Abstract
Accumulation of cerebral amyloid-β peptide (Aβ) is essential for developing synaptic and cognitive deficits in Alzheimer's disease. However, the physiological functions of Aβ, as well as the primary mechanisms that initiate early Aβ-mediated synaptic dysfunctions, remain largely unknown. Here we examine the acute effects of endogenously released Aβ peptides on synaptic transfer at single presynaptic terminals and synaptic connections in rodent hippocampal cultures and slices. Increasing extracellular Aβ by inhibiting its degradation enhanced release probability, boosting ongoing activity in the hippocampal network. Presynaptic enhancement mediated by Aβ was found to depend on the history of synaptic activation, with lower impact at higher firing rates. Notably, both elevation and reduction in Aβ levels attenuated short-term synaptic facilitation during bursts in excitatory synaptic connections. These observations suggest that endogenous Aβ peptides have a crucial role in activity-dependent regulation of synaptic vesicle release and might point to the primary pathological events that lead to compensatory synapse loss in Alzheimer's disease.
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Acknowledgements
We thank A. Lee and M. Wilson for sharing unpublished data on 'natural' spike sequence, D.M. Holtzman for providing the HJ5.1 hybridoma cell line, A.I. Bush, R. Cappai and H. Zheng for App−/− mice, C. Kaether for the human APP695-YFP cDNA construct, and the members of our laboratory for comments on the manuscript. We thank A.I. Bush and E. Gazit for discussions. This work was supported by a Rosalinde and Arthur Gilbert Foundation/American Federation for Aging Research research grant (I.S.), the Legacy Heritage Biomedical Program of the Israel Science Foundation (I.S.), the Israel Ministry of Health (I.S.), the National Institute of Psychobiology in Israel founded by the Charles E. Smith family (I.S.), and the Center for Nanoscience and Nanotechnology of Tel Aviv University (I.D.).
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E.A., I.D., H.F., E.R. and I.S. designed, performed and analyzed experiments. H.F. wrote the program for image processing. G.D.C. provided the App−/− mice colony. I.S. designed and supervised the project. I.S., E.A. and I.D. wrote the manuscript.
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Abramov, E., Dolev, I., Fogel, H. et al. Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses. Nat Neurosci 12, 1567–1576 (2009). https://doi.org/10.1038/nn.2433
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DOI: https://doi.org/10.1038/nn.2433
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