title: Regulation of neuronal APL-1 expression by cholesterol starvation.
abstract: 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.
  
  
  RESULTS
  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.
authors.affiliation: Huffington Center on Aging and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Wiese
authors.forename: Adam
authors.initials: A
authors.lastname: Antebi
authors.forename: Hui
authors.initials: H
authors.lastname: Zheng
mesh_terms: D000448:Aldicarb / Q000494:pharmacology; D000818:Animals; D017173:Caenorhabditis elegans / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D002784:Cholesterol / Q000172:deficiency* / Q000494:pharmacology; D004032:Diet; D005786:Gene Expression Regulation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D049452:Green Fluorescent Proteins / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D018978:Molting / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D034622:RNA Interference / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: C084891:APL-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins; D049452:Green Fluorescent Proteins; D000448:Aldicarb; D002784:Cholesterol