Alzheimer disease (AD) is the most common type of dementia and the sixth leading death cause in the US. Brain accumulation of the amyloid beta peptide (Ab) is proposed as one of the causative events in AD pathogenesis. The Ab peptide is the result of the proteolytic cleavage of the transmembrane protein amyloid precursor protein (APP). However, the molecular mechanism underlying APP action has been difficult to determine due to the presence of two functionally redundant proteins, which together with APP have an essential function in mammals. C. elegans has a unique APP-related gene,
apl-1, which is essential for viability. The extracellular domain of APL-1 (APL-1-EXT) is necessary and sufficient to rescue the lethality of the
apl-1 null mutant. To determine the cellular function of APL-1-EXT, we examined the
apl-1(
yn5) mutant, which is viable and generates high levels of the extracellular fragment. Among other phenotypes,
apl-1(
yn5) shows developmental delay and a temperature-dependent lethality. A mutation in R155.2/moa-1 (modifier of
apl-1), which encodes a tyrosine phosphatase receptor, suppresses the
apl-1(
yn5) temperature-dependent lethality. By generating transcriptional and translational reporter lines, we determined that
moa-1 is expressed in many cell types, including neurons and pharyngeal, intestinal, and vulval cells, and is co-expressed with
apl-1 in some tissues. Interestingly, high levels of
moa-1 intestinal expression are induced at 27 deg C. Furthermore, this temperature-dependent induction of
moa-1 requires functional
crh-1, the C. elegans orthologue of the CREB transcription factor, which has been shown to be important for thermotaxis and learning. Downregulation of
moa-1 by RNAi produces temperature-dependent lethality and developmental delay; this lethality is enhanced in a
crh-1 null mutant background. MOA-1 and APL-1 do not appear to interact in in vitro pull-down and yeast-two-hybrid assays. Our results suggest that
moa-1 is a novel temperature-dependent regulated gene that may work with
apl-1 to regulate development and viability. Further research now focuses on elucidating how
apl-1 and
moa-1 interact and on determining which downstream pathways are affected.