ES2325350T1 - Diagnostico de la enfermedad de alzheimer basado en una fosforilacion de proteina quinasa activada por agentes mitogenos. - Google Patents
Diagnostico de la enfermedad de alzheimer basado en una fosforilacion de proteina quinasa activada por agentes mitogenos. Download PDFInfo
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- ES2325350T1 ES2325350T1 ES08002964T ES08002964T ES2325350T1 ES 2325350 T1 ES2325350 T1 ES 2325350T1 ES 08002964 T ES08002964 T ES 08002964T ES 08002964 T ES08002964 T ES 08002964T ES 2325350 T1 ES2325350 T1 ES 2325350T1
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- 208000024827 Alzheimer disease Diseases 0.000 title claims abstract 8
- 239000003795 chemical substances by application Substances 0.000 title claims 8
- 238000003745 diagnosis Methods 0.000 title claims 5
- 102000001253 Protein Kinase Human genes 0.000 title 1
- 239000003226 mitogen Substances 0.000 title 1
- 108060006633 protein kinase Proteins 0.000 title 1
- 230000026731 phosphorylation Effects 0.000 claims abstract 19
- 238000006366 phosphorylation reaction Methods 0.000 claims abstract 19
- 101150018665 MAPK3 gene Proteins 0.000 claims abstract 16
- 150000001875 compounds Chemical class 0.000 claims abstract 15
- 101800004538 Bradykinin Proteins 0.000 claims abstract 10
- QXZGBUJJYSLZLT-UHFFFAOYSA-N H-Arg-Pro-Pro-Gly-Phe-Ser-Pro-Phe-Arg-OH Natural products NC(N)=NCCCC(N)C(=O)N1CCCC1C(=O)N1C(C(=O)NCC(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CO)C(=O)N2C(CCC2)C(=O)NC(CC=2C=CC=CC=2)C(=O)NC(CCCN=C(N)N)C(O)=O)CCC1 QXZGBUJJYSLZLT-UHFFFAOYSA-N 0.000 claims abstract 10
- 102100035792 Kininogen-1 Human genes 0.000 claims abstract 10
- QXZGBUJJYSLZLT-FDISYFBBSA-N bradykinin Chemical compound NC(=N)NCCC[C@H](N)C(=O)N1CCC[C@H]1C(=O)N1[C@H](C(=O)NCC(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CO)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O)CCC1 QXZGBUJJYSLZLT-FDISYFBBSA-N 0.000 claims abstract 10
- 238000000034 method Methods 0.000 claims abstract 10
- 102000004169 proteins and genes Human genes 0.000 claims abstract 5
- 108090000623 proteins and genes Proteins 0.000 claims abstract 5
- 210000004027 cell Anatomy 0.000 claims 23
- 108091054455 MAP kinase family Proteins 0.000 claims 9
- 102000043136 MAP kinase family Human genes 0.000 claims 9
- 238000000338 in vitro Methods 0.000 claims 8
- 239000003112 inhibitor Substances 0.000 claims 7
- 210000002950 fibroblast Anatomy 0.000 claims 6
- 210000001626 skin fibroblast Anatomy 0.000 claims 5
- 201000010099 disease Diseases 0.000 claims 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims 4
- MMWCIQZXVOZEGG-HOZKJCLWSA-N [(1S,2R,3S,4S,5R,6S)-2,3,5-trihydroxy-4,6-diphosphonooxycyclohexyl] dihydrogen phosphate Chemical compound O[C@H]1[C@@H](O)[C@H](OP(O)(O)=O)[C@@H](OP(O)(O)=O)[C@H](O)[C@H]1OP(O)(O)=O MMWCIQZXVOZEGG-HOZKJCLWSA-N 0.000 claims 3
- 230000000694 effects Effects 0.000 claims 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims 2
- 102000003923 Protein Kinase C Human genes 0.000 claims 2
- 108090000315 Protein Kinase C Proteins 0.000 claims 2
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 claims 2
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 claims 2
- 229910052791 calcium Inorganic materials 0.000 claims 2
- 239000011575 calcium Substances 0.000 claims 2
- 230000003834 intracellular effect Effects 0.000 claims 2
- -1 phospho Chemical class 0.000 claims 2
- 230000002265 prevention Effects 0.000 claims 2
- 108020003175 receptors Proteins 0.000 claims 2
- 102000005962 receptors Human genes 0.000 claims 2
- 238000012216 screening Methods 0.000 claims 2
- 230000004936 stimulating effect Effects 0.000 claims 2
- 230000006269 (delayed) early viral mRNA transcription Effects 0.000 claims 1
- 108010051479 Bombesin Proteins 0.000 claims 1
- 102000013585 Bombesin Human genes 0.000 claims 1
- BTBUEUYNUDRHOZ-UHFFFAOYSA-N Borate Chemical compound [O-]B([O-])[O-] BTBUEUYNUDRHOZ-UHFFFAOYSA-N 0.000 claims 1
