JP2020515846A - タウタンパク質凝集を調節する化合物の検出のための方法 - Google Patents
タウタンパク質凝集を調節する化合物の検出のための方法 Download PDFInfo
- Publication number
- JP2020515846A JP2020515846A JP2019553335A JP2019553335A JP2020515846A JP 2020515846 A JP2020515846 A JP 2020515846A JP 2019553335 A JP2019553335 A JP 2019553335A JP 2019553335 A JP2019553335 A JP 2019553335A JP 2020515846 A JP2020515846 A JP 2020515846A
- Authority
- JP
- Japan
- Prior art keywords
- tau protein
- formation
- phf
- tau
- vitro
- Prior art date
- Legal status (The legal status 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 status listed.)
- Ceased
Links
- 102000013498 tau Proteins Human genes 0.000 title claims abstract description 62
- 108010026424 tau Proteins Proteins 0.000 title claims abstract description 62
- 238000000034 method Methods 0.000 title claims abstract description 50
- 150000001875 compounds Chemical class 0.000 title claims description 22
- 238000001514 detection method Methods 0.000 title abstract description 5
- 230000004845 protein aggregation Effects 0.000 title 1
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 38
- 238000000338 in vitro Methods 0.000 claims abstract description 26
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 239000000203 mixture Substances 0.000 claims abstract description 10
- 229920001307 poly(hydroxymethylethylene hydroxymethyl formal) Polymers 0.000 claims abstract 6
- JADVWWSKYZXRGX-UHFFFAOYSA-M thioflavine T Chemical compound [Cl-].C1=CC(N(C)C)=CC=C1C1=[N+](C)C2=CC=C(C)C=C2S1 JADVWWSKYZXRGX-UHFFFAOYSA-M 0.000 claims description 20
- 238000011534 incubation Methods 0.000 claims description 12
- 238000012360 testing method Methods 0.000 claims description 11
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 claims description 8
- 229960002897 heparin Drugs 0.000 claims description 8
- 229920000669 heparin Polymers 0.000 claims description 8
- 238000001506 fluorescence spectroscopy Methods 0.000 claims description 7
- 108090000623 proteins and genes Proteins 0.000 claims description 7
- 230000002401 inhibitory effect Effects 0.000 claims description 6
- 230000001737 promoting effect Effects 0.000 claims description 6
- 102000004169 proteins and genes Human genes 0.000 claims description 6
- 239000012634 fragment Substances 0.000 claims description 4
- 102000029749 Microtubule Human genes 0.000 claims description 3
- 108091022875 Microtubule Proteins 0.000 claims description 3
- 102000001708 Protein Isoforms Human genes 0.000 claims description 3
- 108010029485 Protein Isoforms Proteins 0.000 claims description 3
- 210000004688 microtubule Anatomy 0.000 claims description 3
- 238000003271 compound fluorescence assay Methods 0.000 claims 1
- 230000001939 inductive effect Effects 0.000 claims 1
- 230000002776 aggregation Effects 0.000 description 28
- 238000004220 aggregation Methods 0.000 description 28
- 238000010899 nucleation Methods 0.000 description 15
- 208000024827 Alzheimer disease Diseases 0.000 description 13
- PZBFGYYEXUXCOF-UHFFFAOYSA-N TCEP Chemical compound OC(=O)CCP(CCC(O)=O)CCC(O)=O PZBFGYYEXUXCOF-UHFFFAOYSA-N 0.000 description 13
- 230000012010 growth Effects 0.000 description 9
- 230000006698 induction Effects 0.000 description 7
- 238000005259 measurement Methods 0.000 description 7
- 230000006911 nucleation Effects 0.000 description 7
- 238000003556 assay Methods 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000001419 dependent effect Effects 0.000 description 6
