Regulation of neuronal APL-1 expression by cholesterol starvation

PLoS One. 2012;7(2):e32038. doi: 10.1371/journal.pone.0032038. Epub 2012 Feb 21.


Background: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by the deposition of β-amyloid plaques composed primarily of the amyloid-β 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 ε4 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldicarb / pharmacology
  • Animals
  • Caenorhabditis elegans / cytology
  • Caenorhabditis elegans / drug effects
  • Caenorhabditis elegans / metabolism*
  • Caenorhabditis elegans Proteins / genetics
  • Caenorhabditis elegans Proteins / metabolism*
  • Cholesterol / deficiency*
  • Cholesterol / pharmacology
  • Diet
  • Gene Expression Regulation / drug effects
  • Gene Knockdown Techniques
  • Green Fluorescent Proteins / metabolism
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Molting / drug effects
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism*
  • RNA Interference / drug effects
  • Synaptic Transmission / drug effects
  • Transcription, Genetic / drug effects


  • APL-1 protein, C elegans
  • Caenorhabditis elegans Proteins
  • Membrane Proteins
  • Green Fluorescent Proteins
  • Aldicarb
  • Cholesterol