title: Intracellular trafficking and synaptic function of APL-1 in Caenorhabditis elegans.
abstract: BACKGROUND
  Alzheimer's disease (AD) is a neurodegenerative disorder primarily characterized by the deposition of β-amyloid plaques in the brain. Plaques are composed of the amyloid-β peptide derived from cleavage of the amyloid precursor protein (APP). Mutations in APP lead to the development of Familial Alzheimer's Disease (FAD), however, the normal function of this protein has proven elusive. The organism Caenorhabditis elegans is an attractive model as the amyloid precursor-like protein (APL-1) is the single ortholog of APP, and loss of apl-1 leads to a severe molting defect and early larval lethality.
  
  
  RESULTS
  We report here that lethality and molting can be rescued by full length APL-1, C-terminal mutations as well as a C-terminal truncation, suggesting that the extracellular region of the protein is essential for viability. RNAi knock-down of apl-1 followed by drug testing on the acetylcholinesterase inhibitor aldicarb showed that loss of apl-1 leads to aldicarb hypersensitivity, indicating a defect in synaptic function. The aldicarb hypersensitivity can be rescued by full length APL-1 in a dose dependent fashion. At the cellular level, kinesins UNC-104/KIF-1A and UNC-116/kinesin-1 are positive regulators of APL-1 expression in the neurons. Knock-down of the small GTPase rab-5 also leads to a dramatic decrease in the amount of apl-1 expression in neurons, suggesting that trafficking from the plasma membrane to the early endosome is important for apl-1 function. Loss of function of a different small GTPase, UNC-108, on the contrary, leads to the retention of APL-1 in the cell body.
  
  
  CONCLUSIONS
  Our results reveal novel insights into the intracellular trafficking of APL-1 and we report a functional role for APL-1 in synaptic transmission.
authors.affiliation: Huffington Center on Aging and Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
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: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D020816:Amino Acid Motifs; D000818:Animals; D017173:Caenorhabditis elegans / Q000737:chemistry / Q000235:genetics / Q000254:growth & development / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D002462:Cell Membrane / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D011992:Endosomes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D018978:Molting; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D021381:Protein Transport; D013569:Synapses / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D009435:Synaptic Transmission
chemical_list: C084891:APL-1 protein, C elegans; D029742:Caenorhabditis elegans Proteins; D008565:Membrane Proteins; D020559:Monomeric GTP-Binding Proteins