR
Africa SANDONIS CONSUEGRA
Inmaculada CRESPO GALAN
Mª Isabel GUERRERO VEGA
Carmen IBÁÑEZ PÉREZ
Jordi MALAPEIRA ARGUILAGA
Joaquin ARRIBAS
Akihiko SHIMONO
Original Assignee
Consejo Superior De Investigaciones Científicas (Csic)
Vall D'hebron Institut De Recerca (Vhir)
Vall D'hebron Institute Of Oncology (Vhio)
Institució Catalana De Recerca I Estudis Avançats (Icrea)
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Publication of WO2012136871A1 publication Critical patent/WO2012136871A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • 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
    • G01N2333/4703—Regulators; Modulating activity

Definitions

  • the present invention belongs to the field of Molecular Biology and refers to sfrpl as a biomarker for Alzheimer's disease at its earliest stage and its use for the early diagnosis of said disease.
  • AD Alzheimer's disease
  • NMR Nuclear Magnetic Resonance
  • PET Positron Emission Tomography
  • the Clinical diagnosis can be made with only 65-90% accuracy.
  • the definitive diagnosis of AD is only made post mortem, when the autopsy reveals the senile plaques and neurofibrillary tangles in the brain tissue. Plaques are the result of aggregation of ⁇ peptides and are believed to be involved in the pathology of AD. (Hardy, J, Selkoe, DJ. 2002. Science, 297: 353-356).
  • biomarker of AD for the early diagnosis of AD is a critical first step in the development of methodologies for early disease intervention, and would have several advantages. It would be able to identify AD at a very early stage of the disease, before cognitive symptoms can be detected in neuropsychological tests, and before brain NMR or PET imaging can show signs of degeneration. Differential diagnosis of AD is difficult, and a biomarker that reflects neuropathological changes at the molecular level in the brain could make it possible to distinguish Alzheimer's patients not only from people with mild cognitive impairment who do not develop AD, but also from patients with depression. A biomarker would also contribute greatly to the detection of new therapies, especially those aimed at preventing neuropathological changes.
  • AD cannot be diagnosed by a valid clinical method or by a biomarker before the disease has progressed so much that dementia is evident.
  • AD Alzheimer's disease
  • APP is an integral membrane protein that is present in many types of tissues, but is particularly abundant in neuronal synapses. APP may suffer two alternative types of processing that are mutually exclusive.
  • the non-amyloidogenic processing of the APP protein is carried out by ADAM10, a metalloprotease with ⁇ -secretase activity, which cuts APP within the ⁇ peptide, more specifically in amino acid 16 of APP, causing the release of the soluble extracellular domain of APP (sAPPa) and preventing the generation of the toxic peptide ⁇ .
  • sAPPa soluble extracellular domain of APP
  • APP may undergo an amyloidogenic processing, performed by a ⁇ -secretase that cuts at one end of the ⁇ peptide. This peptide is again processed by ⁇ -secretase and gives rise to toxic ⁇ peptides. (Lichtenthaler, SF. 201 1. J Neurochem. 1 16: 10-21).
  • SFRPs proteins secreted by Frizzled related proteins
  • Wnt signaling pathway name derived from the "Wingless” and “int” genes
  • ADAM ADAM
  • the present invention relates to the use of SFRP as a biomarker for Alzheimer's disease (AD).
  • AD Alzheimer's disease
  • the present invention is a new biomarker for the early detection of AD.
  • the levels of the SFRP1 protein are altered in Alzheimer patients with respect to control subjects. In this way, the detection and / or quantification of this protein allows the early diagnosis of Alzheimer's disease.
  • the present invention relates to a method of diagnosis of AD or for the determination of the risk of suffering from AD or for the determination of the evolution of an AD in a subject susceptible to suffering from AD comprising the following steps: a) detect and / or quantify the expression product of a nucleotide sequence of an sfrpl gene in an isolated sample;
  • step (b) compare the quantity detected and / or quantified in step (a) with a reference quantity
  • step (c) attribute the significant deviation identified in step (c) to the presence of AD or to the risk of suffering from AD.
  • determination of evolution refers to the monitoring of disease development, such as, but not limited to, the evaluation of the response to a particular treatment.
  • expression product refers to the product resulting from transcription (RNA synthesis) or translation (protein synthesis) of a gene or nucleotide sequence of DNA, or any form resulting from the processing of product resulting from the transcription or expression of a gene or a nucleotide sequence of DNA.
  • the sfrpl gene is the "secreted Frizzled related protein 1" gene.
