Abstract: Successful CNS drug discovery requires a scalable, highly physiological neuronal model. Using directed differentiation of mouse embryonic stem (mES) cells, including mES cells isolated from a mouse model of Alzheimer's disease (AD), a highly homogeneous primary neuronal model amenable to phenotypic assays for production and synaptotoxicity of amyloid ?-peptide was developed. This model furnishes a highly physiological and AD-relevant platform suitable for high throughput small molecule and functional genetic screens, providing specific small molecule compounds identified by such screens.

Abstract: Successful CNS drug discovery requires a scalable, highly physiological neuronal model. Using directed differentiation of mouse embryonic stem (mES) cells, including mES cells isolated from a mouse model of Alzheimer's disease (AD), a highly homogeneous primary neuronal model amenable to phenotypic assays for production and synaptotoxicity of amyloid ?-peptide was developed. This model furnishes a highly physiological and AD-relevant platform suitable for high throughput small molecule and functional genetic screens, providing specific small molecule compounds identified by such screens.

Abstract: The present invention relates to methods of treating Alzheimer's Disease which utilize agents that increase neuronal phosphotidylinositol 4,5-biphosphate (PIP2), and to differentiated stem cell-based assay systems that may be used to identify agents that modulate phosphoinositide levels and thereby treat a variety of diseases. It is based, at least in part, on the discovery that edelfosine, an agent that increases PIP2 levels by inhibiting an enzyme that catalyzes PIP2 breakdown, decreases levels of neurotoxic A&bgr;42 peptide, particularly in cells expressing a mutant presenilin gene associated with Familial Alzheimer's Disease.