Alzheimer''s Disease (AD) is an age-dependent, neurodegenerative disease. Aggregation of the b-amyloid peptide is toxic to neurons and may be the main cause of neurodegeneration in AD. The b-amyloid peptide is a cleavage product of the amyloid precursor protein (APP). Although the processing of APP has been elucidated, the physiological function of APP remains unclear. In C. elegans, APL-1 has high sequence similarity to human APP, but does not contain the b-amyloid peptide. Similarly to APP, APL-1 is also cleaved to produce a large extracellular fragment and a small intracellular stub. Null mutations of
apl-1 lead to an L1 lethality, which can be rescued by neuronal expression of only the extracellular fragment of APL-1 (APL-1EXT), suggesting the importance of
apl-1 for development and viability. Duplication of the human APP locus can lead to familial AD. Hence, we examined how APL-1 overexpression can affect later stages. Overexpressing APL-1 resulted in a shortened body length and decreased mean lifespan in a dose-dependent manner. Overexpression of only the extracellular domain of APL-1 was also sufficient to decrease lifespan and body length. Since APL-1 is expressed in neurons and other cell types, we hypothesized that APL-1 overexpression in neurons was responsible for the decreased lifespan. Surprisingly, driving APL-1 expression with a predominantly neuronal promotor (Psnb-1::
apl-1) increased the mean lifespan by 20%. Overexpressing only the extracellular domain of APL-1 under the control of the
snb-1 promotor (Psnb-1::APL-1EXT) was also sufficient to enhance lifespan. To determine whether this lifespan effect is due exclusively to neuronal overexpression, we drove APL-1 expression with the
rab-3 promotor (Prab-3::
apl-1), which only expresses in neurons. Although the Prab-3::
apl-1 construct is sufficient to rescue the
apl-1 L1 lethality, these animals do not have an enhanced lifespan. Hence, the APL-1-dependent lifespan effect must be due to overexpression in a different tissue. To further characterize the tissue-specific lifespan effect of APL-1, we tested whether APL-1 overexpression effects were dependent on
daf-16, a transcription factor regulating lifespan in a tissue-specific manner. The increased lifespan of animals carrying Psnb-1::
apl-1 was abolished in a
daf-16 null background, suggesting the requirement of DAF-16 for lifespan extension. Furthermore, while overexpression of APL-1 decreases body length, the normal length of the animal can be restored in a
daf-16 null mutant background. Hence, DAF-16 is required for two APL-1 overexpression phenotypes, the tissue-specific lifespan effects and the short body length, suggesting a genetic interaction between
daf-16 and
apl-1.