Treatments for neurotoxicity in alzheimer's disease
AssigneesMassachusetts Institute of Technology, Whitehead Institute for Biomedical Research
InventorsVernon M. Ingram, Barbara J. Blanchard, Brent R. Stockwell
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Abstract
The invention involves identification of a mechanism of β-amyloid peptide cytotoxicity, which enables treatment of conditions caused by β-amyloid peptide aggregates by administration of compounds which antagonize the mechanism of cytotoxicity. The invention includes the identification and isolation of compounds which can reduce the neurotoxic effects of such aggregates. Methods for treating conditions resulting from neurotoxic β-amyloid peptide aggregates, such as Alzheimer's disease and pharmaceutical preparations are provided. Also provided are methods for selecting additional compounds which can reduce the neurotoxic effects of β-amyloid aggregates.
Claims48
A method for treating Alzheimer's disease, comprising,
- contacting a neuronal cell with an amount of a composition comprising one or more compounds that decrease membrane depolarization of neuronal cells caused by aggregated β-amyloid (Aβ) protein degradation products, effective to decrease the membrane depolarization.
A method for treating a subject having a condition characterized by neuronal membrane depolarization, comprising
- administering to a subject in need of such treatment a composition selected from the group consisting of tyrosine kinase inhibitors, chloride channel antagonists, dopamine receptor agonists, and alpha2-adrenergic receptor antagonists in an amount effective to reduce membrane depolarization, wherein the subject is free of symptoms otherwise calling for treatment with the composition.
A composition comprising
- one or more compounds that decrease membrane depolarization of neuronal cells caused by aggregated β-amyloid (Aβ) protein degradation products, and
- one or more compounds that decrease calcium influx of neuronal cells caused by aggregated β-amyloid (Aβ) protein degradation products.
A composition comprising
- one or more compounds that decrease membrane depolarization of neuronal cells caused by aggregated β-amyloid (Aβ) protein degradation products, and
- a secretase inhibitor.
A composition comprising
- one or more compounds that decrease calcium influx in neuronal cells caused by aggregated β-amyloid (Aβ) protein degradation products, and
- a secretase inhibitor.
A method for treating Alzheimer's disease, comprising
- administering an Aβ vaccine to a subject in need of such treatment,
- administering to the subject an amount of a neuronal membrane depolarization inhibitor effective to inhibit membrane depolarization.
A method for identifyng le ad compounds for a pharmacologi cal agent usefnl in the treatment of conditions associated with increased neuronal depolarization induced by the presence of β-amyloid peptide (Aβ) aggregates, comprising
- providing a neuronal cell in a medium containing a potentiometric compound, wherein the influx into the neuronal cell of the potentiomethic compound upon depolarization of the neuronal cell is detectable,
- contacting the neuronal cell with Aβ aggregates under conditions which permit influx of a control amount of the potentiometric compound into the neuronal cell,
- contacting the neuronal cell with a candidate pharmacological agent, and
- detecting the potentiometric compound in the neuronal cell as a measure of the relative depolarization of the neuronal cell in the presence of the candidate pharmacological agent, wherein detection of a lesser amount of potentiometric compound in the neuronal cell than is present when the neuronal cell is contacted with Aβ aggregates but not the candidate pharmacological agent indicates that the candidate pharmacological agent is a lead compound for a pharmacological agent which reduces Aβ aggregate induced neuronal cell depolarization.
Dependencies are inferred from the claim text.