WO2020045962A1 - Biomarqueur peptidique permettant le diagnostic de la maladie d'alzheimer - Google Patents

Biomarqueur peptidique permettant le diagnostic de la maladie d'alzheimer Download PDF

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Publication number
WO2020045962A1
WO2020045962A1 PCT/KR2019/010947 KR2019010947W WO2020045962A1 WO 2020045962 A1 WO2020045962 A1 WO 2020045962A1 KR 2019010947 W KR2019010947 W KR 2019010947W WO 2020045962 A1 WO2020045962 A1 WO 2020045962A1
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alzheimer
dementia
peptide
seq
antibody
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PCT/KR2019/010947
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English (en)
Korean (ko)
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박성규
심규영
이건호
김병채
Original Assignee
광주과학기술원
전남대학교산학협력단
조선대학교산학협력단
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Priority claimed from KR1020180100614A external-priority patent/KR102108171B1/ko
Priority claimed from KR1020180100615A external-priority patent/KR102108176B1/ko
Application filed by 광주과학기술원, 전남대학교산학협력단, 조선대학교산학협력단 filed Critical 광주과학기술원
Publication of WO2020045962A1 publication Critical patent/WO2020045962A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • 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

Definitions

  • the present invention relates to a diagnosis of Alzheimer's dementia of a peptide that binds to a specific autoantibody of an Alzheimer's dementia patient, and specifically includes a peptide consisting of at least one amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 10 as an active ingredient.
  • Alzheimer's dementia diagnostic composition Diagnostic kits; Information providing method for diagnosing Alzheimer's dementia using the composition; And an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 10, to a peptide that binds to a specifically increasing antibody in Alzheimer's dementia patients.
  • diagnostic methods used for diagnosing Alzheimer's disease include genetic tests, neuropsychological tests, cognitive function tests, cerebrospinal fluid tests, and brain imaging tests (MRI, PET).
  • Genetic testing is a test that detects the risk of Alzheimer's dementia by testing for an Alzheimer's dementia specific gene called ApoE4.
  • ApoE4 may increase the risk of dementia invention, but because it is not a decisive factor, it is difficult to diagnose Alzheimer's dementia by the test alone.
  • the neuropsychological test and cognitive function test is a method for measuring the degree of cognitive impairment of the patient through the questionnaire, there is a simple mental state test (MMSE), Montreal cognitive test (MoCA), SNSB.
  • the cerebrospinal fluid test is a method of extracting cerebrospinal fluid to quantitatively diagnose beta-amyloid or tau protein, which is known as an Alzheimer's trigger. May cause rejection.
  • Brain imaging tests (MRI, PET) is a method that analyzes the brain damage and beta-amyloid and tau proteins, MRI or PET imaging, and Alzheimer's triggers. Although it has high accuracy for diagnosis, it requires expensive equipment and expertise in imaging when Alzheimer's dementia is diagnosed, so there is a limitation in distribution and high diagnostic cost.
  • Alzheimer's factor As such, there are various techniques for diagnosing Alzheimer's dementia, but each technique has various limitations such as accuracy problems, cost problems, time problems, and physical pain.
  • the limitation of this prior art is that the Alzheimer's factor, beta-amyloid and tau protein, does not appear significant in the blood enough to be used for diagnosing dementia, and there is no limit to the fact that there is no biomarker for diagnosing Alzheimer's dementia available through blood There is this.
  • the present inventors have diligently studied to prepare a composition for diagnosing Alzheimer's disease that can use blood, and when using a peptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1 to 10, the conventional Alzheimer's dementia diagnosis method has The present invention was completed by overcoming limitations due to cost, time, pain and side effects, and confirming that Alzheimer's dementia can be diagnosed through blood.
  • One object of the present invention is to provide a composition for diagnosing Alzheimer's dementia, comprising as an active ingredient a peptide consisting of at least one amino acid sequence selected from the group consisting of SEQ ID NO: 1 to 10.
