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Title: Amyloid precursor protein 96-110 and beta-amyloid 1-42 elicit developmental anomalies in sea urchin embryos and larvae that are alleviated by neurotransmitter analogs for acetylcholine, serotonin and cannabinoids.

Authors: Buznikov, Gennady A; Nikitina, Lyudmila A; Seidler, Frederic J; Slotkin, Theodore A; Bezuglov, Vladimir V; Milosević, Ivan; Lazarević, Lidija; Rogac, Ljubica; Ruzdijić, Sabera; Rakić, Ljubisa M

Published In Neurotoxicol Teratol, (2008 Nov-Dec)

Abstract: Amyloid precursor protein (APP) is overexpressed in the developing brain and portions of its extracellular domain, especially amino acid residues 96-110, play an important role in neurite outgrowth and neural cell differentiation. In the current study, we evaluated the developmental abnormalities caused by administration of exogenous APP(96-110) in sea urchin embryos and larvae, which, like the developing mammalian brain, utilize acetylcholine and other neurotransmitters as morphogens; effects were compared to those of beta-amyloid 1-42 (Abeta42), the neurotoxic APP fragment contained within neurodegenerative plaques in Alzheimer's Disease. Although both peptides elicited dysmorphogenesis, Abeta42 was far more potent; in addition, whereas Abeta42 produced abnormalities at developmental stages ranging from early cleavage divisions to the late pluteus, APP(96-110) effects were restricted to the intermediate, mid-blastula stage. For both agents, anomalies were prevented or reduced by addition of lipid-permeable analogs of acetylcholine, serotonin or cannabinoids; physostigmine, a carbamate-derived cholinesterase inhibitor, was also effective. In contrast, agents that act on NMDA receptors (memantine) or alpha-adrenergic receptors (nicergoline), and that are therapeutic in Alzheimer's Disease, were themselves embryotoxic, as was tacrine, a cholinesterase inhibitor from a different chemical class than physostigmine. Protection was also provided by agents acting downstream from receptor-mediated events: increasing cyclic AMP with caffeine or isobutylmethylxanthine, or administering the antioxidant, a-tocopherol, were all partially effective. Our findings reinforce a role for APP in development and point to specific interactions with neurotransmitter systems that act as morphogens in developing sea urchins as well as in the mammalian brain.

PubMed ID: 18565728 Exiting the NIEHS site

MeSH Terms: Acetylcholine/analogs & derivatives*; Acetylcholine/metabolism; Amyloid beta-Peptides/pharmacology*; Amyloid beta-Protein Precursor/pharmacology*; Animals; Cannabinoids/agonists; Cannabinoids/metabolism*; Cannabinoids/pharmacology; Chlorpyrifos/pharmacology; Dose-Response Relationship, Drug; Drug Interactions; Embryo, Nonmammalian; Embryonic Development/drug effects*; Larva/drug effects; Peptide Fragments/pharmacology*; Sea Urchins/drug effects*; Sea Urchins/growth & development; Serotonin/analogs & derivatives*; Serotonin/metabolism; Serotonin/pharmacology; Time Factors

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