University of California

The General Hospital Corporation

Massachusetts General Hospital Corporation

Tanzi, Rudolph E.

Steven L Wagner

Rudolph Emile Tanzi

William C Mobley

Dennis D Cunningham

William E Van Nostrand

Graham Johnson

Soan Cheng

Robert Jason Herr

Nicholas James Mayhew

Ronald Buckle

Kevin D Rynearson

Provided herein are compounds and methods for treating a disorder associated with aberrant A&#x3b2; peptide levels, including Alzheimer's disease.

Potent gamma-secretase modulators

Provided herein are compounds and methods for treating a disorder associated with aberrant A3 peptide levels, including Alzheimer's disease. Provided herein are compositions and methods for treating a disorder associated with aberrant A&#x3b2; peptide levels, including AD. Provided herein are compounds of Formula (A) or a pharmaceutically acceptable salt thereof, wherein, L' is selected from the group consisting of C(O), C(R1)(R2), substituted or unsubstituted &#x2014;C2-6 alkylene-, and substituted or unsubstituted &#x2014;C3-6 cycloalkylene. 

There are provided, inner alia, compounds and methods for lowering total AB peptide production by inhibiting the catalytic activity of gamma-secretase. Since all of the major AB peptide variants, including the pathogenic AB42 as known in the art, are ultimately generated by gamma-secretase-mediated proteolysis of APP-C99 (i.e., the beta-secretase-mediated cleavage product of the amyloid protein precursor IAPPI), one approach to therapeutic intervention (e.g., intervention in Alzheimer's Disease, AD) relates to lowering total AB peptide production by inhibiting the catalytic activity of gamma-secretase.

Gamma-secretase modulators

The invention provides a novel compound having a structure corresponding to Formula (I):(A)-(B)-(C)-(D)&#x2003;&#x2003;(I)or a pharmaceutically acceptable salt or prodrug thereof and methods for using them.

Compounds and uses thereof in modulating levels of various amyloid beta peptide alloforms

Monoclonal antibody and the hybridoma producing the antibody are disclosed. The antibody is produced against an epitope on native secreted forms of .beta.APP. A characteristic of the antibody is that the antibody specifically binds to at least one protein in culture medium in which neuroblastoma cells have been grown. This protein co-migrates in non-reducing polyacrylamide gel electrophoresis with PN-2 isolated from human fibroblast cultures. Other characteristics of the antibody are that the antibody specifically binds to PN-2 and to the secreted form of .beta.APP lacking the Kunitz-type inhibitor domain, the antibody selectively binds to neuritic plaques, and the antibody is sufficiently sensitive to detect secreted forms of .beta.APP in CSF, down to a total concentration of the secreted forms of .beta.APP of 3.75 .mu.g/ml or lower.

Monoclonal antibody produced against native .beta.amyloid precursor

A method of diagnosing a disease with cerebrovascular deposition of amyloid, including Alzheimer's disease, hereditary cerebral hemorrhage with amyloidosis-Dutch type and other amyloidoses, in a mammal is disclosed in which a sample of cerebrospinal fluid is obtained, the level of immunoreactivity toward a monoclonal antibody raised against native PN-2/.beta.APP or other amyloid precursor protein in the sample is measured, and this measured level is compared to the level of immunoreactivity toward this antibody in a sample from

Method of diagnosis of amyloidoses

Immunopurification of Protease Nexin-2 and .beta. amyloid precursor protein is disclosed. Methods of detecting Protease Nexin-2 and the use of these methods in the diagnosis of Alzheimer's disease and other conditions are also disclosed. Additionally, pharmaceutical preparations including Protease Nexin-2 or modified forms thereof are disclosed. Medical uses for the pharmaceutical preparations are also disclosed. These uses include the treatment and prevention of amyloid plaques in Alzheimer's disease and Down's Syndrome

Purification, detection and methods of use of protease Nexin-2

Monoclonal antibodies having a specificity for protease nexin-1 are described. Preferably an antibody has specificity to the reactive protease-binding site. The antibody is used in the affinity purification of PN-1 to produce large quantities of substantially pure PN-1, free of other biologically active molecules. Over a 2000-fold purification of a crude preparation of PN-1 may be obtained. The affinity-purified PN-1 is suitable for use in pharmacological preparations used in the treatment of neurological disease associated with serine protease-mediated inhibition of regenerative processes.

Growing community of inventors

San Diego, CA, United States of America

Steven L Wagner