  • Another object of the present invention to provide a kit for diagnosing Alzheimer's dementia, comprising as an active ingredient a peptide consisting of at least one amino acid sequence selected from the group consisting of SEQ ID NO: 1 to 10.
  • Yet another object of the present invention is to provide an information providing method for diagnosing Alzheimer's dementia, comprising detecting an antibody or measuring expression of an antibody in a sample using the composition from a sample isolated from an individual.
  • Yet another object of the present invention is to provide a peptide that binds to an antibody that is specifically increased in Alzheimer's dementia patients consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-10.
  • Peptides consisting of one or more amino acid sequences selected from the group consisting of SEQ ID NOs: 1 to 10 according to the present invention can specifically bind to antibodies that specifically increase in the blood of Alzheimer's dementia patients.
  • FIG. 1A and 1B show a volcano plot of peptides for Alzheimer's dementia specific antibodies (FIG. 1A: IgM, FIG. 1B: IgG). Peptides that target specifically increasing antibodies in Alzheimer's dementia are indicated in the right box.
  • ROC operating operating curve
  • 3A and 3B show AUC values through the ROC analysis of these combinations by selecting the top five AUC values among the peptides selected in FIGS. 2A and 2B, respectively.
  • Figures 5a and 5b is to select the top five peptides of the AUC value among the peptides selected in Figs. 2a and 2b, respectively, antibodies targeting each of the five peptides (Fig. 5a: IgM, Fig. 5b: IgG)
  • the MFI value of is shown as a dot plot.
  • Figures 6a and 6b is to select the top five peptides of the AUC value among the peptides selected in Figs. 2a and 2b, respectively, to determine the MFI value of the antibody (Fig. 6a: IgM, Fig. 6b: IgG) targeting these combinations It is represented by a dot plot.
  • Figure 7 shows a Pearson correlation coefficient analysis of the peptide of SEQ ID NO: 1 correlated with K-MMSE among the selected peptides.
  • one embodiment of the present invention provides a composition for diagnosing Alzheimer's dementia, comprising as an active ingredient a peptide consisting of at least one amino acid sequence selected from the group consisting of SEQ ID NO: 1 to 10.
  • the peptide of the present invention may be a peptide consisting of one or more amino acid sequences selected from the group consisting of SEQ ID NOs: 1 to 10 described in Table 1 below. Or a combination of five peptides consisting of the amino acid sequences of SEQ ID NOs: 1 to 5 or a combination of five peptides consisting of the amino acid sequences of SEQ ID NOs: 6 to 10, or a peptide 10 consisting of the amino acid sequences of SEQ ID NOs: 1 to 10 It may be a combination of species, but is not limited thereto.
  • Peptide sequence number Peptide amino acid sequence AUC value SEQ ID NO: 1 RGPLRQGRNTGAAGA 0.837 SEQ ID NO: 2 VFTAWMGLEFAYGDK 0.825 SEQ ID NO: 3 HKRIFGSHHPTHDLG 0.825 SEQ ID NO: 4 GRVWNVDMRRCDFSE 0.823 SEQ ID NO: 5 GQRDAPMVTHRPSPH 0.820 SEQ ID NO: 6 PPHVISYHSYPDAWD 0.867 SEQ ID NO: 7 SKGTDPTRTVWERPF 0.820 SEQ ID NO: 8 FLDMDQRPWNPFVWD 0.817 SEQ ID NO: 9 EHPHRDELQQRFFPD 0.817 SEQ ID NO: 10 SNLIRLKEFTDYLFF 0.814
  • the peptide may bind to autoantibodies that are specifically upregulated or downregulated in Alzheimer's dementia patients, specifically binding to IgG or IgM antibodies that specifically increase in Alzheimer's dementia patients, It is not limited to this.
  • Alzheimer's dementia of the present invention means the symptoms of dementia caused by Alzheimer's disease.
  • the Alzheimer's disease refers to the most common degenerative brain disease causing dementia, first reported by Dr. Alzheimer's, Germany, and it is known that as Alzheimer's disease progresses, the overall cognitive function including memory is gradually weakened.
  • diagnosis refers to determining the susceptibility of a subject to a particular disease or disorder, determining whether the subject currently has a particular disease or disorder, the prognosis of the subject having a particular disease or disorder. determining prognosis, or therametrics (eg, monitoring the condition of an individual to provide information about treatment efficacy).
  • the selected 64 or 49 peptides are clearly defined as the Alzheimer's dementia population (AD) and the normal population (ND). It was confirmed that it can be divided (Fig. 4a and 4b).
  • microarray intensity (MFI) analysis confirmed that each of the five peptides selected and their combinations showed significant differences in MFI values between the AD and ND populations (FIGS. 5A, 5B and 6A, 5B). ).