  • step (a) is not intended to be correct in 100% of the samples analyzed. However, it requires that a statistically significant amount of the analyzed samples be classified correctly.
  • the amount that is statistically significant can be established by a person skilled in the art by using different statistical tools, for example, but not limited, by determining confidence intervals, determining the p-value, Student's test or discriminant functions of Fisher
  • the confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99%.
  • the value of p is less than 0.1, 0.05, 0.01, 0.005 or 0.0001.
  • the present invention allows the disease to be correctly detected in at least 60%, in at least 70%, in at least 80%, or in at least 90% of the subjects of a certain group or population analyzed.
  • the appropriate reference amount can be determined from a reference sample that can be analyzed, for example, simultaneously or consecutively, by the method of the first aspect of the invention, together with the isolated sample from a subject susceptible to AD. . More preferably, the reference amount may be derived from the normal distribution limits of a physiological amount found in a population of control subjects. Said physiological amount can be determined by several techniques well known to the person skilled in the art.
  • the nucleotide sequence of the sfrpl gene encodes an amino acid sequence having at least eighty percent, at least eighty-five percent, at least Ninety percent, at least ninety-five percent, at least ninety-nine percent identity with SEQ ID NO: 1.
  • the nucleotide sequence of the sfrpl gene encodes for the amino acid sequence SEQ ID NO: 1.
  • both percent identity or “percent identity” as used herein, refers to either percent or percent identity between two amino acid sequences.
  • the percentage or percentage of identity is the result of counting the number of positions along the alignment of two sequences where all amino acids in the same position are identical.
  • the percentage of identity existing between two sequences can be easily identified by a person skilled in the art, for example, with the help of an appropriate computer program to compare sequences.
  • Table 1 Percentage of sequence identity for the human SRFP1 gene and protein of different species.
  • SEQ ID NO: 1 is the sequence of the human SFRP1 protein found in the NCBI database (National Center for Biotechnology Information) with the reference number: NP_003003.3.
  • the sample isolated from step (a) is a biological fluid.
  • the biological fluid is cerebrospinal fluid (CSF), blood, serum or blood plasma. More preferably, the biological fluid is blood serum. More preferably, the biological fluid is CSF.
  • the isolated sample comprises cells.
  • the isolated sample comprises a tissue.
  • the expression product of a nucleotide sequence of a sfrpl gene is an amino acid sequence with at least 90% identity with SEQ ID NO: 1.
  • the expression product of a nucleotide sequence of a sfrpl gene is the amino acid sequence SEQ ID NO: 1.
  • the expression product is detected by PCR.
  • the expression product is detected by electrophoresis, immunoassay, chromatography, microarray technology and / or mass spectrometry.
  • the expression product is detected by immunoassay.
  • the immunoassay is an ELISA.
  • the expression product is detected by mass spectrometry.
  • step (a) of the method of the invention can be carried out by any combination of any of the techniques mentioned. Detection can be performed by evaluating the presence or absence of the expression product or a fragment thereof.
  • An immunoassay is a biochemical assay that measures the concentration of a substance in a sample using a reaction of an antibody or antibodies against its antigen.
  • the assay is based on the specific binding of an antibody with its antigen.
  • the detection and / or quantification of the antibody and / or the antigen can be carried out with various methods.
  • One of the most common is the antigen or antibody mapping.
  • This marking may consist, but is not limited to, an enzyme, a radioisotope (radioimmunoassay), a magnetic marker (magnetic immunoassay) or a fluorophore.
  • radioisotope radioisotope
  • magnetic marker magnetic immunoassay
  • fluorophore fluorophore
  • Heterogeneous immunoassays can be competitive or non-competitive.
  • a competitive immunoassay the response is inversely proportional to the antigen concentration of the sample.
  • a non-competitive assay also called a sandwich assay, the results are directly proportional to the antigen concentration.
  • An immunoassay technique that can be used in the present invention is the enzyme-linked immunoadsorbent assay or ELISA (Enzyme-Linked ImmunoSorbent Assay ').
  • the immunoassay is an immunohistochemistry (IHQ).
  • IHQ immunohistochemistry
