BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of -amyloid plaques composed primarily of the amyloid- peptide, a cleavage product of amyloid precursor protein (APP). While mutations in APP lead to the development of Familial Alzheimer's Disease (FAD), sporadic AD has only one clear genetic modifier: the 4 allele of the apolipoprotein E (ApoE) gene. Cholesterol starvation in Caenorhabditis elegans leads to molting and arrest phenotypes similar to loss-of-function mutants of the APP ortholog,
apl-1 (amyloid precursor-like protein 1), and
lrp-1 (lipoprotein receptor-related protein 1), suggesting a potential interaction between
apl-1 and cholesterol metabolism. METHODOLOGY/PRINCIPAL FINDINGS: Previously, we found that RNAi knock-down of
apl-1 leads to aldicarb hypersensitivity, indicating a defect in synaptic function. Here we find the same defect is recapitulated during
lrp-1 knock-down and by cholesterol starvation. A cholesterol-free diet or loss of
lrp-1 directly affects APL-1 levels as both lead to loss of APL-1::GFP fluorescence in neurons. However, loss of cholesterol does not affect global transcription or protein levels as seen by qPCR and Western blot. CONCLUSIONS: Our results show that cholesterol and
lrp-1 are involved in the regulation of synaptic transmission, similar to
apl-1. Both are able to modulate APL-1 protein levels in neurons, however cholesterol changes do not affect global
apl-1 transcription or APL-1 protein indicating the changes are specific to neurons. Thus, regulation of synaptic transmission and molting by LRP-1 and cholesterol may be mediated by their ability to control APL-1 neuronal protein expression.