Sea urchin embryonic development provides a model for evaluating therapies against beta-amyloid toxicity.
Accumulation of beta-amyloid protein is an Alzheimer's disease hallmark but also may be mechanistically involved in neurodegeneration. One of its cleavage peptides, Abeta42, has been used to evaluate the mechanisms underlying amyloid-induced cytotoxicity and targeting of acetylcholine systems. We studied Sphaerechinus granularis sea urchin embryos which utilize acetylcholine and other neurotransmitters as morphogens. At a threshold concentration of 0.1 microM Abeta42, there was damage to the larval skeleton, accumulation of ectodermal cells in the blastocoele and underdevelopment of larval arms. Raising the Abeta42 concentration to 0.2-0.4 microM produced anomalies depending on the stage at which Abeta42 was introduced: at the first cleavage divisions, abnormalities appeared within 1-2 cell cycles; at the mid-blastula stage, the peak period of sensitivity to Abeta42, gastrulation was blocked; at later stages, there was progressive damage to the larval skeleton, digestive tract and larval spicules, as well as regression of larval arms. Each of these anomalies could be offset by the addition of lipid-permeable analogs of acetylcholine (arachidonoyl dimethylaminoethanol), serotonin (arachidonoyl serotonin) and cannabinoids (arachidonoyl vanillylamine), with the greatest activity exhibited by the acetylcholine analog. These results indicate that sea urchin embryos provide a model suitable to characterize the mechanisms underlying the cytotoxicity of Abeta42, as well as providing a system that enables the rapid screening of potential therapeutic interventions. The protection provided by neurotransmitter analogs, especially that for acetylcholine, points to unsuspected advantages of existing therapies that enhance cholinergic function, as well as indicating novel approaches that may prove protective in Alzheimer's disease.
D000367:Age Factors; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004341:Drug Evaluation / Q000379:methods*; D004625:Embryo, Nonmammalian; D047108:Embryonic Development / Q000187:drug effects*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D018377:Neurotransmitter Agents / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000633:toxicity*; D012617:Sea Urchins / Q000196:embryology
D016229:Amyloid beta-Peptides; D018377:Neurotransmitter Agents; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)