Li, Christine Project Summary Deposition of beta-amyloid (Aβ)-rich dense plaques and the presence of hyperphosphorylated tau neurofibrillary tangles are two postmortem criteria used in the diagnosis of Alzheimer's disease (AD). Although Aβ is derived from a larger amyloid protein precursor (APP), the function of APP and its various cleavage products and the targets/pathways in which they act are still poorly understood. A family of APP-related proteins is present in mammals. Knockout of the APP family in mice leads to postnatal lethality and type II lissencephaly, indicating that the APP family has essential functions during development. sAPPα can modulate BACE activity and levels of tau phosphorylation, suggesting that sAPPα can modulate levels two markers of AD pathology. Like the mammalian APP family, the Caenorhabditis elegans ortholog apl-1 is critical for survival; loss of apl-1 leads to larval lethality, which can be rescued by germline transformation with an apl-1 genomic fragment or constructs encoding only the extracellular domain of APL-1. We will leverage the strengths of C. elegans and mouse to identify the function and cellular pathways in which APP acts and regulates. We have performed biochemical and mutagenesis screens to identify protein interactors and suppressors of the apl- 1 lethality, respectively; our goal is to verify interacting proteins and identify the molecular identity of the suppressor genes. Our second goal is to look at global changes in the whole animal C. elegans transcriptome when APL-1 levels are perturbed in mutant and transgenic strains. The C. elegans findings will be translated into the mouse system to determine whether homologues have similar functions in APP biology. By using data uncovered in the C. elegans system and testing them in the mouse system, we have a unique opportunity to identify pathways in which APL-1/APP act, including pathways involved in the survival and proper functioning of neurons. Our results may provide novel insights into how alterations in these pathways may contribute to the pathologies seen in AD and highlight ways to formulate new therapeutic strategies to effectively treat AD.