| Summary: | <p>Abstract</p> <p>Background</p> <p>Our previous work indicated that novel analogs of choline have cytoprotective effects <it>in vitro </it>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 <it>in vitro </it>and <it>in vivo</it>.</p> <p>Results</p> <p>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 <it>Caenorhabditis elegans </it>(<it>C. elegans</it>) as an <it>in vivo </it>model organism to identify potential molecular targets of these compounds. In the <it>C. elegans </it>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.</p> <p>Conclusion</p> <p>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).</p>
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