The J. David Gladstone Institutes

University of California

Lennart Mucke

Li Gan

Erik Roberson

Eliezer Masliah

Sarah Mueller-Steiner

Jacob Raber

Tony Wyss-Coray

Edward Rockenstein

Manuel J Buttini

Robert W Mahley

Makoto Hashimoto

Moustapha Cisse

Jorge J Palop

Robert E Pitas

Erik D Roberson

The present invention provides methods for reducing the level of amyloid beta protein in a cell or tissue, the methods generally involving contacting the cell or tissue with an agent that reduces cystatin C levels and/or activity. The present invention provides methods for treating Alzheimer's disease (AD), and methods for treating cerebral angiopathy, in an individual, the methods generally involving administering to an individual having AD a therapeutically effective amount of an agent that reduces cystatin C levels and/or activity. The present invention further provides methods for identifying an agent that reduces cystatin C levels and/or activity.

Methods and compositions for reducing amyloid beta levels

The present invention provides methods of identifying candidate agents for treating excitotoxicity-related disorders. The present invention further provides methods for treating excitotoxicity-related disorders.

Agents that reduce neuronal overexcitation

The present disclosure provides a method of increasing the level and/or function of an Eph receptor B2 in a neuronal cell; and methods of treating an amyloid-beta-induced neurodegenerative disease in an individual. The present disclosure further provides methods of identifying an agent that increases the level and/or function of an Eph receptor B2 in a neuronal cell.

Methods of treating neurodegenerative disease

Agents that reduce the level of a tau gene product in a cell, e.g., in a neuron, include antisense nucleic acids. For example, antisense nucleic acids can be used to down-regulate expression of a tau gene in a cell (e.g., in a neuron). The antisense sequence is complementary to the mRNA of the targeted gene (e.g., tau), and inhibits expression of the targeted gene products. Suitable oligonucleotides can be chemically modified from the native phosphodiester structure, in order to increase their intracellular stability and binding affinity. A number of such modifications have been described in the literature, which modifications alter the chemistry of the backbone, sugars, or heterocyclic bases.

The present invention provides a method of increasing cathepsin B-induced cleavage of amyloid-&#x3b2; (A&#x3b2;) peptide in a cell or tissue, the method generally involving contacting the cell or tissue with an agent that increases the level of cathepsin B in the cell or tissue. The present invention further provides variant cathepsin B polypeptides that are resistant to inhibition by a cysteine protease inhibitor; as well as nucleic acids encoding the variants, and host cells comprising the nucleic acids.

Method of increasing cathepsin B-induced cleavage of amyloid-&#x3b2; peptides

In methods for screening treatments for, and treatment of, neurodegenerative diseases, aggregation in neurons of NACP/&#x3b1;-synuclein is measured and expression of a non-amyloidogenic protein is stimulated in order to reduce the level aggregration. For purposes of screening agents for treatment of neurodegenerative disease, oxidative stress in the neuronal cells is stimulated by introducing a mixture of metal-ions and hydrogen peroxide. Examples of appropriate metals include iron, aluminum, and copper. After introduction of the agent under evaluation for stimulation of expression of non-amyloidogenic protein, the effectiveness is measured by testing for a decrease in the level of aggregation of NACP/&#x3b1;-synuclein. In an exemplary embodiment, the non-amyloidogenic protein is &#x3b2;-synuclein. The aggregation of NACP/&#x3b1;-synuclein is dependent upon the concentration of metal ions in the neuronal cells. In addition, the presence of chelating agents appears to modulate the build-up of NACP/&#x3b1;-synuclein aggregates which are responsible for synaptic and neuronal dysfunction.

Human &#x3b1; synuclein expressing transgenic mice

The present invention provides methods of detecting an amyloid peptide-related neurological disorder in an individual; and methods for staging an amyloid peptide-related neurological disorder in an individual. The methods involve detecting a level of a calcium-responsive gene product, such as calbindin, in a hippocampal neuron, especially a granule cell of the dentate gyrus. The invention further provides identifying an agent that treats an amyloid peptide-related neurological disorder, as well as agents identified by the methods.

Methods of detecting neurological disorders

Methods and compositions for use in treating anxiety are provided. In the subject methods, an effective amount of an agent having ApoE3 activity is administered to a host suffering from an anxiety, e.g. excessive anxiety, unwanted anxiety, an anxiety disorder, etc. Also provided are methods and compositions for modulating adrenal steroidogenesis and/or release, particularly stress induced adrenal steroidogenesis and/or release, and the hippocampal-pituitary-adrenal (HPA) axis. In these methods, an effective amount of an ApoE activity modulating agent, e.g. an ApoE agonist or antagonist, is administered to the host.

Method of screening a compound for anxiolytic activity in an Apolipoprotein e knockout animal

The present invention features non-human transgenic animal models for Alzheimer's disease (AD) and CAA, wherein the transgenic animal is characterized by 1) expression of bioactive transforming growth factor-&bgr;1 (TGF-&bgr;1) or 2) both expression of bioactive TGF-&bgr;1 and expression of a human amyloid &bgr; precursor protein (APP) gene product. The transgenic animals may be either homozygous or heterozygous for these alterations. Bigenic animals are further characterized by development of AD-associated and/or CAA-associated pathology within about two to three months of age, and at about twelve months of age are characterized by a reduced number of neuritic plaques relative to singly transgenic animals. The invention also features methods of screening for biologically active agents that facilitate reduction of &bgr;-amyloid deposits in vivo and methods for facilitating reduction of formation of neuritic plaques in a subject susceptible to AD.

Transgenic mice expressing human APP and TGF-&bgr; demonstrate cerebrovascular amyloid deposits

The present invention features non-human transgenic animal models for Alzheimer's disease (AD) and CAA, wherein the transgenic animal is characterized by 1) overexpression of bioactive transforming growth factor-&bgr;1 (TGF-&bgr;1) or 2) both overexpression of bioactive TGF-&bgr;1 and expression of a human amyloid &bgr; precursor protein (APP) gene product. The transgenic animals may be either homozygous or heterozygous for these alterations. Bigenic animals are further characterized by development of AD-associated and/or CAA-associated pathology within about two to three months of age.

Transgenic mouse model of alzheimer's disease and cerebral amyloid angiopathy

The present invention features non-human transgenic animal models for gene function, wherein the transgenic animal is characterized by having altered endogenous apolipoprotein E gene function and a transgene for an exogenous human apolipoprotein E isoform. The transgenic animals may be either homozygous or heterozygous for the transgene. The invention also features methods for using non-human transgenic animal models for the study of apolipoprotein E-mediated pathologies and the identification of compounds and therapies for such pathologies.

Growing community of inventors

San Francisco, CA, United States of America

Lennart Mucke