Elan Pharmaceuticals, Inc.

Other

Eli Lilly and Company

Pharmacia & Upjohn Company

Athena Neurosciences, Inc.

Lisa Claire McConlogue

Sukanto Sinha

Jay S Tung

Guriqbal Basi

Gwen Tatsuno

Varghese John

John P Anderson

Michael Power

Normand Frigon

Shuwen Wang

Minh Tam Doan

John Logan Anderson

Kate Dora Games

Dale Bernard Schenk

Mark E Gurney

Christopher Michael Semko

John Anderson

Theodore A Yednock

Peter Andrew Seubert

Russell E Rydel

Jun Zhao

Elizabeth Messersmith

Tan Hua

Susanna Chrysler

Human BACE polypeptides having modifications to the N-linked glycosylation sites including one or more of the following amino acid substitutions: S174I, N223A, N153Q and N354S. DNA sequences, vectors, and host cells for producing the polypeptides. Crystalline protein compositions formed from the purified polypeptides. Methods of screening for compounds that inhibit A&#x3b2; using the polypeptides.

Glycosylation variants of BACE

The invention provides transgenic non-human animals and transgenic non-human mammalian cells harboring a transgene encoding an APP polypeptide comprising the Swedish mutation.

Monitoring APP cleavage in transgenic rodents comprising an APP Swedish mutation

Disclosed is an active, isolated &#x3b2;-secretase enzyme in purified and recombinant form. This enzyme is implicated in the production of amyloid plaque components which accumulate in the brains of individuals afflicted with Alzheimer's disease. Recombinant cells that produce this enzyme either alone or in combination with some of its natural substrates (APP and APPsw) are also disclosed. These compositions are useful for use in methods of selecting compounds that modulate &#x3b2;-secretase. Inhibitors of &#x3b2;-secretase are implicated as therapeutics in the treatment of neurodegenerative diseases, such as Alzheimer's disease.

&#x3b2;-secretase enzyme compositions and methods

Disclosed are various forms of an active, isolated &#x3b2;-secretase enzyme in purified and recombinant form. This enzyme is implicated in the production of amyloid plaque components which accumulate in the brains of individuals afflicted with Alzheimer's disease. Recombinant cells that produce this enzyme either alone or in combination with some of its natural substrates (&#x3b2;-APPwt and &#x3b2;-APPsw) are also disclosed, as are antibodies directed to such proteins. These compositions are useful for use in methods of selecting compounds that modulate &#x3b2;-secretase. Inhibitors of &#x3b2;-secretase are implicated as therapeutics in the treatment of neurodegenerative diseases, such as Alzheimer's disease.

Beta-secretase enzyme compositions and methods

The invention provides transgenic animals that are heterozygous or homozygous for a nonfunctional allele of BACE-1. These animals show normal development indicating that BACE-1 is not necessary for development and hence is an appropriate therapeutic target. The transgenic animals are useful in various screening assays including identifying inhibitors of other enzymes involved in processing of APP to A&#x3b2; and determining a toxicity profile of inhibitors of BACE-1.

Transgenic mice knockouts of BACE-1

Disclosed are various forms of an active, isolated &#x3b2;-secretase enzyme in purified and recombinant form. This enzyme is implicated in the production of amyloid plaque components which accumulate in the brains of individuals afflicted with Alzheimer's disease Recombinant cells that produce this enzyme either alone or in combination with some of its natural substrates (&#x3b2;-APPwt and &#x3b2;-APPsw) are also disclosed, as are antibodies directed to such proteins. These compositions are useful for use in methods of selecting compounds that modulate &#x3b2;-secretase. Inhibitors of &#x3b2;-secretase are implicated as therapeutics in the treatment of neurodegenerative diseases, such as Alzheimer's disease.

The construction of transgenic animal models of human Alzheimer's disease, and methods of using the models to screen potential Alzheimer's disease therapeutics, are described. The models are characterized by pathologies similar to pathologies observed in Alzheimer's disease, based on expression of all three forms of the &bgr;-amyloid precursor protein (APP), APP695, APP751, and APP770, as well as various point mutations based on naturally occurring mutations, such as the London and Indiana familial Alzheimer's disease (FAD) mutations at amino acid 717, predicted mutations in the APP gene, and truncated forms of APP that contain the A&bgr; region. Animal cells can be isolated from the transgenic animals or prepared using the same constructs with standard techniques such as lipofection or electroporation. The transgenic animals, or animal cells, are used to screen for compounds altering the pathological course of Alzheimer's disease as measured by their effect on the amount of APP, &bgr;-amyloid peptide, and numerous other Alzheimer's disease markers in the animals, the neuropathology of the animals, as well as by behavioral alterations in the animals.

Method for selecting a transgenic mouse model of alzheimer's disease

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.

Selecting compounds to reduce inflammation associated with Alzheimer's disease

Disclosed are various forms of an active, isolated &bgr;-secretase enzyme in purified and recombinant form. This enzyme is implicated in the production of amyloid plaque components which accumulate in the brains of individuals afflicted with Alzheimer's disease. Recombinant cells that produce this enzyme either alone or in combination with some of its natural substrates (&bgr;-APPwt and &bgr;-APPsw) are also disclosed, as are antibodies directed to such proteins. These compositions are useful for use in methods of selecting compounds that modulate &bgr;-secretase. Inhibitors of &bgr;-secretase are implicated as therapeutics in the treatment of neurodegenerative diseases, such as Alzheimer's disease.

&bgr;-secretase enzyme compositions and methods

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San Francisco, CA, United States of America

Lisa Claire McConlogue