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Free keywords:
Aldicarb/pharmacology
Animals
Caenorhabditis elegans/cytology/drug effects/*metabolism
Caenorhabditis elegans Proteins/genetics/*metabolism
Cholesterol/*deficiency/pharmacology
Diet
Gene Expression Regulation/drug effects
Gene Knockdown Techniques
Green Fluorescent Proteins/metabolism
Membrane Proteins/genetics/*metabolism
Molting/drug effects
Neurons/cytology/drug effects/*metabolism
RNA Interference/drug effects
Synaptic Transmission/drug effects
Transcription, Genetic/drug effects
Abstract:
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of beta-amyloid plaques composed primarily of the amyloid-beta 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 epsilon4 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.
