Abstract
BackgroundOur 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.ResultsWe 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.ConclusionWe 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).
Highlights
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)
We found that JAY2-22-33 at a concentration 100 μM did not delay Ab-induced paralysis in worms fed with bacteria containing either acr-16 (p = 0.23, Figure 6D) or unc-38 RNA interference (RNAi) bacteria (p = 0.82, Figure 6E), indicating that both nicotinic acetylcholine receptors (nAChRs) were required for the protective effect of JAY2-22-33
We evaluated the effect of JAY2-22-33 and JWB1-84-1 in a C. elegans model of Ab toxicity
Summary
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). 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 investigate the neuroprotective capabilities of these lead compounds both in vitro and in vivo. The neuroprotective effects of nicotine are thought to be mediated via effects at a7 nicotinic acetylcholine receptor (nAChR) [6]. This receptor is involved in learning and memory and has been implicated in the pathophysiology of AD. This leads to a reasonable rationale for designing drugs with activity at nAChRs especially the a7 subtype
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