Abstract: Provided are methods and compositions for identifying candidate agents for treatment of obesity, liver disease, and/or diabetes. Such methods include, e.g., contacting a mammalian cell or cell population with a test agent, and measuring an expression level and/or activity level of ClpP in the mammalian cell or in cells of the cell population. Also provided are methods and compositions for treating an individual (e.g., one who is obese and/or has diabetes). Treatment methods include administering an inhibitor of ClpP to the individual (e.g., to prevent or reduce weight gain, to increase insulin sensitivity, and/or to increase glucose tolerance).

Abstract: Provided are methods and compositions for identifying candidate agents for treatment of obesity, liver disease, and/or diabetes. Such methods include, e.g., contacting a mammalian cell or cell population with a test agent, and measuring an expression level and/or activity level of ClpP in the mammalian cell or in cells of the cell population. Also provided are methods and compositions for treating an individual (e.g., one who is obese and/or has diabetes). Treatment methods include administering an inhibitor of ClpP to the individual (e.g., to prevent or reduce weight gain, to increase insulin sensitivity, and/or to increase glucose tolerance).

Abstract: Provided are methods and compositions for identifying candidate agents for treatment of obesity, liver disease, and/or diabetes. Such methods include, e.g., contacting a mammalian cell or cell population with a test agent, and measuring an expression level and/or activity level of ClpP in the mammalian cell or in cells of the cell population. Also provided are methods and compositions for treating an individual (e.g., one who is obese and/or has diabetes). Treatment methods include administering an inhibitor of ClpP to the individual (e.g., to prevent or reduce weight gain, to increase insulin sensitivity, and/or to increase glucose tolerance).

Abstract: The present invention provides methods for treating apoE-related disorders. The methods generally involve administering an effective amount of an agent that inhibits activity of an enzyme that cleaves apoE.

Abstract: The present invention provides compounds that inhibit apoE4 domain interaction; and compositions, including pharmaceutical compositions, comprising the compounds. The present invention provides methods of treating apoE4-related disorders. The methods generally involve administering to an individual in need thereof a therapeutically effective amount of an apoE4 domain interaction inhibitor.

Abstract: The present invention provides methods inhibiting formation of neurofibrillary tangles; and methods for treating disorders relating to apolipoprotein E (apoE) in a subject. The methods generally involve reducing the level of a carboxyl-terminal truncated form of apoE in a neuronal cell of a subject. The invention further provides isolated cells comprising a nucleic acid molecule encoding a carboxyl-terminal truncated form of apoE; and methods of screening compounds using the cells. The invention further provides compounds that inhibit an apoE cleavage enzyme, and that reduce the formation of neurofibrillary tangles in a neuronal cell. The invention further provides transgenic non-human animals that include as a transgene a nucleic acid that encodes a carboxyl-terminal truncated form of apoE; as well as methods of screening compounds using transgenic animals.

Abstract: The present invention provides a selected population of neural cells, including neural stem cells, neural progenitor cells, neural precursor cells, and progeny thereof, which neural cells are selected for an apoE4? phenotype. In some embodiments, the neural cells are further selected for an apoE3+ phenotype. The selected population of neural cells is useful in treating various disorders, such as neurodegenerative disorders and demyelination diseases. The present invention further provides methods of treating neurodegenerative disorders and demyelinating diseases, generally involving administering a subject selected cell population.

Abstract: The present invention provides isolated cells comprising a nucleic acid encoding a toxic form of apoE. The present invention further provides screening methods for identifying compounds that reduce apoE-induced impairment of mitochondrial integrity and/or function. The present invention further provides kits for use in carrying out a subject screening method. The present invention provides agents that reduce apoE-induced impairment of mitochondrial integrity and/or function; and use of such agents in the treatment of apoE-related disorders.

Abstract: The present invention provides methods inhibiting formation of neurofibrillary tangles; and methods for treating disorders relating to apolipoprotein E (apoE) in a subject. The methods generally involve reducing the level of a carboxyl-terminal truncated form of apoE in a neuronal cell of a subject. The invention further provides isolated cells comprising a nucleic acid molecule encoding a carboxyl-terminal truncated form of apoE; and methods of screening compounds using the cells. The invention further provides compounds that inhibit an apoE cleavage enzyme, and that reduce the formation of neurofibrillary tangles in a neuronal cell. The invention further provides transgenic non-human animals that include as a transgene a nucleic acid that encodes a carboxyl-terminal truncated form of apoE; as well as methods of screening compounds using transgenic animals.

Abstract: The present invention provides methods inhibiting formation of neurofibrillary tangles; and methods for treating disorders relating to apolipoprotein E (apoE) in a subject. The methods generally involve reducing the level of a carboxyl-terminal truncated form of apoE in a neuronal cell of a subject. The invention further provides isolated cells comprising a nucleic acid molecule encoding a carboxyl-terminal truncated form of apoE; and methods of screening compounds using the cells. The invention further provides compounds that inhibit an apoE cleavage enzyme, and that reduce the formation of neurofibrillary tangles in a neuronal cell. The invention further provides transgenic non-human animals that include as a transgene a nucleic acid that encodes a carboxyl-terminal truncated form of apoE; as well as methods of screening compounds using transgenic animals.

Abstract: The present invention provides methods inhibiting formation of neurofibrillary tangles; and methods for treating disorders relating to apolipoprotein E (apoE) in a subject. The methods generally involve reducing the level of a carboxyl-terminal truncated form of apoE in a neuronal cell of a subject. The invention further provides isolated cells comprising a nucleic acid molecule encoding a carboxyl-terminal truncated form of apoE; and methods of screening compounds using the cells. The invention further provides compounds that inhibit an apoE cleavage enzyme, and that reduce the formation of neurofibrillary tangles in a neuronal cell. The invention further provides transgenic non-human animals that include as a transgene a nucleic acid that encodes a carboxyl-terminal truncated form of apoE; as well as methods of screening compounds using transgenic animals.

Abstract: Methods of treating a host suffering from hyperlipidemia resulting from elevated levels of at least one of VLDL and triglycerides are provided. In the subject methods, an effective amount of agent that reduces the level of active apoE, e.g. apoE inhibitor or apoE expression inhibitor, is administered to the host. The subject methods find particular use in the treatment of hosts suffering from Type IV or Type IIb hyperlipidemia. Also provided are non-human transgenic animal models for hyperlipidemia, as well as methods for making and using the subject animal models, e.g. in therapeutic agent screening applications.

Abstract: Compounds, compositions and therapeutic methods are disclosed for the treatment of the central nervous system. The compounds are derived from the disclosed assay system which tests compounds for their ability to effect neuronal remodeling and neurite outgrowth. The assay uses cell cultures which have been genetically engineered to effect the expression of apoE3 and/or apoE4. A test compound is brought into contact with engineered neuronal cells in the presence of a lipid such as &bgr;-VLDL to determine the affects of the compound, if any, on the neuronal remodeling and neurite outgrowth. Compounds found to promote neurite outgrowth are used therapeutically in the treatment of diseases and/or damage to the central nervous system.

Abstract: 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.