The amyloid hypothesis of Alzheimer's disease (AD) proposes that the primary event in AD pathogenesis correlating with disease progression and cognitive decline is the accumulation of amyloid-a peptide (Aa?) an abnormally expressed fragment of the amyloid precursor protein. Accordingly, approaches to slow AD progression are designed to prevent central nervous system (CNS) accumulation of Aa, either by pharmacological inhibition of its synthesis or by development of Aa vaccines and antibodies that augment clearance of Aa by microglia. Moreover, a secondary event in disease pathology results from release of proinflammatory cytokines, chemokines, and neurotoxic reactive oxygen species (ROS) and reactive nitrogen species (RNS) by microglia in response to activation by Aa. Although several drug discovery approaches show promise in suppressing Aa ??accumulation, drug candidates derived from many of these approaches have side effects that remain problematic. In this SBIR study, we will discover agents which target unexploited pathways to both promote the reduction of Aa in AD brain and suppress the associated neuroinflammation. Specifically, we will: 1) Develop high throughput assays using human microglial cell lines to measure Aa phagocytosis and screen small molecule libraries of known drugs, bioactives and drug-like compounds to discover compounds that promote Aa phagocytosis, 2) Develop assays to measure production of mediators of neuroinflammation and test whether compounds found to augment Aa phagocytosis can suppress production of Aa induced mediators of neuroinflammation in human microglial cell lines and primary human microglia, and 3) Compounds found to augment Aa induced phagocytosis and suppress Aa induced mediators of neuroinflammation in cell culture are tested for their ablility to induce primary human microglia to clear Aa from clinically relevant post-mortem brain tissues obtained from AD patients. After completion of this Phase I project, the necessary AD assays, proof of concept for small molecule intervention, and required expertise for additional studies will be in place for identification and optimization of lead drug candidates in Phase II. Project In the United States, 4.5 million people have Alzheimer's Disease (AD) where direct and indirect costs of care are estimated at $100 billion annually. The disease is currently not curable and is the leading cause of institutionalization. Emotional costs to families are considerable. Our SBIR studies are designed to probe new avenues to arrive at effective drug treatments for AD. Public
