Eli Lilly and Company

Athena Neurosciences, Inc.

Elan Pharmaceuticals, Inc.

Other

University of California

The Brigham and Women's Hospital, Inc.

Peter A Seubert

Dale Bernard Schenk

Carmen Vigo-Pelfrey

Robin McDaid Barbour

Lawrence C Fritz

Sukanto Sinha

Dennis J Selkoe

Michael G Schlossmacher

Harry F Dovey

Gary S Lynch

Jun Zhao

Lisa Clair McConlogue

Martin Citron

David D Eveleth, Jr

Dale B Shenk

This invention provides methods useful in aiding in the diagnosis of Alzheimer's disease. The methods involve measuring the amount of amyloid-&#x3b2; peptide (x&#x2212;&#x2267;41) in the cerebrospinal fluid of a patient. High levels of the peptide generally are inconsistent with a diagnosis of Alzheimer's. Low levels of the peptide are consistent with the disease and, with other tests, can provide a positive diagnosis. Other methods involve measuring the amounts of both A&#x3b2;(x&#x2212;&#x2267;41) and tau. Low levels of A&#x3b2;(x&#x2212;&#x2267;41) and high levels of tau are a positive indicator of Alzheimer's disease, while high levels of A&#x3b2;(x&#x2212;&#x2267;41) and low levels of tau are a negative indication of Alzheimer's disease.

Methods for aiding in the diagnosis of Alzheimer's disease by measuring amyloid-&#x3b2; peptide (x-&#x2267;41) and tau

This invention provides methods useful in aiding in the diagnosis of Alzheimer's disease. The methods involve measuring the amount of amyloid-&#x3b2; peptide (x-&#x2267;41) in the cerebrospinal fluid of a patient. High levels of the peptide generally are inconsistent with a diagnosis of Alzheimer's. Low levels of the peptide are consistent with the disease and, with other tests, can provide a positive diagnosis. Other methods involve measuring the amounts of both A&#x3b2;(x-&#x2267;41) and tau. Low levels of A&#x3b2;(x-&#x2267;41) and high levels of tau are a positive indicator of Alzheimer's disease, while high levels of A&#x3b2;(x-&#x2267;41) and low levels of tau are a negative indication of Alzheimer's disease.

Methods for aiding in the diagnosis of alzheimer's disease by measuring amyloid-&#x3b2; peptide (X-&#x3e;41) and tau

Methods for aiding in the diagnosis of alzheimer's disease by measuring amyloid-&#x3b2; peptide (x-&#x2267;41) and tau

A method for identifying inhibitors of the production of &bgr;-amyloid peptides by administration of a compound to a mammalian host is provided.

Method for identifying &bgr;-amyloid peptide production inhibitors

This invention provides methods useful in aiding in the diagnosis of Alzheimer's disease. The methods involve measuring the amount of amyloid-.beta. peptide (x-.gtoreq.41) in the cerebrospinal fluid of a patient. High levels of the peptide generally are inconsistent with a diagnosis of Alzheimer's. Low levels of the peptide are consistent with the disease and, with other tests, can provide a positive diagnosis.

Methods for aiding in the diagnosis of Alzheimer's disease by measuring

Processing of .beta.-amyloid precursor protein (.beta.APP) is monitored by detecting the secretion of a soluble .beta.APP fragment resulting from cleavage of .beta.APP at the amino-terminus of .beta.-amyloid peptide. In vivo monitoring of secretion of the .beta.APP fragment may be monitored for diagnosis and prognosis of Alzheimer's disease and other .beta.-amyloid-related diseases, while in vitro monitoring of such secretion from cultured cells may be monitored to identify inhibitors of .beta.-amyloid production. The .beta.APP fragment may be detected using antibodies and other specific binding substances which recognize a carboxy-terminal residue on the fragment.

Methods and compositions for monitoring cellular processing of

Soluble .beta.-amyloid peptide (.beta.AP) is measured in biological fluids at very low concentrations, typically in the range from 0.1 ng/ml to 10 ng/ml. The measurement of .beta.AP concentrations in animals or conditioned medium from cultured cells can be used for drug screening, where test compounds are administered to the animals or exposed to the cultured cells and the accumulation of .beta.AP in the animal or culture medium observed. It has been found that elevated levels of .beta.AP in body fluids, such as blood and cerebrospinal fluid, is associated with the presence of a .beta.AP-related condition in a patient, such as Alzheimer's Disease. Methods for diagnosing and monitoring .beta.AP-related conditions comprise measuring the levels of .beta.AP in such body fluids from a patient.

Methods and compositions for the detection of soluble .beta.-amyloid

Antibodies and fragments thereof which bind the carboxyl-terminus of an

The present invention provides methods for identifying beta amyloid production inhibitors, wherein cells are cultured under conditions which result in secretion of a soluble fragment of beta amyloid precursor protein. The amino acid sequence of the fragment extends from the amino terminus of beta APP to the amino terminus of the beta amyloid peptide. The cultured cells are exposed to test compounds which cause a change in the secreted amount of the soluble fragment of beta APP which is determined.

Processing of .beta.-amyloid precursor protein (.beta.APP) is monitored by detecting the secretion of a soluble amino-terminal fragment or .beta.APP (ATF-.beta.APP) resulting from cleavage of .beta.APP at the amino-terminus of .beta.-amyloid peptide. Secretion of ATF-.beta.APP in animal models may be monitored to identify inhibitors of .beta.-amyloid production. The ATF-.beta.APP may be detected using antibodies and other specific binding substances which recognize a carboxy terminal residue on the fragment. Animals expressing the Swedish mutation of .beta.APP are described which produce abundant amounts of ATF-.beta.APP.

Methods of screening for .beta.-amyloid peptide production inhibitors

Methods for the detection of soluble .beta.-amyloid peptide

Methods for monitoring cellular processing of .beta.-amyloid precursor

A proteolytic enzyme isolated from human tissue which exhibits a proteolytic activity to hydrolyze Met-Asp peptide bond in an amyloid-like substrate is disclosed. This enzyme has been designated 'amyloidin' because it proteolytically cleaves a Met-Asp bond similar to the one present in the amyloid precursor protein to release a fragment having the mature Asp terminus of the .beta.-amyloid peptide. Antibodies to the amyloidin protease are also provided. Methods to isolate and purify the amyloidin protease are provided, as well as assays to screen for inhibitors of the amyloidin protease. Also disclosed is the gene encoding the protease and methods for expression of the protease by recombinant DNA means.

Amyloidin protease and uses thereof

The invention provides a method for the detection of cellular pathology by means of an immunoassay to determine the presence of stable breakdown products, termed BDP's or BDP1 and BDP2, of the cytoskeleton component spectrin. In one aspect of the invention, the components from a sample of spectrin-containing cells are physically separated, as by exposure to an electric field, in such a way that BDP and spectrin are separated. Antibodies reactive with BDP are then contacted with the separated sample, and their binding to that portion of the sample containing any BDP determined. In another aspect of the invention, an assay, such as an ELISA assay, is performed to detect total spectrin immunoreactivity as an indication of cellular death or degradation.

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South San Francisco, CA, United States of America

Peter A Seubert