  • Immunohistochemical techniques allow the identification, on tissue or cytological samples of characteristic antigenic determinants. Immunohistochemical analysis is performed on tissue cuts, either frozen or included in paraffin, from an isolated sample of a subject. These sections hybridize with a specific antibody or primary antibody that recognizes the SFRP1 protein, its variants or fragments thereof. The sections are then hybridized with a secondary antibody capable of specifically recognizing the primary antibody and which is conjugated or bound with a marker compound. In an alternative embodiment, it is the primary antibody that recognizes the SFRP1 protein, its variant or a fragment thereof, that is conjugated or bound to a marker compound, and the use of a secondary antibody is not necessary.
  • the molecules can be separated according to their load, their size or their molecular weight, their polarity or their redox potential, among others.
  • the chromatographic technique can be, but not limited to, liquid chromatography (partition, absorption, exclusion, ion exchange), gas chromatography or supercritical fluid chromatography.
  • Microarray technology refers, for example, but not limited to the fixation on a solid support of a molecule that recognizes the expression product of the present invention.
  • the antibody microarray is one of the most common protein microarrays. In this case the antibodies are placed in small points, fixed on the solid support (called a protein chip) and used to capture molecules and thus detect the proteins in an isolated sample, such as a cell lysate, a conditioned medium, serum, urine or CSF.
  • solid support refers to a wide variety of materials, for example, but not limited to, ion exchange resin or adsorption, glass, plastic, latex, nylon, gel, esters or Cellulose, paramagnetic spheres or a combination of some of them.
  • the present invention relates to the use of the expression product of a nucleotide sequence of a sfrpl gene as a marker for the determination of the risk of suffering from AD, to determine the presence of AD and / or to predict progression. of an EA in a subject susceptible to AD.
  • the present invention relates to the use of a kit comprising primers and / or probes that hybridize with the nucleotide sequence of an sfrpl gene encoding an amino acid sequence that has at least 90% identity with SEQ ID NO: 1, or coding for the amino acid sequence SEQ ID NO: 1, to determine the risk of suffering from AD or to determine the presence of an AD or to predict the progression of an AD in a subject susceptible to AD, in An isolated sample.
  • primers refers to oligonucleotides with identical or complementary reverse nucleotide sequences that allow amplification of any fragment of the gene in question by, for example, polymerase chain reaction (PCR).
  • primer refers to sequences of between 15-30 nucleotides that hybridize with one of the template nucleic acid chains and allow amplification of a DNA sequence by a PCR reaction.
  • probe refers to an RNA or DNA sequence that may or may not be labeled with any marker compound known in the state of the art.
  • the present invention relates to the use of a kit comprising antibodies that specifically bind to an amino acid sequence encoded by the nucleotide sequence of a sfrpl gene where said amino acid sequence has at least 90% identity with SEQ ID. NO: 1, or where said amino acid sequence is SEQ ID NO: 1, to determine the risk of suffering from AD or to determine the presence of an AD or to predict the progression of an AD in a subject susceptible to AD, in a isolated sample.
  • Figure 1 It shows that the levels of SFRP1 in the blood serum of Alzheimer's patients (AD) are significantly different from the levels in healthy subjects (control).
  • Figure 2. It shows that in the absence of sfrpl (TgAPP; PS1; Sfrp1) less deposits of ⁇ are formed in the cerebral cortex in a murine model for AD (TgAPP; PS1). The data were analyzed using the Student test. *** indicates p ⁇ 0.001 vs. control.
  • FIG. 3 It shows that in a murine model for AD (TgAPP; PS1), episodic memory is very deficient compared to that observed in wild animals (WT), while in the same EA model it also lacks sfrpl (TgAPP ; PS1; Sfrp1 " ' " ), episodic memory is comparable to that of wild animals.
  • FIG. 4 It shows that, in a murine model for AD (TgAPP; PS1), the level of spatial memory acquisition is lower than in wild animals (WT) while in the same EA model it also lacks sfrpl ( TgAPP; PS1; Sfrp1 " ' " ), the spatial memory is closer to that of wild animals.
  • FIG. 5 It shows that in a murine model for AD (TgAPP; PS1), the level of spatial information retrieval from the Morris test is lower than in wild animals (WT) while in the same EA model that It also lacks sfrpl (TgAPP; PS1; Sfrp1 " ' " ), this recovery is closer to that of wild animals.
  • EXAMPLE 1 Analysis of serum SFRP1 levels in patients with Alzheimer's disease. SFRP1 protein levels were analyzed in blood serum samples from 10 Alzheimer's patients and in 5 non-dementia subjects aged between 76 and 81 years, which were considered control subjects.
