Proceedings of the National Academy of Sciences · 2009 · 106 citations · 27 references
Life SciencesNeurobiologyNeuroscienceEndocytosisMolecular NeurobiologyMolecular NeuroscienceAlzheimer DiseaseNeurodegenerative DiseasesNeurodegenerative DisordersNeurotransmissionSynaptic TransmissionVesicle DockingAmyloid Oligomer FormationAmyloid-associated NeurotoxicityClathrin-coated VesiclesPresynaptic Calcium SignalingSynaptic PathologySynaptic Transmission ModulationSynaptic Vesicle TransportTherapeutic Targeting Of Amyloid
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.
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Axonopathy and Transport Deficits Early in the Pathogenesis of Alzheimer's Disease
Gorazd B. Stokin, Concepción Lillo, Tomás L. Falzone et al. · Science · 2005 · 1.2K citations