Selecting compounds to reduce inflammation associated with Alzheimer's disease
AssigneeElan Pharmaceuticals, Inc.
InventorsLisa C. McConlogue, Kate D. Games, Theodore A. Yednock, Tan Hua, Elizabeth Messersmith, Frederique Bard
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Abstract
The invention includes identification of specific markers, the elevation of which in central nervous tissue is associated with Alzheimer's Disease. The invention also includes improved assay methods for selecting compounds useful in reducing or preventing onset of the pathology associated with Alzheimer's Disease.
Claims43
A method of selecting a compound effective in reducing inflammation associated with Alzheimer's Disease in a mammalian subject, comprising
- subjecting a non-human mammalian subject to a cerebral ischemic event characterized by elevation in an affected region of a marker selected from the group consisting of IL1β, TNFα, MIP-1α, GFAP, MHC IIα, MHC II Li, CD86, fractalkine and CX3CR1,
- administering to the test subject a test compound,
- selecting the test compound as effective in reducing inflammation associated with Alzheimer's Disease (AD) if an amount of the marker present in the affected region is significantly lower than an amount of marker protein present in an affected region in a control ischemic subject.
A method of selecting a compound effective to reduce inflammation associated with Alzheimer's Disease in the central nervous system, comprising
- lesioning a nerve in a test non-human mammalian subject to produce a denervated cell body region characterized by elevation in an affected region of a marker protein selected from the group consisting of IL1β, TNFα, MIP-1α, GFAP, MHC IIα, MHC II Li, CD86, fractalkine and CX3CR1,
- administering to the test subject a test compound,
- selecting the test compound as effective in reducing inflammation associated with Alzheimer's Disease if an amount of the marker protein present in the denervated region is significantly lower than an amount of marker protein present in a denervated region in a control subject.
A method of selecting a compound effective to reduce inflammation associated with Alzheimer's Disease, comprising administering a test compound to a transgenic mouse whose genome comprises a mutant gene for amyloid precursor protein (APP), the mouse exhibiting AD-like inflammation in its central nervous system upon production of APP least one marker selected from the group consisting of osteopontin, CD86, fractalkine and CX3CR1,
- measuring the amount of mRNA in the test animal central nervous system specific for a marker selected from the group consisting of osteopontin, CD86, fractalkine and CX3CR1,
- selecting the compound as effective to reduce inflammation associated with Alzheimer's Disease if the amount said marker is significantly less than an amount said marker measured in a corresponding central nervous system sample from a control transgenic animal.
A method of selecting a compound effective to reduce inflammation associated with Alzheimer's Disease, comprising administering a test compound to a transgenic mouse whose genome comprises a mutant gene for amyloid precursor protein (APP), the mouse exhibiting amyloid plaque formation in its central nervous system, comprising
- measuring in the test animal central nervous system the amount of marker selected from the group consisting of osteopontin, CD86, fractalkine and CX3CR1,
- selecting the compound as effective to reduce inflammation associated with Alzheimer's Disease if the amount said marker is significantly less than an amount of the marker measured in a corresponding central nervous system sample from a control transgenic animal.
A method of monitoring inflammation associated with Alzheimer's Disease, comprising
- administering Aβ42 or a fragment thereof to a transgenic mouse whose genome comprises a mutant gene for amyloid precursor protein (APP), the mouse exhibiting AD-like inflammation in its central nervous system upon production of APP, wherein said AD-like inflammation includes induction of at least one marker selected from the group consisting of IL1β, TNFα, MIP-1α, GFAP, MHC IIα, MHC II Li, osteopontin, CD86, fractalkine and CX3CR1,
- measuring the amount of mRNA or protein in the transgenic mouse central nervous system specific for at least one marker selected from the group;
- measuring the amount of mRNA or protein specific for the at least one marker in a control transgenic mouse central nervous system;
- wherein a difference in level of the marker indicates the administered Aβ42 or a fragment affects inflammation in the transgenic mouse to which the Aβ42 or a fragment was administered.
Dependencies are inferred from the claim text.