- 108091008585 IP3 receptors Proteins 0.000 claims 1
- 102000007640 Inositol 1,4,5-Trisphosphate Receptors Human genes 0.000 claims 1
- 108010032354 Inositol 1,4,5-Trisphosphate Receptors Proteins 0.000 claims 1
- 239000000556 agonist Substances 0.000 claims 1
- DNDCVAGJPBKION-DOPDSADYSA-N bombesin Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(N)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](CC=1NC2=CC=CC=C2C=1)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1NC(=O)CC1)C(C)C)C1=CN=CN1 DNDCVAGJPBKION-DOPDSADYSA-N 0.000 claims 1
- 238000002405 diagnostic procedure Methods 0.000 claims 1
- 230000006806 disease prevention Effects 0.000 claims 1
- 239000002243 precursor Substances 0.000 claims 1
- 230000004952 protein activity Effects 0.000 claims 1
- 230000017854 proteolysis Effects 0.000 claims 1
- 239000000018 receptor agonist Substances 0.000 claims 1
- 229940044601 receptor agonist Drugs 0.000 claims 1
- 108091006082 receptor inhibitors Proteins 0.000 claims 1
- 230000028327 secretion Effects 0.000 claims 1
- 230000000638 stimulation Effects 0.000 claims 1
- 102000013498 tau Proteins Human genes 0.000 claims 1
- 108010026424 tau Proteins Proteins 0.000 claims 1
- 238000001262 western blot Methods 0.000 claims 1
- 239000012190 activator Substances 0.000 abstract 2
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- 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
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/69—Boron compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
- G01N2333/47—Assays involving proteins of known structure or function as defined in the subgroups
- G01N2333/4701—Details
- G01N2333/4709—Amyloid plaque core protein
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- G01N2333/90—Enzymes; Proenzymes
- G01N2333/91—Transferases (2.)
- G01N2333/912—Transferases (2.) transferring phosphorus containing groups, e.g. kinases (2.7)
- G01N2333/91205—Phosphotransferases in general
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- 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
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Abstract
Método de diagnóstico de la enfermedad de Alzheimer que comprende: poner en contacto células in vitro de un individuo con un agente que provoca la liberación de calcio intracelular a través del receptor del inositol 1,4,5-trifosfato (IP3), medir la cantidad de fosforilación de una proteína MAPK en las células del individuo in vitro en uno o más tiempos después de la etapa de contacto, y comparar la cantidad de fosforilación de la proteína MAPK en las células del individuo in vitro en uno o más tiempos con la cantidad de fosforilación en células de un individuo de control sin Alzheimer in vitro en los mismos tiempos después de poner en contacto las células de control con el agente, en el que la fosforilación aumentada de la proteína MAPK en las células del individuo comparada con las células de control, es un diagnóstico para la enfermedad de Alzheimer.
Claims (11)
1. Método de diagnóstico de la enfermedad de
Alzheimer que comprende:
- \quad
- poner en contacto células in vitro de un individuo con un agente que provoca la liberación de calcio intracelular a través del receptor del inositol 1,4,5-trifosfato (IP3),
- \quad
- medir la cantidad de fosforilación de una proteína MAPK en las células del individuo in vitro en uno o más tiempos después de la etapa de contacto, y
- \quad
- comparar la cantidad de fosforilación de la proteína MAPK en las células del individuo in vitro en uno o más tiempos con la cantidad de fosforilación en células de un individuo de control sin Alzheimer in vitro en los mismos tiempos después de poner en contacto las células de control con el agente,
- \quad
- en el que la fosforilación aumentada de la proteína MAPK en las células del individuo comparada con las células de control, es un diagnóstico para la enfermedad de Alzheimer.