- 230000001575 pathological effect Effects 0.000 description 6
- 235000018102 proteins Nutrition 0.000 description 5
- 206010012289 Dementia Diseases 0.000 description 4
- 201000011240 Frontotemporal dementia Diseases 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 238000006116 polymerization reaction Methods 0.000 description 4
- 208000034799 Tauopathies Diseases 0.000 description 3
- 238000011481 absorbance measurement Methods 0.000 description 3
- 238000007818 agglutination assay Methods 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 230000008033 biological extinction Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000003112 inhibitor Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 208000011990 Corticobasal Degeneration Diseases 0.000 description 2
- 241001198387 Escherichia coli BL21(DE3) Species 0.000 description 2
- 208000002339 Frontotemporal Lobar Degeneration Diseases 0.000 description 2
- 208000000609 Pick Disease of the Brain Diseases 0.000 description 2
- 238000001042 affinity chromatography Methods 0.000 description 2
- DZHSAHHDTRWUTF-SIQRNXPUSA-N amyloid-beta polypeptide 42 Chemical class C([C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](C(C)C)C(=O)NCC(=O)NCC(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(O)=O)[C@@H](C)CC)C(C)C)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@@H](NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC=1N=CNC=1)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC(O)=O)C(C)C)C(C)C)C1=CC=CC=C1 DZHSAHHDTRWUTF-SIQRNXPUSA-N 0.000 description 2
- 230000003698 anagen phase Effects 0.000 description 2
- 238000000089 atomic force micrograph Methods 0.000 description 2
- 238000004630 atomic force microscopy Methods 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 2
- 239000000539 dimer Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000001493 electron microscopy Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000004770 neurodegeneration Effects 0.000 description 2
- 210000002682 neurofibrillary tangle Anatomy 0.000 description 2
- 229920000447 polyanionic polymer Polymers 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 201000002212 progressive supranuclear palsy Diseases 0.000 description 2
- 230000000630 rising effect Effects 0.000 description 2
- 238000012216 screening Methods 0.000 description 2
- 239000011550 stock solution Substances 0.000 description 2
- 102000001049 Amyloid Human genes 0.000 description 1
- 108010094108 Amyloid Proteins 0.000 description 1
- 208000037259 Amyloid Plaque Diseases 0.000 description 1
- 102000013455 Amyloid beta-Peptides Human genes 0.000 description 1
- 108010090849 Amyloid beta-Peptides Proteins 0.000 description 1
- 101710137189 Amyloid-beta A4 protein Proteins 0.000 description 1
- 101710151993 Amyloid-beta precursor protein Proteins 0.000 description 1
- 102100022704 Amyloid-beta precursor protein Human genes 0.000 description 1
- 206010061818 Disease progression Diseases 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 1
- 102100040243 Microtubule-associated protein tau Human genes 0.000 description 1
- 101710115937 Microtubule-associated protein tau Proteins 0.000 description 1
- 239000002033 PVDF binder Substances 0.000 description 1
- 235000004279 alanine Nutrition 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 150000001945 cysteines Chemical class 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000003748 differential diagnosis Methods 0.000 description 1
