TY - JOUR
T1 - Spike bursts increase amyloid-β 40/42 ratio by inducing a presenilin-1 conformational change
AU - Dolev, Iftach
AU - Fogel, Hilla
AU - Milshtein, Hila
AU - Berdichevsky, Yevgeny
AU - