CA2279555A1 - Amyloid beta protein (globular assembly and uses thereof) - Google Patents
Amyloid beta protein (globular assembly and uses thereof) Download PDFInfo
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- CA2279555A1 CA2279555A1 CA002279555A CA2279555A CA2279555A1 CA 2279555 A1 CA2279555 A1 CA 2279555A1 CA 002279555 A CA002279555 A CA 002279555A CA 2279555 A CA2279555 A CA 2279555A CA 2279555 A1 CA2279555 A1 CA 2279555A1
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- 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
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
The invention provides amyloid beta-derived dementing ligands (ADDLs) that comprise amyloid .beta. protein assembled into globular non-fibrillar oligomeric structures capable of activating specific cellular processes. The invention also provides methods for assying the formation, presence, receptor protein binding and cellular activity of ADDLs, as well as compounds that block the formation or activity of ADDLs, and methods of identifying such compounds. The invention further provides methods of using ADDLs, and modulating ADDL formation and/or activity, inter alia in the treatment of learning and/or memory disorders.
Claims (51)
1. An isolated soluble, globular, non-fibrillar amyloid 8 oligomeric structure comprising at least from 3 to 12 amyloid .beta. proteins and which exhibits neurotoxicity.
2. An isolated oligomeric structure according to claim 1 wherein said oligomeric structure comprises an oligomeric form selected from the group consisting of trimer, tetramer, pentamer, and hexamer.
3. 4n isolated oligomeric structure according to claim 1 or 2 wherein said oligomeric structure has a molecular weight of from about 26 kD to about 28 kD
as determined by non-denaturing gel electrophoresis.
as determined by non-denaturing gel electrophoresis.
4. An isolated oligomeric structure according to any of claims 1 to 3 wherein said oligomeric structure has a molecular weight of from about 22 kD
to about 24 kD or from about 18 kD to about 19 kD as determined by electrophoresis on a 15% SDS-polyacrylamide gel.
to about 24 kD or from about 18 kD to about 19 kD as determined by electrophoresis on a 15% SDS-polyacrylamide gel.
5. An isolated oligomeric structure according to any of claims 1 to 4 wherein said oligomeric structure comprises globules of dimensions of from about 4.7 nm to about 6.2 nm as measured by atomic force microscopy.
6. An isolated oligomeric structure according to any of claims 1 to 5 wherein said oligomeric structure comprises globules of dimensions of from about 4.9 nm to about 5,4 nm as measured by atomic force microscopy.
7. An isolated oligomeric structure according to any of claims 1 to 5 wherein said oligomeric structure comprises globules of dimensions of from about 5.7 nm to about 6.2 nm as measured by atomic force microscopy.
8. An isolated oligomeric structure according to any of claims 1 to 5 wherein from about 40% to about 75% of said oligomeric structure comprises globules of dimensions of from about 4.9 am to about 5.4 nm, and dimensions of from about 5.7 nm to about 6.2 nm, as measured by atomic force microscopy.
9. A method for assaying the effects of a oligomeric structure according to any of claims 1 to 8 comprising:
(a) administering said oligomeric structure to the hippocampus of an animal;
(b) applying an electrical stimulus; and (c) measuring the cell body spike amplitude over time to determine the longterm potentiation response, with the proviso that administration of said oligomeric structure is not done for therapy.
(a) administering said oligomeric structure to the hippocampus of an animal;
(b) applying an electrical stimulus; and (c) measuring the cell body spike amplitude over time to determine the longterm potentiation response, with the proviso that administration of said oligomeric structure is not done for therapy.
10. The method of claim 9, wherein the long-term potentiation response of said animal is compared to the long-term potentiation response of another another treated in the same fashion except having saline administered instead of oligomeric structure prior to application of the electrical stimulus.
11. A method for protecting an animal against decreases in learning or memory due to the elects of a oligomeric structure according to any of claims 1 to 8, said method comprising administering a compound that blocks the formation of said oligomeric structure.
12. A method for protecting an animal against decreases in learning or memory due to the effects of a oligomeric structure according to any of claims 1 to 8, said method comprising administering a compound that blocks the activity of said oligomeric structure that lead to decreases in learning or memory.
13. A method for reversing in an animal decreases in learning or memory due to the effects of a oligomeric structure according to any of claims 1 to 8, said method comprising administering a compound that blocks the formation of said oligomeric structure.
14. A method for reversing in an animal decreases in learning or memory due to the effects of a oligomeric structure according to any of claims 1 to 8, said method comprising administering a compound that blocks the activity of said oligomeric structure that lead to decreases is learning or memory.
15. The method of any of claims 11 to 14 applied in the treatment of a disease, disorder, or condition selected from the group consisting of Alzheimer's disease, adult Down's syndrome, sad smile dementia.
16. A method for protecting a nerve cell against decreases in long-term potentiation due to the effects of a oligomeric structure according to any of claims 1 to 8, said method comprising contacting said cell with a compound that blocks the formation of said oligomeric structure.
17. A method for protecting a nerve cell against decreases in long-term potentiation due to the effects of a oligomeric structure according to any of claims 1 to 8, said method comprising contacting said cell with a compound that blocks the activity of said oligorneric structure that lead to decreases in long-term potentiation.
18. A method for reversing in a nerve cell decreases in long-term potentiation due to the effects of a oligomeric structure according to any of claims 1 to 8, said method comprising cantacting said cell with a compound that blocks the formation of said oligomezic structure.
19. A method for reversing in a nerve cell decreases in long-term potentiation due to the effects of a oligomeric structure according to any of claims 1 to 8, said method comprising contacting said cell with a compound that blocks the activity of said oligomeric structure that lead to decreases is long-term potentiation.
20. A method for detecting in a test material the oligomeric structure of any of claims 1 to 8 comprising:
(a) contacting said test material with 6E10 antibody; and (b) detecting binding to said oligomeric structure of said antibody.
(a) contacting said test material with 6E10 antibody; and (b) detecting binding to said oligomeric structure of said antibody.
21. A method for detecting in a test material the oligotneric structure of any of claims 1 to 8 comprising:
(a) contacting said test material with serum-starved neuroblastoma cells; and (b) measuring morphological changes in said cells by comparing the morphology of said cells against neuroblastoma cells that have not bees contacted with said test material.
(a) contacting said test material with serum-starved neuroblastoma cells; and (b) measuring morphological changes in said cells by comparing the morphology of said cells against neuroblastoma cells that have not bees contacted with said test material.
22. A method for detecting in a test material the oligomeric structure of any of claims 1 to 8 comprising:
(a) contacting said test material with brain slice cultures; and (b) measuring brain cell death as compared against brain slice cultures that have net been contacted with said test material.
(a) contacting said test material with brain slice cultures; and (b) measuring brain cell death as compared against brain slice cultures that have net been contacted with said test material.
23. A method for detecting in a test material the oligomeric structure of any of claims 1 to 8 comprising:
(a) contacting said test material with neuroblastoma cells; and (b) measuring increases in Fyn kinase activity by comparing Fyn kinase activity in said cells against Fyn kinase activity in neuroblastoma cells that have not been contacted with said test material.
(a) contacting said test material with neuroblastoma cells; and (b) measuring increases in Fyn kinase activity by comparing Fyn kinase activity in said cells against Fyn kinase activity in neuroblastoma cells that have not been contacted with said test material.
24. A method for detecting in a test material the oligomeric structure of any of claims 1 to 8 comprising:
(a) contacting said test material with cultures of primary astrocytes; and (b) determining activation of said astrocytes as compared to cultures of primary astrocytes that have not been contacted with said test material.
(a) contacting said test material with cultures of primary astrocytes; and (b) determining activation of said astrocytes as compared to cultures of primary astrocytes that have not been contacted with said test material.
25. A method far detecting in a test material the oligomeric structure of any of claims 1 to 8 comprising:
(a) contacting said test material with cultures of primary astrocytes; and (b) measuring in said astrocytes increases in the mRNA for proteins selected from the group consisting of interleukin-1, inducible nitric oxide synthase, Apo E, Apo J, and .alpha.1-antichymotrypsin by comparing said mRNA levels in said astrocytes against the corresponding mRNA levels in cultures of primary astrocytes that have not been contacted with said test material.
(a) contacting said test material with cultures of primary astrocytes; and (b) measuring in said astrocytes increases in the mRNA for proteins selected from the group consisting of interleukin-1, inducible nitric oxide synthase, Apo E, Apo J, and .alpha.1-antichymotrypsin by comparing said mRNA levels in said astrocytes against the corresponding mRNA levels in cultures of primary astrocytes that have not been contacted with said test material.
26. A method for identifying compounds that modulate the effects of a oligomeric structure according to any of claims 1 to 8 comprising:
(a) administering either saline or a test compound to the hippocampus of an animal;
(b) applying an electrical stimulus;
(c) measuring the cell body spike amplitude over time to determine the long-team potentiation response; and (d) comparing the long-term potentiation response of animals having saline administered to the long-term potentiation response of animals having test compound administered with the proviso that administration of said oligomeric structure is not done for therapy.
(a) administering either saline or a test compound to the hippocampus of an animal;
(b) applying an electrical stimulus;
(c) measuring the cell body spike amplitude over time to determine the long-team potentiation response; and (d) comparing the long-term potentiation response of animals having saline administered to the long-term potentiation response of animals having test compound administered with the proviso that administration of said oligomeric structure is not done for therapy.
27. The method of claim 26 which further comprises administering oligomeric structure to said hippocampus either before, along with, or after administering sand saline or test compound.
28. A method for identifying compounds that block the neurotoxicity of the oligotneric structure of any of claims 1 to 8 comprising:
(a) contacting separate cultures of neuronal cells with said oligomeric structure either in the presence or absence of contacting with said test compound;
(b) measuring the proportion of viable cells in each culture: and (c) comparing the proportion of viable cells in each culture, with compounds that block the neurotoxicity of said oligomeric structure being identified as resulting in an increased proportion of viable cells in said culture as compared to the corresponding culture contacted with said oligotneric structure in the absence of said test compound.
(a) contacting separate cultures of neuronal cells with said oligomeric structure either in the presence or absence of contacting with said test compound;
(b) measuring the proportion of viable cells in each culture: and (c) comparing the proportion of viable cells in each culture, with compounds that block the neurotoxicity of said oligomeric structure being identified as resulting in an increased proportion of viable cells in said culture as compared to the corresponding culture contacted with said oligotneric structure in the absence of said test compound.
29. A method for identifying compounds that block binding to a cell surface protein of the oligomaic structure of any of claims 1 to 8 comprising:
(a) contacting separate cultures of neuronal cells with said oligomeric structure either is the presence or absence of contacting with said test compound;
(b) adding a reagent that binds to said oligomeric structure, said reagent being fluorescent;
(c) analyzing said separate cell cultures by fluorescence-activated cell sorting; and (d) comparing the fluorescence of the cultures, with compounds that block binding to a cell surface protein of the oligomeric structure being identified as resulting in a reduced fluorescence of said culture as compared to the corresponding culture contacted with said oligomeric structure in the absence of said test compound.
(a) contacting separate cultures of neuronal cells with said oligomeric structure either is the presence or absence of contacting with said test compound;
(b) adding a reagent that binds to said oligomeric structure, said reagent being fluorescent;
(c) analyzing said separate cell cultures by fluorescence-activated cell sorting; and (d) comparing the fluorescence of the cultures, with compounds that block binding to a cell surface protein of the oligomeric structure being identified as resulting in a reduced fluorescence of said culture as compared to the corresponding culture contacted with said oligomeric structure in the absence of said test compound.
30. A method for identifying compounds that block binding to a cell surface protein of the oligomeric structure of any of claims 1 to 8 comprising:
(a) forming said oligomeric structure from amyloid .beta. protein such that it becomes a labeled oligomeric structure comprising a binding moiety capable of binding a fluorescent reagent;
(b) contacting separate cultures of neuronal cells with said labeled oligomeric structure either in the presence or absence of contacting with said test compound;
(c) adding a fluorescent reagent that binds to said oligomeric structure;
(d) analyzing said separate cell cultures by fluorescence-activated cell sorting: and (e) comparing the fluorescence of the cultures, with compounds that block binding to a cell surface protein of the oligomeric structure being identified as resulting in a reduced fluorescence of said culture as compared to the corresponding culture contacted with said oligomeric structure in the absence of said feet compound.
(a) forming said oligomeric structure from amyloid .beta. protein such that it becomes a labeled oligomeric structure comprising a binding moiety capable of binding a fluorescent reagent;
(b) contacting separate cultures of neuronal cells with said labeled oligomeric structure either in the presence or absence of contacting with said test compound;
(c) adding a fluorescent reagent that binds to said oligomeric structure;
(d) analyzing said separate cell cultures by fluorescence-activated cell sorting: and (e) comparing the fluorescence of the cultures, with compounds that block binding to a cell surface protein of the oligomeric structure being identified as resulting in a reduced fluorescence of said culture as compared to the corresponding culture contacted with said oligomeric structure in the absence of said feet compound.
31. A method for identifying compounds that block formation or binding to a cell surface protein of the oligotmeric structure of any of claims 1 to 8 comprising:
(a) preparing separate samples of amyloid .beta. protein that either have or have not been mixed with said test compound;
(b) forming said oligomeric structure in said separate samples;
(c) contacting separate cultures of neuronal cells with said separate samples;
(d) adding a reagent that binds to said oligomeric structure, said reagent being fluorescent;
(e) analyang said separate cell cultures by fluorescence-activated cell sorting; and (f) comparing the fluorescence of the cultures, with compounds that block formation or binding to a cell surface protein of the oligomeric structure being identified as resulting in a reduced fluorescence of said culture as compared to the corresponding culture contacted with said oligorneric structure in the absence of said test compound.
(a) preparing separate samples of amyloid .beta. protein that either have or have not been mixed with said test compound;
(b) forming said oligomeric structure in said separate samples;
(c) contacting separate cultures of neuronal cells with said separate samples;
(d) adding a reagent that binds to said oligomeric structure, said reagent being fluorescent;
(e) analyang said separate cell cultures by fluorescence-activated cell sorting; and (f) comparing the fluorescence of the cultures, with compounds that block formation or binding to a cell surface protein of the oligomeric structure being identified as resulting in a reduced fluorescence of said culture as compared to the corresponding culture contacted with said oligorneric structure in the absence of said test compound.
32. A method for identifying compounds that block formation or binding to a cell surface protein of the oligomeric structure of any of claims 1 to 8 comprising:
(a) preparing separate samples of amyloid .beta. protein that either have or have not been mixed with said test compound;
(b) forming said oligomeric structure in said separate samples such that it becomes a labeled oligomeric structure comprising a binding molety capable of binding a fluorescent reagent in each of said separate samples;
(c) contacting separate cultures of neuronal cells with said separate samples;
(d) adding a fluorescent reagent that binds to said oligomeric structure;
(e) analyzing said soparate cell cultures by fluorescence-activated cell sorting; and (f) comparing the fluorescence of the cultures, with compounds that block formation or binding to a cell surface protein of the oligomeric structure being identified as resulting in a reduced fluorescence of said culture as compared to the corresponding culture contacted with said oligomeric structure in the absence of said test compound.
(a) preparing separate samples of amyloid .beta. protein that either have or have not been mixed with said test compound;
(b) forming said oligomeric structure in said separate samples such that it becomes a labeled oligomeric structure comprising a binding molety capable of binding a fluorescent reagent in each of said separate samples;
(c) contacting separate cultures of neuronal cells with said separate samples;
(d) adding a fluorescent reagent that binds to said oligomeric structure;
(e) analyzing said soparate cell cultures by fluorescence-activated cell sorting; and (f) comparing the fluorescence of the cultures, with compounds that block formation or binding to a cell surface protein of the oligomeric structure being identified as resulting in a reduced fluorescence of said culture as compared to the corresponding culture contacted with said oligomeric structure in the absence of said test compound.
33. The method of claim 31 or 32, wherein the fluorescence of said cultures further is compared with the fluorescence of cultures that have been treated in the same fashion except that instead of adding or not adding test compound prior to formation of the oligomeric structure, said test compound either is or is not added after formation of the oligomeric structure, with compounds that block formation of the oligameric structure being identified es resulting in a reduced fluorescence of said culture as compared to the corresponding culture contacted witls said oligomeric structure in the absence of said test compound, only when said compound is added prior to oligomeric structure, and compounds that block binding to a cell surface protein of the oligomeric structure being identified as resulting in a reduced fluorescence of said culture as compared to the corresponding culture contacted with said oligoroeric structure in the absence of said test compound, when said compound is added either prior to or after oligotneric structure.
34. A method of detecting binding to a cell surface protein of the oligomeric structure of any of claims 1 to 8 comprising:
(a) forming said oligomeric structure from amyloid .beta. protein;
(b) contacting a culture of neuronal cells with said oligomeric structure;
(c) adding as antibody that binds said oligomeric structure, said antibody including a conjugating moiety;
(d) washing away unbound antibody;
(f) linking an enzyme to said antibody bound to said oligomeric structure by means of said conjugating moiety;
(g) adding a colorless substrate that is cleaved by paid enzyme to yield a color change; and (h) determining said color change as a measure of binding to a cell surface protein of said oligomeric structure.