  • composition of the present invention comprising a peptide consisting of at least one amino acid sequence selected from the group consisting of SEQ ID NOS: 1 to 10 as an active ingredient is a target of an antibody that is specifically increased in Alzheimer's dementia patients, Alzheimer's dementia It was confirmed that the excellent diagnostic efficacy of.
  • all five peptides consisting of the amino acid sequence of SEQ ID NO: 1 to 5 or all five peptides consisting of the amino acid sequence of SEQ ID NO: 6 to 10 shows a very high AUC value, very significant Alzheimer's diagnostic efficacy It could be confirmed that it has.
  • kits for diagnosing Alzheimer's dementia comprising as an active ingredient a peptide consisting of at least one amino acid sequence selected from the group consisting of SEQ ID NOs.
  • the kit of the present invention refers to a kit including the composition for diagnosing Alzheimer's dementia, and using the kit of the present invention, it may be determined that a patient with Alzheimer's dementia or the risk of developing Alzheimer's dementia.
  • the kit for diagnosing Alzheimer's dementia of the present invention includes one or more other constructs suitable for analytical methods as well as the peptide for measuring the detection or expression of autoantibodies, in particular IgM or IgG, which are specifically increased in Alzheimer's patients. Component compositions, solutions or devices may be included.
  • the kit of the present invention may include a substrate, a suitable buffer, a secondary antibody labeled with a coloring enzyme or a fluorescent substance, a coloring substrate, and the like for immunological detection of the antibody.
  • the substrate may be a nitrocellulose membrane, a 96-well plate synthesized with a polyvinyl resin, a 96-well plate synthesized with a polyester resin, a slide glass made of glass, and the like, and the chromase is peroxidase, alkaline.
  • the phosphatase Alkaline Phosphatase
  • the fluorescent material can be used FITC, RITC and the like
  • the colorant substrate liquid is ABTS (2,2'-azino-bis (3-ethylbenzothiazoline-6-sulfonic acid) ))
  • OPD ⁇ -phenylenediamine
  • TMB tetramethyl benzidine
  • Another aspect of the invention provides a method for providing information for diagnosing Alzheimer's dementia, comprising detecting an antibody in a sample or measuring expression thereof using the composition from a sample isolated from an individual.
  • the antibody may be an IgM or IgG antibody.
  • the peptide included in the composition may be any one or more of five peptides consisting of amino acid sequences of SEQ ID NOs: 1 to 5, and may include all five peptides.
  • the antibody is an IgG antibody, at least one of five peptides consisting of the amino acid sequences of SEQ ID NOs: 6 to 10 may be included and all five peptides may be included. But it is not limited thereto.
  • the term "individual" of the present invention refers to a subject for whom to diagnose Alzheimer's dementia or to predict the risk of developing it.
  • the subject may include any person, including a dog, a horse, a cow, a rat, a goat, a rabbit, a chicken, a duck, a goose, and any animal that may develop Alzheimer's dementia.
  • sample of the present invention refers to a sample such as tissue, cells, whole blood, serum, plasma, saliva, sputum, cerebrospinal fluid or urine derived from the subject and capable of detecting autoantibodies specifically upregulated in Alzheimer's dementia. And the like, in particular, but not limited to, a blood sample isolated from an individual.
  • the information providing method of the present invention is a method for diagnosing Alzheimer's dementia or providing information for determining the risk of developing Alzheimer's. Or detecting an antibody in a sample isolated from the subject to determine the degree of up-regulation or down-regulation of the antibody; Or measuring the expression thereof.
  • the information providing method may further comprise comparing the expression level of the antibody with the expression level of the antibody in a sample isolated from the normal control.
  • the reference value for comparing the expression level of the antibody may be, but not limited to, the area under the curve (AUC) or the microarray intensity (MFI) of the receiver manipulation characteristic curve (ROC).
  • AUC area under the curve
  • MFI microarray intensity
  • ROC receiver manipulation characteristic curve
