Moreno Herman, Yu Eunah, Pigino Gustavo, Hernandez Alejandro I, Kim Natalia, Moreira Jorge E, Sugimori Mutsuyuki, Llinás Rodolfo R
Department of Neurology and Physiology/Pharmacology, State University of New York Downstate Medical Center, Brooklyn, NY 11203, USA.
Proc Natl Acad Sci U S A. 2009 Apr 7;106(14):5901-6. doi: 10.1073/pnas.0900944106. Epub 2009 Mar 20.
Early Alzheimer's disease (AD) pathophysiology is characterized by synaptic changes induced by degradation products of amyloid precursor protein (APP). The exact mechanisms of such modulation are unknown. Here, we report that nanomolar concentrations of intraaxonal oligomeric (o)Abeta42, but not oAbeta40 or extracellular oAbeta42, acutely inhibited synaptic transmission at the squid giant synapse. Further characterization of this phenotype demonstrated that presynaptic calcium currents were unaffected. However, electron microscopy experiments revealed diminished docked synaptic vesicles in oAbeta42-microinjected terminals, without affecting clathrin-coated vesicles. The molecular events of this modulation involved casein kinase 2 and the synaptic vesicle rapid endocytosis pathway. These findings open the possibility of a new therapeutic target aimed at ameliorating synaptic dysfunction in AD.
早期阿尔茨海默病(AD)的病理生理学特征是由淀粉样前体蛋白(APP)降解产物诱导的突触变化。这种调节的确切机制尚不清楚。在此,我们报告,轴突内纳摩尔浓度的寡聚体(o)Aβ42,而非oAβ40或细胞外oAβ42,可在乌贼巨大突触处急性抑制突触传递。对该表型的进一步表征表明,突触前钙电流未受影响。然而,电子显微镜实验显示,在注射oAβ42的终末中停靠的突触小泡减少,而网格蛋白包被小泡未受影响。这种调节的分子事件涉及酪蛋白激酶2和突触小泡快速内吞途径。这些发现为旨在改善AD突触功能障碍的新治疗靶点开辟了可能性。