2. Método, según la reivindicación 1, en el que
el agente es bradiquinina, un agonista del receptor de la
bradiquinina o bombesina.
3. Método, según la reivindicación 1 ó 2, en el
que la proteína MAPK es Erk1/2.
4. Método, según cualquiera de las
reivindicaciones 1 a 3, en el que las células son fibroblastos de
piel.
5. Método para el cribado de compuestos para la
identificación de un compuesto útil para el tratamiento o
prevención de la enfermedad de Alzheimer, que comprende:
- \quad
- poner en contacto células de prueba de un individuo con AD con un compuesto que se está cribando,
- \quad
- estimular las células de prueba antes, durante o después de la etapa de contacto con un agente que provoca la liberación del calcio intracelular a través del receptor del inositol 1,4,5-trifosfato (IP3),
- \quad
- medir la cantidad de fosforilación de la proteína MAPK en las células de prueba en uno o más tiempos después de la estimulación de las células de prueba,
- \quad
- comparar la cantidad de fosforilación de la proteína MAPK en las células de prueba en uno o más tiempos con la cantidad de fosforilación en el mismo tiempo o tiempos en las células de control de un individuo con AD que no se han puesto en contacto con el compuesto, y
- \quad
- aceptar un compuesto que inhibe o evita la fosforilación aumentada como compuesto principal, y rechazar un compuesto que no inhibe o evita la fosforilación aumentada.
6. Método, según la reivindicación 5, en el que
el agente es bradiquinina o un agonista del receptor de
bradiquinina.
7. Método, según la reivindicación 5 ó 6, en el
que la proteína MAPK es Erk1/2.
8. Equipo de prueba de diagnóstico de la
enfermedad de Alzheimer que comprende un anticuerpo
anti-fosfo-proteína MAPK y
bradiquinina.
9. Método de diagnóstico de la enfermedad de
Alzheimer que comprende:
a) poner en contacto células de fibroblastos de
piel in vitro de un individuo con una concentración de
bradiquinina eficaz, estimuladora de la fosforilación;
b) poner en contacto células de fibroblastos de
piel in vitro de un individuo de control sin Alzheimer con
una concentración de bradiquinina eficaz, estimuladora de la
fosforilación;
c) Medir la cantidad de Erk1/2 fosforilada en
las células del individuo in vitro en uno o más tiempos
seleccionados del grupo que consiste en 2 minutos, 5 minutos, 10
minutos, 20 minutos, y 30 minutos; mediante transferencia Western,
utilizando un anticuerpo específico de fosfo Erk1/2;
d) Medir la cantidad de Erk1/2 fosforilada en
las células in vitro de un individuo de control sin Alzheimer
en el mismo tiempo o tiempos que en (c);
e) Normalizar la cantidad de Erk1/2 fosforilada
en las etapas (c) y (d) a la cantidad de proteína presente en
dichas células;
comparando la cantidad de Erk1/2 fosforilada en
las células del individuo con la cantidad de Erk1/2 fosforilada en
las células de control sin Alzheimer, en el que una cantidad
aumentada de Erk1/2 fosforilada en las células del individuo
comparada con la de las células de control sin Alzheimer es un
diagnóstico para la enfermedad de
Alzheimer.
Alzheimer.
10. Método de cribado para la identificación de
un compuesto útil para el tratamiento o la prevención de la
enfermedad de Alzheimer que comprende:
a) poner en contacto fibroblastos de piel de
prueba de un individuo con enfermedad de Alzheimer con un compuesto
que se va a cribar;
b) poner en contacto fibroblastos de piel de
control de dicho individuo con un agente de control para dicho
compuesto o incubar dichos fibroblastos de piel de control en
ausencia de dicho compuesto o bien de dicho agente de control;
c) estimular los fibroblastos de prueba y de
control antes, durante o después del contacto en las etapas (a) y
(b) con una concentración de bradiquinina eficaz,
estimuladora de fosforilación;
d) medir la cantidad de Erk1/2 fosforilada en
los fibroblastos de prueba y de control en uno o más tiempos
seleccionados del grupo que consiste en 2 minutos, 5 minutos, 10
minutos, 20 minutos, y 30 minutos, mediante transferencia Western,
utilizando un anticuerpo específico de fosfo Erk1/2, en el que la
cantidad de Erk1/2 fosforilada se normaliza a la cantidad de
proteína presente en dichos fibroblastos de prueba y de control;
e) comparar la cantidad de Erk1/2 fosforilada en
los fibroblastos de prueba con la cantidad de Erk1/2 fosforilada en
los fibroblastos de control para determinar si el compuesto inhibe o
evita el aumento en fosforilación de Erk1/2 inducido por
bradiquinina en las células de prueba comparado con las células de
control, en el que un compuesto que inhibe o evita la fosforilación
aumentada se identifica como útil para el tratamiento o prevención
de la enfermedad de Alzheimer.
