Deposition of dense plaques and the presence of neurofibrillary tangles are two postmortem criteria used in the definitive diagnosis of Alzheimer's disease. The major component of the dense plaques is a 40-42 amino acid beta-amyloid peptide that is derived from the larger amyloid precursor protein (APP), a single pass transmembrane domain protein. Mice carrying a knockout of APP show several behavioral and cognitive defects, which can be rescued by knockin of full-length APP or only the extracellular domain of APP. However, 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. We are interested in studying the function of APP and are approaching this problem by examining an APP-related gene in a simple model system, the nematode Caenorhabditis elegans. Knockout of apl-1 leads to larval lethality, which can be rescued by germline transformation of an apl-1 genomic fragment or a fragment encoding only the extracellular domain of APL-1. Animals carrying the apl-1(yn5) mutation are viable, produce high levels of only the APL-1 extracellular domain, and show several phenotypes, including a slowed development and shortened lifespan. We are specifically interested in the role of sAPL-1 and how its cleavage is regulated. We have developed tools to follow sAPL-1 after its cleavage at the cell surface, which will allow us to identify the cells to which sAPL-1 binds and the signaling pathway initiated in these cells. Interfering with ?-secretase activity changes overall levels of APL-1 and its cleavage products; the mechanism underlying these changes will be examined. Understanding APL-1 function, and particularly the role of sAPL-1, may provide insights into the function of APP in higher animals, such as man.
Alzheimer's disease affects over 4.5 million Americans; mutations in the Amyloid Precursor Protein (APP) gene have been correlated with familial Alzheimer's disease, but the cellular function of APP is still unknown. We are leveraging the strengths of the Caenorhabditis elegans model system to examine how the APP gene functions.