- 230000005750 disease progression Effects 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000835 fiber Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000000099 in vitro assay Methods 0.000 description 1
- 239000000411 inducer Substances 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000005541 medical transmission Effects 0.000 description 1
- 108020004999 messenger RNA Proteins 0.000 description 1
- 102000021160 microtubule binding proteins Human genes 0.000 description 1
- 108091011150 microtubule binding proteins Proteins 0.000 description 1
- 230000001537 neural effect Effects 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- -1 polyanions Chemical class 0.000 description 1
- 229920002981 polyvinylidene fluoride Polymers 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 239000012460 protein solution Substances 0.000 description 1
- 239000010453 quartz Substances 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicon dioxide Inorganic materials O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
- C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
- C07K14/4711—Alzheimer's disease; Amyloid plaque core protein
-
- 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
- G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
- G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
- G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Chemical & Material Sciences (AREA)
- Immunology (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Urology & Nephrology (AREA)
- General Health & Medical Sciences (AREA)
- Biochemistry (AREA)
- Medicinal Chemistry (AREA)
- Biotechnology (AREA)
- General Physics & Mathematics (AREA)
- Cell Biology (AREA)
- Food Science & Technology (AREA)
- Microbiology (AREA)
- Physics & Mathematics (AREA)
- Analytical Chemistry (AREA)
- Pathology (AREA)
- Neurology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Toxicology (AREA)
- Organic Chemistry (AREA)
- Neurosurgery (AREA)
- Tropical Medicine & Parasitology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Gastroenterology & Hepatology (AREA)
- Investigating Or Analysing Biological Materials (AREA)
- Peptides Or Proteins (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
Description
(a)PHFの形成を促進する条件下で所定の期間タウタンパク質調製物とポリアニオン性補助因子を含む混合物をインキュベートする工程;及び
(b)顕微鏡的手段又は分光学的手段によって、形成されたPHFを検出する工程
を含むインビトロの方法を提供する。
(a)試験化合物の非存在下及び存在下で上記の方法を実施する工程;並びに
(b)前記試験化合物の非存在下でのPHFの形成の動力学を、前記試験化合物の存在下でのPHFの形成の動力学と比較する工程
を含むインビトロの方法を提供する。
−誘導期後の指数的成長を示すシグモイドの動力学;
−核形成をバイパスする効率的なシーディング(すなわち、シードを加えるとき、指数的成長が観察されるはずであり、且つ誘導期が完全にバイパスされる;及び
−濃度依存性
である。
(a)PHFの形成を促進する条件下で所定の期間タウタンパク質とポリアニオン性補助因子をインキュベートする工程;及び
(b)顕微鏡的手段又は分光学的手段によって、形成されたPHFを検出する工程
を含むインビトロの方法を提供する。
全長タウを大腸菌(E.coli)BL21(DE3)において発現させ、His−トラップアフィニティークロマトグラフィーにより精製し、−80℃でPBS pH=7.4(一定分量)中に保存した。チオフラビンT(ThT)原液500μMを、乾燥粉末(Sigma−Aldrich、St Louis、MO、USA)をPBS、pH7.4中で溶解させることによって調製し、滅菌0.22μm孔径PESメンブランフィルタ(Corning、NY、USA)に通して濾過した。22000M−1 cm−1の吸光係数を用いた411nmでの吸光度測定によって濃度を決定した。ヘパリン原液を、乾燥粉末(Mw=17〜19kDa;Sigma−Aldrich、St Louis、MO、USA)をPBS、pH7.4中で溶解させることによって新たに調製し、滅菌0.22μm孔径PVDFメンブランフィルタ(Merck Millipore、Tullagreen、Cork、IRL)に通して濾過した。
全長タウ二重システイン変異体(DCysM Tau)を大腸菌(E.coli)BL21(DE3)において発現させ、His−トラップアフィニティークロマトグラフィーにより精製し、
−80℃でPBS pH=7.4(一定分量)中に保存した。ThT蛍光動力学測定を、440nmの励起波長及び485nmの発光波長で、Biotek Synergy Neo2マルチ−モードマイクロプレートリーダー(Biotek、VT、USA)中の96ウェルプレート(Thermo Scientific、Vantaa、Finland)において37℃で行った。
−誘導期後の指数的成長を示すシグモイドの動力学(図7)
−凝集体は原線維構造を示す(図8)
−核形成をバイパスする効率的なシーディング(シードを加えるとき、シードと単量体の間で100%の適合性がある場合、指数的成長が観察されるはずである;図9)
−濃度依存性(図10)
