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
Department of Pharmacology & Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710-3813, United States.
Neurotoxicol Teratol. 2008 Nov-Dec;30(6):503-9. doi: 10.1016/j.ntt.2008.05.003. Epub 2008 May 16.
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.
淀粉样前体蛋白（APP）在发育中的大脑中过度表达，其细胞外结构域的某些部分，尤其是氨基酸残基96 - 110，在神经突生长和神经细胞分化中起重要作用。在本研究中，我们评估了在海胆胚胎和幼虫中施用外源性APP（96 - 110）所导致的发育异常，海胆胚胎和幼虫与发育中的哺乳动物大脑一样，利用乙酰胆碱和其他神经递质作为形态发生素；将这些影响与β-淀粉样蛋白1 - 42（Aβ42）的影响进行了比较，Aβ42是阿尔茨海默病神经退行性斑块中含有的神经毒性APP片段。尽管两种肽都引发了畸形发生，但Aβ42的作用要强得多；此外，Aβ42在从早期卵裂到晚期长腕幼虫的发育阶段都会产生异常，而APP（96 - 110）的影响仅限于中期囊胚阶段。对于这两种物质，添加乙酰胆碱、血清素或大麻素的脂质可渗透类似物可预防或减少异常；毒扁豆碱，一种氨基甲酸酯衍生的胆碱酯酶抑制剂，也有效。相比之下，作用于NMDA受体（美金刚）或α-肾上腺素能受体（尼麦角林）且在阿尔茨海默病治疗中有疗效的药物本身具有胚胎毒性，与毒扁豆碱化学类别不同的胆碱酯酶抑制剂他克林也是如此。受体介导事件下游起作用的药物也提供了保护作用：用咖啡因或异丁基甲基黄嘌呤增加环磷酸腺苷，或施用抗氧化剂α-生育酚，都有部分效果。我们的研究结果强化了APP在发育中的作用，并指出了其与神经递质系统的特定相互作用，这些神经递质系统在发育中的海胆以及哺乳动物大脑中充当形态发生素。