  • the degree of binding between the antibody and the composition in the sample isolated from the individual is measured, and when the individual shows an increased degree of binding compared to the normal control or is higher than a specific cut-off value, It may be determined that the patient has Alzheimer's dementia or the risk of developing Alzheimer's dementia is high.
  • the expression level of the antibody is higher than the expression level of the antibody in the sample isolated from the normal control, the subject may be determined to be Alzheimer's dementia, or the risk of developing Alzheimer's dementia.
  • Another aspect of the invention provides a peptide that binds to an antibody that specifically increases in Alzheimer's dementia patient, consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-10.
  • the antibody may be an IgM or IgG antibody.
  • the peptide may be any one or more of five peptides consisting of amino acid sequences of SEQ ID NOs: 1 to 5, and when the antibody is an IgG antibody, the peptide is an amino acid sequence of SEQ ID NOs: 6 to 10 At least one of five peptides consisting of.
  • Peptides of the invention can also be used as probes, which refers to labeled peptides capable of binding to specific autoantibodies in Alzheimer's dementia patients.
  • Another aspect of the invention provides the use of a peptide consisting of an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-10 for preparing a composition for diagnosing Alzheimer's dementia.
  • Another aspect of the invention provides the use of a polynucleotide encoding said peptide.
  • the peptide is as described above.
  • the serum samples used in the examples below are serum samples of 19 Alzheimer's dementia patients (experimental group, AD) obtained from Chosun University Hospital and Chungnam National University Medical School and 19 normal individuals (control, ND) of age matched with the experimental group. . In addition, because Alzheimer's dementia develops more frequently in women, all serum samples were obtained from women to reduce potential sexual bias. The clinical diagnosis of Alzheimer's dementia was based on criteria defined by the National Institute on Aging-Alzheimer's Association. To confirm the diagnosis of Alzheimer's dementia, all experimental (AD) and control (ND) subjects were subjected to magnetic resonance imaging or positron emission tomography using F-18 florbetaben (NeuraCeq TM). received.
  • Korean Mini-Mental State Examination (K-MMSE) score was measured to evaluate the severity of dementia.
  • Chips of random peptide microarrays were coated with duplicates of 29,240 peptides (58,480 peptide spots).
  • FLAG (DYKDDDKAS) peptide and HA (YPYDVPDYAG) peptide were further coated with control peptide.
  • Coated microarrays were blocked with blocking buffer MB-070 (Rocland, Gilbertsville, PA, USA) for 30 minutes. The chip was then incubated for 45 minutes with goat anti-human IgM or IgG conjugated to DyLight680 diluted 1: 5000 at room temperature (RT). This was done to check the background between the secondary antibody and the peptide library in the plate.
  • the random peptide microarray data obtained by the above procedure was subjected to the following signal intensity correction process.
  • microarray data was removed from the background noise using Spotxel® microarray Image and Data Analysis software.
  • the background signal between the secondary antibody and peptide library was then removed based on the intensity of the averaged median.
  • Raw data between microarray chips was quantile normalized using the devtools package of R 3.4.0 software (R Development Core Team, 2017) to compensate for variations between chips.
  • microarray intensity fold change (ND / AD ⁇ 2) and Student's t between Alzheimer's dementia and normal individuals Peptide candidates were selected using the P-value ( ⁇ 5) using the test's t test.
  • IgM was specifically upregulated in Alzheimer's dementia patients by screening using fold change (ND / AD ⁇ 2) and P-value ( ⁇ 5) of 29,490 types of peptides identified by random peptide microarrays.
  • Peptides targeting the antibody ( FIG . 1A ) or IgG ( FIG. 1B ) were selected and indicated in red (right box Peptides).
  • 170 peptide candidate groups were selected for the IgM antibody and 144 peptide candidate groups were selected for the IgG antibody.
  • AUC receiver operating characteristic curve
  • the AUC value is a quantitative expression of the Alzheimer's diagnostic performance of a peptide marker that is a target of an antibody that is specifically increased in Alzheimer's dementia patients. Specifically, when the AUC value of the peptide marker is 0.75 or more, it can be considered to have a normal diagnostic performance, and when the AUC value is 0.80 or more, it has excellent diagnostic performance.