rTauの凝集した試料を50時間後にプールし、rtauの新たな凝集のためのシードとして使用した(図9)。超音波処理した凝集体をrTauの新しい溶液に加えることによって、rTauの自発的転換において観察される誘導期の完全なバイパス(NDP機構の厳密な基準の1つ)を引き起こした。
15μMのrTauを、50μMのThT、8μMのヘパリン及び0.5mMのTCEPを含有する200μlのPBS溶液中において、単独又は3μM、6μM及び9μMのCBTAU 27.1(タウ結合抗体)の存在下でインキュベートした。プレートをプレートシーラー(R&D Systems、Minneapolis、MN)で密閉し、継続的に振盪しながら(425cpm、3mm)、測定値を900秒毎に記録した(図11を参照のこと)。9μMのCBTAU−27.1の存在下で、rtauの転換が、アッセイの全期間(160時間)完全に阻止されることを観察することができた。6μMのCBTAU−27.1の存在下では、転換の誘導期が70時間に延長され、転換は、160時間のアッセイ期間において完了しなかった。3μMのCBTAU−27.1もまた、rtauの転換を阻害しており、長い誘導期と低い最終的なプラトーによって強調される。
Claims (13)
- タウタンパク質の対らせん状細線維(PHF)のインビトロ形成のための方法であって、PHFの形成を促進する条件下で所定の期間タウタンパク質調製物とポリアニオン性補助因子を含む混合物をインキュベートすることを含む方法。
- PHFの形成を促進する前記条件が、350〜500cpm、好ましくは400〜450cpm、特に425cpmでインキュベーション混合物を振盪することを含む、請求項1に記載の方法。
- 前記タウタンパク質が、全長組換えタウタンパク質であり、好ましくは2つのN末端インサート及び4つの微小管結合ドメインを含有する最長のアイソフォームである、請求項1又は2に記載の方法。
- 前記タウタンパク質調製物が実質的に純粋なタウ調製物である、請求項1、2又は3に記載の方法。
- 前記インキュベーション混合物中のタウタンパク質の濃度が、10〜30μM、好ましくは12〜20μMの範囲である、請求項1〜4のいずれか一項に記載の方法。
- 前記タウタンパク質が還元型である、請求項1〜5のいずれか一項に記載の方法。
- 前記インキュベーションが、6.0と7.4の間のpH、好ましくは6.5と7.0の間のpH、より好ましくは6.7のpHで実施される、請求項1〜6のいずれか一項に記載の方法。
- 前記インキュベーションが、36℃と38℃の間の温度、好ましくは37℃の温度で実施される、請求項1〜7のいずれか一項に記載の方法。
- 前記ポリアニオン性補助因子がヘパリンである、請求項1〜8のいずれか一項に記載の方法。
- タウタンパク質の対らせん状細線維(PHF)の形成を検出するためのインビトロの方法であって、
(a)請求項1〜9のいずれか一項に記載の方法を使用してPHFの形成を誘導する工程;及び
(b)顕微鏡的手段又は分光学的手段によって、形成されたPHFを検出する工程
を含むインビトロの方法。 - 前記分光学的手段が、蛍光分光法、好ましくはチオフラビンT蛍光アッセイを含む、請求項10に記載の方法。
- タウタウタンパク質の対らせん状細線維の形成を阻害又は促進することができる化合物の同定のためのインビトロの方法であって、
(a)試験化合物の非存在下及び存在下で請求項10又は11に記載の方法を実施する工程;並びに
(b)前記試験化合物の非存在下でのPHFの形成の動力学を、前記試験化合物の存在下でのPHFの形成の動力学と比較する工程
を含むインビトロの方法。 - 前記化合物が抗体又はその断片である、請求項12に記載の方法。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP17163426 | 2017-03-28 | ||
EP17163426.4 | 2017-03-28 | ||
PCT/EP2018/057781 WO2018178080A1 (en) | 2017-03-28 | 2018-03-27 | Methods for detection of tau protein aggregation modulating compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
JP2020515846A true JP2020515846A (ja) | 2020-05-28 |
Family
ID=58464226
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2019553335A Ceased JP2020515846A (ja) | 2017-03-28 | 2018-03-27 | タウタンパク質凝集を調節する化合物の検出のための方法 |
Country Status (10)
Country | Link |
---|---|
US (1) | US11249093B2 (ja) |
EP (1) | EP3602046A1 (ja) |
JP (1) | JP2020515846A (ja) |
KR (1) | KR20190127860A (ja) |
CN (1) | CN110446925A (ja) |
AU (1) | AU2018241860A1 (ja) |
CA (1) | CA3055866A1 (ja) |
EA (1) | EA201992280A1 (ja) |
SG (2) | SG11201908085XA (ja) |
WO (1) | WO2018178080A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MA47499A (fr) | 2017-02-17 | 2019-12-25 | Denali Therapeutics Inc | Anticorps anti-tau et leurs procédés d'utilisation |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001506617A (ja) * | 1996-12-13 | 2001-05-22 | マックス プランク−ゲセルシャフト ツール フォールデルング デール ヴィッセンシャフテン エー.ヴェー. | ペアードヘリカルフィラメントの阻害剤を試験するための新規な方法およびアルツハイマー病治療のための使用 |
JP2003508788A (ja) * | 1999-09-09 | 2003-03-04 | マックス−プランク−ゲゼルシャフト ツール フォルデルング デル ヴィッセンシャフテン エー.ファウ. | ペアードヘリカルフィラメントの核形成のための最小タウペプチド |
Family Cites Families (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB9610829D0 (en) * | 1996-05-23 | 1996-07-31 | Medical Res Council | Screening of agents for treatment of azlheimers disease |
US7172875B2 (en) * | 2003-02-18 | 2007-02-06 | The Ohio State University Research Foundation | Identifying inhibitors of intracellular protein fibrillization |
US20070218491A1 (en) * | 2006-02-08 | 2007-09-20 | Oligomerix, Inc. | Oligomerization of amyloid proteins |
