Beta-amyloid disrupted synaptic vesicle endocytosis in cultured hippocampal neurons.
Neuronal death leading to gross brain atrophy is commonly seen in Alzheimer's disease (AD) patients. Yet, it is becoming increasingly apparent that the pathogenesis of AD involves early and more discrete synaptic changes in affected brain areas. However, the molecular mechanisms that underlie such synaptic dysfunction remain largely unknown. Recently, we have identified dynamin 1, a protein that plays a critical role in synaptic vesicle endocytosis, and hence, in the signaling properties of the synapse, as a potential molecular determinant of such dysfunction in AD. In the present study, we analyzed beta-amyloid (Abeta)-induced changes in synaptic vesicle recycling in rat cultured hippocampal neurons. Our results showed that Abeta, the main component of senile plaques, caused ultrastructural changes indicative of impaired synaptic vesicle endocytosis in cultured hippocampal neurons that have been stimulated by depolarization with high potassium. In addition, Abeta led to the accumulation of amphiphysin in membrane fractions from stimulated hippocampal neurons. Moreover, experiments using FM1-43 showed reduced dye uptake in stimulated hippocampal neurons treated with Abeta when compared with untreated stimulated controls. Similar results were obtained using a dynamin 1 inhibitory peptide suggesting that dynamin 1 depletion caused deficiency in synaptic vesicle recycling not only in Drosophila but also in mammalian neurons. Collectively, these results showed that Abeta caused a disruption of synaptic vesicle endocytosis in cultured hippocampal neurons. Furthermore, we provided evidence suggesting that Abeta-induced dynamin 1 depletion might play an important role in this process.
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Department of Cell and Molecular Biology, Feinberg School of Medicine, Northwestern University, Searle Building Room 5-474, 320 East Superior Street, Chicago, IL 60611, USA.
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D000200:Action Potentials / Q000502:physiology; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D004330:Drosophila; D034284:Dynamin I / Q000378:metabolism*; D004705:Endocytosis / Q000502:physiology*; D006624:Hippocampus / Q000378:metabolism* / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism* / Q000648:ultrastructure; D010446:Peptide Fragments / Q000378:metabolism*; D051381:Rats; D013572:Synaptic Vesicles / Q000378:metabolism* / Q000648:ultrastructure
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C078592:amyloid beta-protein (1-40); D034284:Dynamin I