  • FIGS. 2A and 2B Peptides with an AUC value of 0.75 or greater were selected and shown in FIGS. 2A and 2B.
  • the portion marked in red (shaded) represents the selected peptide, and the portion marked in blue represents the unselected peptide.
  • 64 peptides were selected for IgM ( FIG. 2A ) and 49 peptides for IgG ( FIG. 2B ).
  • peptides having the highest AUC values were selected as peptides targeted by IgM or IgG antibodies specifically upregulated in Alzheimer's dementia patients.
  • the AUC values for the selected peptides, the sequence numbers of the selected peptides and the respective amino acid sequences are shown in Table 2 below.
  • the peptide marker of the present invention is a peptide that is a target of an antibody that is specifically increased in Alzheimer's dementia patients, and has excellent diagnostic performance in diagnosing the disease. You can check it.
  • the AUC value was calculated by ROC analysis for the markers of the five peptides selected for the IgM and IgG, respectively, and showed a very high AUC value. (IgM: 0.945, IgG: 0.892).
  • each peptide marker selected as well as a combination thereof can serve as a target of an antibody specifically upregulated in Alzheimer's dementia, having very good diagnostic performance.
  • Example 2 Confirmation of diagnostic efficacy of Alzheimer's dementia using selected peptide markers and combinations thereof
  • the selected 64 species (Fig. 4a) or 49 peptides (Fig. 4b) peptide markers are each specifically upregulated IgM, IgG type antibodies in patients with Alzheimer's dementia
  • AD Alzheimer's dementia population
  • ND normal population
  • the antibody was specifically upregulated in Alzheimer's dementia patients targeting the peptide marker.
  • Random peptide microarray intensity (MFI) values were analyzed in Dot Alzheimer's disease (AD) and normal subjects (ND). Here, it can be interpreted that the greater the difference between MFI values of Alzheimer's dementia patients and normal individuals, the better the diagnostic performance of the peptide marker.
  • Statistical tests for each peptide and combinations thereof were run through Student's t test. * Indicates p ⁇ 0.05, ** indicates p ⁇ 0.01, and *** indicates p ⁇ 0.001.
  • each of the five selected peptide markers showed significant differences in MFI values for Alzheimer's dementia patients (AD) and normal individuals (ND). You can check.
  • the peptide (UM # 1) consisting of the amino acid sequence of SEQ ID NO: 1 among the five peptides for IgM showed the largest difference in MF1 value, and the amino acid sequence of SEQ ID NO: 6 among the five peptides for IgG Since the peptide (UG # 1) has the largest difference in MF1 value, it can be confirmed that the peptide has the best diagnostic performance.
  • the combination of the five selected peptide markers can also be seen that the difference in MFI values for Alzheimer's dementia patients (AD) and normal individuals (ND) is remarkable have.
  • the selected peptide marker and a combination thereof may be a target of antibodies specifically upregulated in Alzheimer's dementia patients, it can be confirmed that it has excellent efficacy in the diagnosis of Alzheimer's dementia.
  • each of the peptide marker and dementia Correlations with K-MMSE scores used as a measure of severity, were analyzed.
  • the K-MMSE score is expressed as at least 0 to 30 points, the higher the score indicates a decrease in cognitive function.
  • the MFI value and K-MMSE score of the peptide (UM # 1) consisting of the amino acid sequence of SEQ ID NO: 1 showing the largest difference in the MFI value in Example 2-2 Indicates that r ⁇ ⁇ 0.5 and p ⁇ 0.001. That is, when the diagnosis of Alzheimer's using the peptide marker, it can be confirmed that K-MMSE score is very similar to the result of diagnosing Alzheimer's dementia. Through this, when using the selected peptide marker of the present invention, it can be confirmed that Alzheimer's dementia can be diagnosed to the extent that the existing Alzheimer's dementia diagnostic method.
  • the selected peptides of the present invention and combinations thereof are targeted to antibodies which are specifically increased in Alzheimer's dementia patients, enabling diagnosis through blood, and thus, the cost of the existing Alzheimer's diagnosis method It was confirmed that it can be used as an excellent diagnostic marker of Alzheimer's dementia, overcoming problems due to time, side effects, and the like.

