Methods and compositions for treating alzheimer's disease

摘要

Aspects of the invention relate to methods and compositions for treating Alzheimer's disease (AD). In some embodiments, the invention provides methods for screening and identifying compounds that selectively inhibit the targeting of the insulin-Akt signaling pathway by Aβ oligomers.

主权项

1. A method of identifying a candidate compound that reduces β-amyloid (Aβ)-mediated inhibition of Akt (protein kinase B, PKB) activity or activation by PDK1 (phosphoinositide-dependent protein kinase 1) for the treatment of Alzheimer's disease, the method comprising
performing an assay to identify a compound that reduces Aβ-mediated inhibition of Akt activation by PDK1, wherein the assay comprises, producing an assay preparation comprising an Akt polypeptide and a PDK1 polypeptide, wherein the Akt polypeptide is bound to and activated by PDK1 polypeptide in the assay preparation, adding an Aβ polypeptide or longer C99 variant comprising the Aβ42 sequence to the assay preparation, wherein addition of the Aβ polypeptide or longer C99 variant comprising the Aβ42 sequence to the assay causes inhibition of the formation of a detectable complex between the Akt polypeptide and the PDK1 polypeptide relative to the absence of the Aβ polypeptide or the longer C99 variant comprising the Aβ42 sequence, adding the test compound to the assay preparation and determining whether a greater amount of the detectable complex is formed in the presence of the test compound relative to a control assay preparation that includes Aβ polypeptide or longer C99 variant comprising the Aβ42 sequence and that does not include the test compound, and identifying the test compound as a candidate for reducing AP-mediated inhibition of Akt activity if a greater amount of the complex is formed in the presence of the test compound.