title: Neuroprotective effects and mechanism of cognitive-enhancing choline analogs JWB 1-84-1 and JAY 2-22-33 in neuronal culture and Caenorhabditis elegans.
abstract: BACKGROUND
  Our previous work indicated that novel analogs of choline have cytoprotective effects in vitro that might be useful in neurodegenerative conditions such as Alzheimer's disease (AD). Furthermore, two lead compounds (JWB1-84-1 and JAY2-22-33) from a library of more than 50 improved cognitive performances in a transgenic mouse model of AD. The purpose of these experiments was to more specifically investigate the neuroprotective capabilities of these lead compounds both in vitro and in vivo.
  
  
  RESULTS
  We used N2a cells which express a Swedish mutation in the amyloid precursor protein and presenilin 1 genes to investigate the effect of JWB1-84-1 and JAY2-22-33 on β-amyloid (Aβ) levels and found that both compounds significantly reduced Aβ levels. JWB1-84-1 and JAY2-22-33 also protected rat primary cortical neurons from Aβ toxicity. Subsequently, we utilized the nematode Caenorhabditis elegans (C. elegans) as an in vivo model organism to identify potential molecular targets of these compounds. In the C. elegans model of Aβ toxicity, human Aβ is expressed intracellularly in the body wall muscle. The expression and subsequent aggregation of Aβ in the muscle leads to progressive paralysis.
  
  
  CONCLUSIONS
  We found that JAY2-22-33 (but not JWB1-84-1) significantly reduced Aβ toxicity by delaying paralysis and this protective effect required both the insulin signaling pathway and nicotinic acetylcholine receptors (nAChRs).
authors.affiliation: Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, MD, USA. Luoy2@csr.nih.gov.
authors.forename: Roongpetch
authors.initials: R
authors.lastname: Keowkase
authors.forename: Marwa
authors.initials: M
authors.lastname: Aboukhatwa
authors.forename: Bao-Ling
authors.initials: BL
authors.lastname: Adam
authors.forename: J Warren
authors.initials: JW
authors.lastname: Beach
authors.forename: Alvin V
authors.initials: AV
authors.lastname: Terry
authors.forename: Jerry J
authors.initials: JJ
authors.lastname: Buccafussco
authors.forename: Yuan
authors.initials: Y
authors.lastname: Luo