11. Utilización de un inhibidor de la
fosforilación de MAPK, para la preparación de una composición
farmacéutica para la reducción de la proteolisis de la proteína
precursora de amiloide, la secreción de la proteína \beta
amiloide, y/o la fosforilación de la proteína tau para tratar, de
este modo, la enfermedad de Alzheimer, y el inhibidor de la
fosforilación se selecciona del grupo que comprende: un inhibidor de
la actividad de la proteína quinasa C, un inhibidor de la actividad
de la proteína C-scr tirosina quinasa y un inhibidor
del receptor de IP-3, en la que el inhibidor de la
actividad de la proteína quinasa C es BiSM-1, el
inhibidor de la actividad de la proteína C-scr
tirosina quinasa es PP1 y el inhibidor del receptor de
IP-3 es borato de
2-aminoetoxidifenilo.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US27141601P | 2001-02-27 | 2001-02-27 | |
| US271416P | 2001-02-27 | ||
| US32950501P | 2001-10-17 | 2001-10-17 | |
| US329505P | 2001-10-17 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2325350T1 true ES2325350T1 (es) | 2009-09-02 |
Family
ID=26954877
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES02723236T Expired - Lifetime ES2305234T3 (es) | 2001-02-27 | 2002-02-27 | Diagnostico de la enfermedad de alzheimer basado en la fosforilacion de una proteina quinosa activada por mitogeno. |
| ES08002964T Pending ES2325350T1 (es) | 2001-02-27 | 2002-02-27 | Diagnostico de la enfermedad de alzheimer basado en una fosforilacion de proteina quinasa activada por agentes mitogenos. |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES02723236T Expired - Lifetime ES2305234T3 (es) | 2001-02-27 | 2002-02-27 | Diagnostico de la enfermedad de alzheimer basado en la fosforilacion de una proteina quinosa activada por mitogeno. |
Country Status (10)
| Country | Link |
|---|---|
| US (3) | US7682807B2 (es) |
| EP (1) | EP1385531B1 (es) |
| JP (3) | JP4246495B2 (es) |
| KR (2) | KR100941597B1 (es) |
| CN (1) | CN1549721B (es) |
| AT (1) | ATE394115T1 (es) |
| AU (1) | AU2002254029A1 (es) |
| DE (2) | DE60226429D1 (es) |
| ES (2) | ES2305234T3 (es) |
| WO (1) | WO2002067764A2 (es) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017001716A1 (es) * | 2015-06-30 | 2017-01-05 | Consejo Superior De Investigaciones Científicas | Método para determinar el riesgo de desarrollar la enfermedad de alzheimer |
Families Citing this family (30)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1549721B (zh) * | 2001-02-27 | 2012-03-07 | 布朗歇特洛克菲勒神经科学研究所 | 基于促分裂原活化的蛋白激酶的磷酸化诊断阿尔茨海默氏病 |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017001716A1 (es) * | 2015-06-30 | 2017-01-05 | Consejo Superior De Investigaciones Científicas | Método para determinar el riesgo de desarrollar la enfermedad de alzheimer |
| US11047867B2 (en) | 2015-06-30 | 2021-06-29 | Consejo Superior De Investigaciones Cientificas | Method for determining the risk of developing alzheimer's disease |
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| JP4246495B2 (ja) | 2009-04-02 |
| KR100941597B1 (ko) | 2010-02-11 |
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| EP1385531A4 (en) | 2004-05-12 |
| JP2013078330A (ja) | 2013-05-02 |
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| CN1549721A (zh) | 2004-11-24 |
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| US20100278803A1 (en) | 2010-11-04 |
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