US9464122B2 (en) * | 2008-08-20 | 2016-10-11 | Oligomerix, Inc. | Methods and compositions comprising tau oligomers |
NZ609984A (en) * | 2010-10-11 | 2015-05-29 | Biogen Idec Internat Neuroscience Gmbh | Human anti-tau antibodies |
US20130337463A1 (en) * | 2010-11-05 | 2013-12-19 | The Trustees Of The University Of Pennsylvania | Cell-Based Models of Neurodegenerative Disease |
US8865754B2 (en) * | 2011-03-03 | 2014-10-21 | Proteotech Inc. | Compounds for the treatment of neurodegenerative diseases |
EP3792278A3 (en) * | 2012-12-21 | 2021-05-26 | Biogen MA Inc. | Human anti-tau antibodies |
WO2016123401A1 (en) * | 2015-01-28 | 2016-08-04 | University Of Delaware | Detection of disease-associated tau protein conformations and applications thereof |
US20190029977A1 (en) * | 2017-04-24 | 2019-01-31 | Mercaptor Discoveries, Inc. | Use of Thiol Compounds to Treat Neurological Disease |
US11629175B2 (en) * | 2018-04-27 | 2023-04-18 | Ecole Polytechnique Federale De Lausanne (Epfl) | Method for preparing PHFS-like Tau aggregates |
-
2018
- 2018-03-27 CA CA3055866A patent/CA3055866A1/en active Pending
- 2018-03-27 EA EA201992280A patent/EA201992280A1/ru unknown
- 2018-03-27 EP EP18712254.4A patent/EP3602046A1/en not_active Withdrawn
- 2018-03-27 US US16/495,352 patent/US11249093B2/en active Active
- 2018-03-27 KR KR1020197030546A patent/KR20190127860A/ko not_active Application Discontinuation
- 2018-03-27 SG SG11201908085X patent/SG11201908085XA/en unknown
- 2018-03-27 JP JP2019553335A patent/JP2020515846A/ja not_active Ceased
- 2018-03-27 SG SG10202110737WA patent/SG10202110737WA/en unknown
- 2018-03-27 AU AU2018241860A patent/AU2018241860A1/en not_active Abandoned
- 2018-03-27 CN CN201880018726.4A patent/CN110446925A/zh active Pending
- 2018-03-27 WO PCT/EP2018/057781 patent/WO2018178080A1/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001506617A (ja) * | 1996-12-13 | 2001-05-22 | マックス プランク−ゲセルシャフト ツール フォールデルング デール ヴィッセンシャフテン エー.ヴェー. | ペアードヘリカルフィラメントの阻害剤を試験するための新規な方法およびアルツハイマー病治療のための使用 |
JP2003508788A (ja) * | 1999-09-09 | 2003-03-04 | マックス−プランク−ゲゼルシャフト ツール フォルデルング デル ヴィッセンシャフテン エー.ファウ. | ペアードヘリカルフィラメントの核形成のための最小タウペプチド |
Non-Patent Citations (2)
Title |
---|
S. BARGHORN: "Toward a Unified Scheme for the Aggregation of Tau into Alzheimer Paired Helical Filaments", BIOCHEMISTRY, vol. 41, no. 50, JPN6022007874, 20 November 2002 (2002-11-20), pages 14885 - 14896, XP055389351, ISSN: 0004716286, DOI: 10.1021/bi026469j * |
TIAN-MING YAO: "Aggregation analysis of the microtubule binding domain in tau protein by spectroscopic methods", J BIOCHEM, vol. 134, no. 1, JPN6022007873, July 2003 (2003-07-01), pages 91 - 99, XP002996491, ISSN: 0004876871, DOI: 10.1093/jb/mvg116 * |
Also Published As
Publication number | Publication date |
---|---|
US11249093B2 (en) | 2022-02-15 |
US20200025777A1 (en) | 2020-01-23 |
KR20190127860A (ko) | 2019-11-13 |
CA3055866A1 (en) | 2018-10-04 |
SG10202110737WA (en) | 2021-11-29 |
EP3602046A1 (en) | 2020-02-05 |
CN110446925A (zh) | 2019-11-12 |
AU2018241860A1 (en) | 2019-09-19 |
WO2018178080A1 (en) | 2018-10-04 |
SG11201908085XA (en) | 2019-10-30 |
EA201992280A1 (ru) | 2020-02-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Mair et al. | FLEXITau: quantifying post-translational modifications of tau protein in vitro and in human disease | |
Mok et al. | Mapping interactions with the chaperone network reveals factors that protect against tau aggregation | |
de Oliveira et al. | The mechanism of sirtuin 2–mediated exacerbation of alpha-synuclein toxicity in models of Parkinson disease | |
