Elan Pharmaceuticals, Inc.

Eli Lilly and Company

Athena Neurosciences, Inc.

Lisa Clair McConlogue

Sukanto Sinha

Jun Zhao

Dale Bernard Schenk

John P Anderson

Hua Tan

Pamela S Keim

Susanna M S Chrysler

Peter A Seubert

Peter Andrew Seubert

Kate Dora Games

Russell E Rydel

The construction of transgenic animal models of human Alzheimer's disease, and methods of using the models to screen potential Alzhe## 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 &#x3b2;-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&#x3b2; 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, &#x3b2;-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.

Testing compounds for effects on synaptophysin in transgenic mice expressing an Alzheimer's disease FAD DNA sequence

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

Compositions comprising a novel protease capable of cleaving &#x3b2;-amyloid precursor protein (APP) on the amino-terminal side of the &#x3b2;-amyloid peptide therein are provided. The protease is designated &#x3b2;-secretase. Reaction systems comprising &#x3b2;-secretase may be used in screening assays to monitor &#x3b2;-secretase modulated cleavage of APP and to identify &#x3b2;-secretase inhibitors, wherein the &#x3b2;-secretase is in the presence of a suitable polypeptide substrate and cleavage of the substrate determined in the presence and absence of the test substance. Antibodies are raised against peptides of &#x3b2;-secretase. Pharmaceutical compositions and methods comprise compounds identified by screening assays.

Methods and compositions for inhibiting &#x3b2;-secretase

Compositions comprising a novel protease capable of cleaving &bgr;-amyloid precursor protein (APP) on the amino-terminal side of the &bgr;-amyloid peptide therein are provided. The protease is designated &bgr;-secretase. Reaction systems comprising &bgr;-secretase may be used in screening assays to monitor &bgr;-secretase modulated cleavage of APP and to identify &bgr;-secretase inhibitors, wherein the &bgr;-secretase is in the presence of a suitable polypeptide substrate and cleavage of the substrate determined in the presence and absence of the test substance. Antibodies are raised against peptides of &bgr;-secretase. Pharmaceutical compositions and methods comprise compounds identified by screening assays.

&bgr;-secretase antibody

Transgenic animals harboring APP allele having swedish mutation

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

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San Francisco, CA, United States of America

Lisa Clair McConlogue