  • EXAMPLE 2 Analysis of SFRP1 levels in cerebrospinal fluid of Alzheimer's patients. SFRP1 protein levels were quantified in cerebrospinal fluid samples from Alzheimer's patients and control subjects.
  • TgAPP animals male PS1 were used as EA model and TgAPP animals; PS1 without sfrpl (TgAPP; PS1; Sfrp1 ⁇ ) male.
  • the cerebral cortex of both groups was studied histologically in 5-month-old animals. The animals were sacrificed with anesthetic / eutanase, fixed by perfusion with 4% paraformaldehyde (PFA), the brain was extracted, cryoprotected and frozen at -80 ° C. Cryostat sections of 10 ⁇ were obtained and immunostained with the antibody specific against ⁇ _4 ⁇ -42 (Millipore) and were marked with DAPI and Congo network. Deposits of ⁇ were observed by anti- ⁇ marking and by staining with Congo red.
  • EXAMPLE 4 The absence of sfrpl in an EA model decreases reactive astrogliosis, the accumulation of active microglia and phosphorylation of Tau.
  • AD is associated with chronic inflammation in the brain, reflected with elevated microgliosis and with the presence of reactive astrocytes.
  • Deletion of the sfrpl gene in a mouse EA model prevents the formation of microgliosis, reactive astrocytosis, and phosphorylation of Tau, all of them pathological signs observed in AD, indicating that in the absence of sfrpl brain histology is preserves
  • EXAMPLE 5 The absence of the sfrpl gene prevents memory deficits present in a murine model of AD.
  • ORT object recognition test
  • TgAPP; PS1 mice show significantly worse performance than wild animals when recognizing objects.
  • TgAPP; PS1; Sfrp1 ⁇ _ mice show a performance similar to that observed in wild animals ( Figure 3).
  • ANOVA p 0.012; post hoc comparisons with Tukey p ⁇ 0.001 WT and TgAPP; PS1; Sfrp1 "" vs.. TgAPP; PS1.
  • the Morris Test was used, which consisted of three phases: habituation, acquisition and recovery.
  • the animals were introduced for 60 seconds in a pool with water at 22 ⁇ 1 o C without the escape platform (PE), 24 hours later the acquisition phase began, in which the pool contained a PE in one of the quadrants (always the same).
  • This phase lasted 4 days, with 4 trials per day in which the animals were introduced by each of the quadrants.
  • the maximum test time was 60 seconds.
  • the recording time (escape latency) was stopped and allowed to be on it for 20 seconds.
  • the recovery phase the pool lacked PE. The animal was introduced in the center of the pool and swam for 60 seconds, recording the time the mouse spent in the quadrant that the PE had in the previous days.
  • EXAMPLE 6 SFRP1 soluble protein accumulates in the cerebral cortex in amyloid plaques in both a murine model of AS and in patients with AD increasingly as the disease progresses.
  • EXAMPLE 7 SFRP1 soluble protein is secreted by the reactive astrocytes and activated microglia surrounding the plaque.
  • TgAPP mice PS1 were sacrificed with anesthetic / eutanasic, fixed by perfusion with 4% PFA, the brain was removed, cryoprotected and frozen at -80 ° C. Cryostat sections of 10 ⁇ were obtained that were immunostained with the specific antibody against SFRP1 and with specific antibodies that recognize neurons (NeuN), GFAP (astrocytes) or tomato lectin (microglia). Colocalization of SFRP1 was observed with GFAP or with tomato lectin in cells located in the vicinity of the plaques present in this mouse. These results indicate that the SFRP1 protein is synthesized by reactive astrocytes and activated microglia found around senile plaques.
  • sfrpl The expression of sfrpl is increased in patients with AD (Blalock et al. 2004 Proc Nati Acad Sci 101, 2173-8). In that study, they compared the expression levels of different mRNAs in hippocampus samples of control individuals and individuals with incipient AD by "microarray" analysis. The sfrpl gene is among the list of genes whose mRNA levels are increased in individuals with incipient AD.
  • sfrpl mRNA correlates with an increase in protein levels in samples of patients with AD.
  • Samples of human cerebral cortex from control individuals or patients with early stage (Braak lll-IV) and late stage (Braak V-VI) were homogenized in lysis buffer and 1% Triton X-100. The samples were re-suspended in loading buffer and analyzed by electrophoresis in 12% acrylamide gels, followed by Western blot analysis. This analysis showed that the SFRP1 protein is more abundant in samples of AD patients than in control individuals. In addition, SFRP1 protein levels increase the more severe the disease is (Figure 6). In brain cortex samples of AD patients, very clear accumulations of SFRP1 are detected by immunocytochemistry when other plaque markers are not yet visible, indicating that their load precedes plaque formation and is therefore an earlier marker than other plate markers described to date.