Thompson et al. | IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome | |
Meraz‐Ríos et al. | Tau oligomers and aggregation in Alzheimer’s disease | |
O’Malley et al. | Aβ dimers differ from monomers in structural propensity, aggregation paths and population of synaptotoxic assemblies | |
Butterfield et al. | Redox proteomics identification of oxidatively modified brain proteins in Alzheimer's disease and mild cognitive impairment: insights into the progression of this dementing disorder | |
Grinberg et al. | Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation | |
Thomas et al. | Dual modification of Alzheimer’s disease PHF-tau protein by lysine methylation and ubiquitylation: a mass spectrometry approach | |
Huang et al. | Alternate aggregation pathways of the Alzheimer β-amyloid peptide: an in vitro model of preamyloid | |
Shih et al. | TDP-43 interacts with amyloid-β, inhibits fibrillization, and worsens pathology in a model of Alzheimer’s disease | |
Sultana et al. | Redox proteomics identification of oxidatively modified proteins in Alzheimer's disease brain and in vivo and in vitro models of AD centered around Aβ (1–42) | |
Inoue et al. | Simultaneous determination of post-translational racemization and isomerization of N-terminal amyloid-β in Alzheimer’s brain tissues by covalent chiral derivatized ultraperformance liquid chromatography tandem mass spectrometry | |
Orosz et al. | TPPP/p25: from unfolded protein to misfolding disease: prediction and experiments | |
Iannuzzi et al. | Glycation accelerates fibrillization of the amyloidogenic W7FW14F apomyoglobin | |
Gu et al. | High-throughput endogenous measurement of S-nitrosylation in Alzheimer's disease using oxidized cysteine-selective cPILOT | |
Janssens et al. | Cardiac troponins may be irreversibly modified by glycation: novel potential mechanisms of cardiac performance modulation | |
Moreira et al. | Dynamic interactions and Ca2+-binding modulate the holdase-type chaperone activity of S100B preventing tau aggregation and seeding | |
Lashley et al. | Extensive anti-CoA immunostaining in Alzheimer’s disease and covalent modification of Tau by a key cellular metabolite coenzyme A | |
JP2016510007A (ja) | コンフォメーション病におけるβタンパク質凝集の新規の分子モジュレーターとしての化学シャペロニン | |
Yu et al. | O-GlcNAcylation modulates the self-aggregation ability of the fourth microtubule-binding repeat of tau | |
Shafiq et al. | Implication of post-translationally modified SOD1 in pathological aging | |
JP2020515846A (ja) | タウタンパク質凝集を調節する化合物の検出のための方法 | |
Mukherjee et al. | Quantitative proteomics of tau and Aβ in detergent fractions from Alzheimer's disease brains | |
Maina et al. | Dityrosine cross-links are present in Alzheimer’s disease-derived tau oligomers and paired helical filaments (PHF) which promotes the stability of the PHF-core tau (297–391) in vitro |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20210317 |
|
A977 | Report on retrieval |
Free format text: JAPANESE INTERMEDIATE CODE: A971007 Effective date: 20220218 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20220301 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20220601 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20220801 |
|
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20220920 |
|
A045 | Written measure of dismissal of application [lapsed due to lack of payment] |
Free format text: JAPANESE INTERMEDIATE CODE: A045 Effective date: 20230131 |