(a) forming said oligomeric structure from amyloid .beta. protein;
(b) contacting a culture of neuronal cells with said oligomeric structure;
(c) adding as antibody that binds said oligomeric structure, said antibody including a conjugating moiety;
(d) washing away unbound antibody;
(f) linking an enzyme to said antibody bound to said oligomeric structure by means of said conjugating moiety;
(g) adding a colorless substrate that is cleaved by paid enzyme to yield a color change; and (h) determining said color change as a measure of binding to a cell surface protein of said oligomeric structure.
35. A method for identifying compounds that block binding to a cell surface protein of the oligomeric structure of any of claims 1 to 8 comprising:
(a) preparing separate samples of amyloid .beta. protein that either have or have not been mixed with said test compound;
(b) forming said oligomecic structure in said separate samples;
(c) contacting separate cultures of neuronal cells with said separate samples;
(d) adding an antibody that binds said oligomeric structure, said antibody including a conjugating moiety;
(e) washing away unbound antibody;
(f) linking an enzyme to said antibody bound to said oligomeric structure by means of said conjugating moiety;
(g) adding a coloriess substrate that is cleaved by said enzyme to yield a color change; and (h) comparing the color change produced by each of said separate samples, with compounds that block formation or binding to a cell surface protein of the oligomeric structure being identified as resulting in a reduced color change produced by said culture as compared to the corresponding culture contacted with said oligomeric structure in the absence of said test compound.
(a) preparing separate samples of amyloid .beta. protein that either have or have not been mixed with said test compound;
(b) forming said oligomecic structure in said separate samples;
(c) contacting separate cultures of neuronal cells with said separate samples;
(d) adding an antibody that binds said oligomeric structure, said antibody including a conjugating moiety;
(e) washing away unbound antibody;
(f) linking an enzyme to said antibody bound to said oligomeric structure by means of said conjugating moiety;
(g) adding a coloriess substrate that is cleaved by said enzyme to yield a color change; and (h) comparing the color change produced by each of said separate samples, with compounds that block formation or binding to a cell surface protein of the oligomeric structure being identified as resulting in a reduced color change produced by said culture as compared to the corresponding culture contacted with said oligomeric structure in the absence of said test compound.
36. The method of claim 35, wherein the color change produced by said cultures further is compared with the color change produced by cultures that have been treated in the same fashion except that instead of adding or not adding test compound prior to formation of the oligomeric structure, said test compound either is or is not added after formation of the oligameric structure, with compounds that block formation of the oligomeric structure being identified as resulting in a reduced color change produced by said culture as compared to the corresponding culture contacted with said oligomeric structure in the absence of said test compound, only when said compound is added prior to oligomeric structure, and compounds that block receptor binding of the oligomeric structure being identified as resulting in a reduced color change produced by said culture as compared to the corresponding culture contacted with said oligomeric structure in the absence of said test compound, when said compound is added either prior to or after oligomeric structure.
37. A method for identifying compounds that block formation of the oligomcric structure of any of claims 1 to 8 comprising:
(a) preparing separate samples of amyloid .beta. protein that either have or have not been mixed with said test compound;
(b) forming said oligomeric structure in said separate samples;
(c) assessing whether any protein assemblies have formed in the separate samples using a method selected from the group consisting of electrophoresis, immunorerognition, and atomic force microscopy, and (d) comparing the formation of said protein assemblies in said separate samples, which compounds that block formation of said oligomeric structure being identified as resulting in decreased formation of said oligomeric structure in said sample as compared with a sample in which said oligomeric structure is formed in the absence of said test compound.
(a) preparing separate samples of amyloid .beta. protein that either have or have not been mixed with said test compound;
(b) forming said oligomeric structure in said separate samples;
(c) assessing whether any protein assemblies have formed in the separate samples using a method selected from the group consisting of electrophoresis, immunorerognition, and atomic force microscopy, and (d) comparing the formation of said protein assemblies in said separate samples, which compounds that block formation of said oligomeric structure being identified as resulting in decreased formation of said oligomeric structure in said sample as compared with a sample in which said oligomeric structure is formed in the absence of said test compound.