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Abstract

La présente invention concerne l'utilisation d'un peptide pour le diagnostic de la maladie d'Alzheimer, le peptide se liant à des auto-anticorps spécifiques chez des patients atteints de la maladie d'Alzheimer. Plus précisément, la présente invention concerne : une composition de diagnostic de la maladie d'Alzheimer contenant, en tant que principe actif, un peptide constitué d'une ou plusieurs séquences d'acides aminés choisies dans le groupe constitué par SEQ ID NO : 1-10 ; un kit de diagnostic ; une méthode de fourniture d'informations permettant de diagnostiquer la maladie d'Alzheimer à l'aide de la composition ; et un peptide constitué de séquences d'acides aminés choisies dans le groupe constitué par SEQ ID NO : 1-10 et se liant à des anticorps qui augmentent de façon spécifique chez des patients atteints de la maladie d'Alzheimer. Comme le peptide de la présente invention peut se lier de façon spécifique à des anticorps qui augmentent de façon spécifique dans le sang de patients atteints de la maladie d'Alzheimer, le peptide peut surmonter les limitations des méthodes classiques de diagnostic de la maladie d'Alzheimer qui ne permettaient pas un diagnostic sanguin, et peut être utilisé pour le diagnostic de la maladie d'Alzheimer à partir du sang.
PCT/KR2019/010947 2018-08-27 2019-08-27 Biomarqueur peptidique permettant le diagnostic de la maladie d'alzheimer WO2020045962A1 (fr)

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KR10-2018-0100615 2018-08-27
KR1020180100614A KR102108171B1 (ko) 2018-08-27 2018-08-27 알츠하이머성 치매 진단용 펩타이드 바이오마커
KR10-2018-0100614 2018-08-27
KR1020180100615A KR102108176B1 (ko) 2018-08-27 2018-08-27 알츠하이머성 치매 진단용 펩타이드 바이오마커

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20140069346A (ko) * 2011-10-04 2014-06-09 아피리스 아게 알츠하이머병 （ａｄ）을 진단하는 방법
US20140303025A1 (en) * 2013-03-15 2014-10-09 The Translational Genomics Research Institute Methods for the diagnosis and prognosis of neurodegenerative diseases
WO2015175898A1 (fr) * 2014-05-16 2015-11-19 Vitruvian Biomedical, Inc. Test de diagnostic et de traitement/prévention de la maladie d'alzheimer
KR20180078783A (ko) * 2016-12-30 2018-07-10 광주과학기술원 알츠하이머병 진단을 위한 신규한 miRNA

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20140069346A (ko) * 2011-10-04 2014-06-09 아피리스 아게 알츠하이머병 （ａｄ）을 진단하는 방법
US20140303025A1 (en) * 2013-03-15 2014-10-09 The Translational Genomics Research Institute Methods for the diagnosis and prognosis of neurodegenerative diseases
WO2015175898A1 (fr) * 2014-05-16 2015-11-19 Vitruvian Biomedical, Inc. Test de diagnostic et de traitement/prévention de la maladie d'alzheimer
KR20180078783A (ko) * 2016-12-30 2018-07-10 광주과학기술원 알츠하이머병 진단을 위한 신규한 miRNA

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BAIG, M. H.: "Use of peptides for the management of alzheimer's disease: diagnosis and inhibition", FRONTIERS IN AGING NEUROSCIENCE, vol. 10, no. 21, 7 February 2018 (2018-02-07), pages 1 - 6, XP055697310 *
FUNKE, S. A: "Peptides for therapy and diagnosis of alzheimer's disease", CURRENT PHARMACEUTICAL DESIGN, vol. 18, 2012, pages 755 - 767, XP009170739, DOI: 10.2174/138161212799277752 *

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