Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 106, Issue 14, Pages 5901-5906Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0900944106
Keywords
Alzheimer's disease; fluorescence microscopy; presynaptic voltage clamp; squid giant synapse; ultrastructure
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Funding
- Fundacao de Amparo a Pesquisa do Estado de Sao Paulo Cooperacao Interinstitucional de Apoio a Pesquisa sobre o Cerebro Program [05-56447-7]
- National Institutes of Health [AG027476, NS 13742-30]
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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)A beta 42, but not oA beta 40 or extracellular oA beta 42, 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 oA beta 42-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.
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