38. A method of preparing an isolated soluble, globular, non-fibrillar amyloid .beta. oligomeric structure according to any of claims 1 to 8, wherein said method comprises:
(a) obtaining a solution of monomeric amyloid .beta. protein, said amyloid .beta.
protein being capable of forming said oligomeric structure;
(b) diluting said protein solution into an appropriate media to a final concentration of from about 5 nM to about 500 µM;
(c) incubating the media resulting from step (b) at about 4°C for from about 2 hours to about 48 hours;
(c) centrifuging said solution at about 14,000 g at about 4°C; and (d) recovering the supernatant resulting from said centrifugation as containing said amyloid .beta. oligomeric structure.
(a) obtaining a solution of monomeric amyloid .beta. protein, said amyloid .beta.
protein being capable of forming said oligomeric structure;
(b) diluting said protein solution into an appropriate media to a final concentration of from about 5 nM to about 500 µM;
(c) incubating the media resulting from step (b) at about 4°C for from about 2 hours to about 48 hours;
(c) centrifuging said solution at about 14,000 g at about 4°C; and (d) recovering the supernatant resulting from said centrifugation as containing said amyloid .beta. oligomeric structure.
39. The method of claim 38, wherein said method comprises incubating the media resulting from step (b) at about 4°C in the presence of clusterin.
40. An isolated soluble, globular, non-fibrillar amyloid .beta. oligomeric structure prepared according to claim 38 or 39.
41. The use of an isolated soluble, globular, non-fibrillar amyloid .beta.
oligomeric structure according to any of claims 1 to 8 to alter the long-term potentiation response of a nerve cell, comprising contacting said cell with said oligomeric structure.
oligomeric structure according to any of claims 1 to 8 to alter the long-term potentiation response of a nerve cell, comprising contacting said cell with said oligomeric structure.
42. The use of an isolated soluble, globular, non-fibrillar amyloid .beta.
oligomeric struture according to any of claims 1 to 8 to alter the learning or memory of as animal, comprising administering said oligomeric structure to said animal.
oligomeric struture according to any of claims 1 to 8 to alter the learning or memory of as animal, comprising administering said oligomeric structure to said animal.
43. The use of an isolated soluble, globular, non-fibrillar amyloid .beta.
oligomeric structure according to any of claims 1 to 8 to cause morphological change of a nerve cell, comprising contacting said cell with said oligomeric structure.
oligomeric structure according to any of claims 1 to 8 to cause morphological change of a nerve cell, comprising contacting said cell with said oligomeric structure.
44. The use according to claim 43, wherein said morphological change includes an effect selected from the group consisting of call killing, altering Fyn kinase activity, altering Fyn kinase subcellular localization, and altering mRNA
levels for proteins including interleukin-1, inducible nitric oxide synthase, Apo E, Apo J, and .alpha.1-antichymotrypsin.
levels for proteins including interleukin-1, inducible nitric oxide synthase, Apo E, Apo J, and .alpha.1-antichymotrypsin.
45. The use of an isolated soluble, globular, non-fibrillar amyloid .beta.
oligomerie structure according to any of claims 1 to 8 to cause astrocyte activation, comprising contacting said astrocyte with said oligomeric structure.
oligomerie structure according to any of claims 1 to 8 to cause astrocyte activation, comprising contacting said astrocyte with said oligomeric structure.
46. The use of an isolated soluble, globular, non-fibrillar amyloid .beta.
oligomeric structure according to any of claims 1 to 8 to identify test compounds that block the neurotoxicity of said oligomeric structure, comprising contacting a nerve cell with said oligomeric structure and said test compound.
oligomeric structure according to any of claims 1 to 8 to identify test compounds that block the neurotoxicity of said oligomeric structure, comprising contacting a nerve cell with said oligomeric structure and said test compound.
47. The use of an isolated soluble, globular, non-fibrillar amylcid .beta.
oligomeric structure according to say of claims 1 to 8 to identify test compounds that block the binding to a cell surface protein of said oligomeric stucture, comprising contacting a nerve cell with said oligomeric structure and said test compound.
oligomeric structure according to say of claims 1 to 8 to identify test compounds that block the binding to a cell surface protein of said oligomeric stucture, comprising contacting a nerve cell with said oligomeric structure and said test compound.
48. The use of an isolated soluble, globular, non-fibrillar amyloid .beta.
oligomeric structure according to any of claims 1 to 8 to identity test compounds that block the formation of said oligomeric structtue, comprising contacting amyloid .beta.
protein with said test compound during incubation to form said oligomeric structure.
oligomeric structure according to any of claims 1 to 8 to identity test compounds that block the formation of said oligomeric structtue, comprising contacting amyloid .beta.
protein with said test compound during incubation to form said oligomeric structure.