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Abstract

La présente invention concerne une méthode de diagnostic de la maladie d'Alzheimer qui consiste (a) à détecter et/ou à quantifier le produit d'expression d'une séquence nucléotidique d'un gène sfrp1 dans un échantillon isolé; (b) à comparer la quantité détectée et/ou quantifiée avec une quantité de référence; (c) à identifier tout écart significatif dans la comparaison des données de l'étape (b); et, (d) à attribuer cet écart significatif identifié à la présence de la maladie d'Alzheimer. Cette invention concerne également un nécessaire qui comprend des amorces et/ou des sondes qui s'hybrident avec la séquence nucléotidique d'un gène sfrp1 ou des anticorps que se lient spécifiquement à une séquence d'acides aminés codée par la séquence nucléotidique d'un gène sfrp1 afin de déterminer la présence de la maladie d'Alzheimer.
PCT/ES2012/070226 2011-04-08 2012-04-03 Méthode de diagnostic de la maladie d'alzheimer qui utilise le sfrp1 comme biomarqueur WO2012136871A1 (fr)

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Cited By (2)

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Publication number Priority date Publication date Assignee Title
CN103951743A (zh) * 2014-04-25 2014-07-30 陈秀定 人sfrp1变体及其应用
EP3696192A1 (fr) * 2019-02-15 2020-08-19 Consejo Superior De Investigaciones Científicas Cible thérapeutique et anticorps monoclonaux contre elle pour le diagnostic et le traitement de la maladie d'alzheimer

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US20070082350A1 (en) * 2005-02-09 2007-04-12 Philip Landfield Assay and method for diagnosing and treating alzheimer's disease

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WO2003028543A2 (fr) * 2001-10-03 2003-04-10 Pfizer Products Inc. Molecules d'acide nucleique, polypeptides et utilisations associees comprenant le diagnostic et le traitement de la maladie d'alzheimer
US20070082350A1 (en) * 2005-02-09 2007-04-12 Philip Landfield Assay and method for diagnosing and treating alzheimer's disease

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103951743A (zh) * 2014-04-25 2014-07-30 陈秀定 人sfrp1变体及其应用
EP3696192A1 (fr) * 2019-02-15 2020-08-19 Consejo Superior De Investigaciones Científicas Cible thérapeutique et anticorps monoclonaux contre elle pour le diagnostic et le traitement de la maladie d'alzheimer
WO2020165453A1 (fr) * 2019-02-15 2020-08-20 Consejo Superior De Investigaciones Científicas Cible thérapeutique et anticorps monoclonaux dirigés contre celle-ci pour le diagnostic et le traitement de la maladie d'alzheimer

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