49. A method for protecting a nerve cell against ADDL-induced aberrant neuronal signaling due to the effects of a oligotnttic structure according to any of claims 1 to 8, said method comprising contacting said cell with a compound that blocks the activity of said oligomeric structure that lead to ADDL-induced aberrant neuronal signaling.
50. A method for detecting in a test material the oligomeric structure of any of claims 1 to 8 comprising:
(a) contacting said test material with a nerve cell; and (b) determining whether said cell exhibits ADDL-induced aberrant neuronal signaling.
(a) contacting said test material with a nerve cell; and (b) determining whether said cell exhibits ADDL-induced aberrant neuronal signaling.
51. The use of an isolated soluble, globular, non fibrillar amyloid .beta.
oligomeric structure according to any of claims 1 to 8 to cause ADDL-induced aberrant neuronal signaling of a nerve cell, comprising contacting said call with said oligomeric structure.
oligomeric structure according to any of claims 1 to 8 to cause ADDL-induced aberrant neuronal signaling of a nerve cell, comprising contacting said call with said oligomeric structure.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/796,089 | 1997-02-05 | ||
| US08/796,089 US6218506B1 (en) | 1997-02-05 | 1997-02-05 | Amyloid β protein (globular assembly and uses thereof) |
| PCT/US1998/002426 WO1998033815A1 (en) | 1997-02-05 | 1998-02-05 | Amyloid beta protein (globular assembly and uses thereof) |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2279555A1 true CA2279555A1 (en) | 1998-08-06 |
| CA2279555C CA2279555C (en) | 2012-05-01 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA2279555A Expired - Lifetime CA2279555C (en) | 1997-02-05 | 1998-02-05 | Amyloid beta protein (globular assembly and uses thereof) |
Country Status (12)
| Country | Link |
|---|---|
| US (2) | US6218506B1 (en) |
| EP (2) | EP1808444A1 (en) |
| JP (2) | JP3512815B2 (en) |
| AT (1) | ATE349467T1 (en) |
| AU (1) | AU735825B2 (en) |
| BR (1) | BR9807185A (en) |
| CA (1) | CA2279555C (en) |
| DE (1) | DE69836740T2 (en) |
| DK (1) | DK0998495T3 (en) |
| ES (1) | ES2280090T3 (en) |
| PT (1) | PT998495E (en) |
| WO (1) | WO1998033815A1 (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
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| DK1298436T3 (en) | 1992-10-26 | 2010-10-25 | Elan Pharm Inc | Process for Identifying Inhibitor Compounds for the Release of Beta-Amyloid Peptide (BAP) |
| US6218506B1 (en) | 1997-02-05 | 2001-04-17 | Northwestern University | Amyloid β protein (globular assembly and uses thereof) |
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- 1997-02-05 US US08/796,089 patent/US6218506B1/en not_active Expired - Lifetime
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- 1998-02-05 DK DK98905006T patent/DK0998495T3/en active
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- 1998-02-05 EP EP06026771A patent/EP1808444A1/en not_active Withdrawn
- 1998-02-05 PT PT98905006T patent/PT998495E/en unknown
- 1998-02-05 BR BR9807185-8A patent/BR9807185A/en not_active Application Discontinuation
- 1998-02-05 ES ES98905006T patent/ES2280090T3/en not_active Expired - Lifetime
- 1998-02-05 EP EP98905006A patent/EP0998495B1/en not_active Expired - Lifetime
- 1998-02-05 AT AT98905006T patent/ATE349467T1/en not_active IP Right Cessation
- 1998-02-05 JP JP53326298A patent/JP3512815B2/en not_active Expired - Lifetime
- 1998-02-05 WO PCT/US1998/002426 patent/WO1998033815A1/en active IP Right Grant
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| EP0998495B1 (en) | 2006-12-27 |
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| EP1808444A1 (en) | 2007-07-18 |
| JP2004091492A (en) | 2004-03-25 |
| US7638283B2 (en) | 2009-12-29 |
| WO1998033815A1 (en) | 1998-08-06 |
| ATE349467T1 (en) | 2007-01-15 |
| PT998495E (en) | 2007-03-30 |
| US6218506B1 (en) | 2001-04-17 |
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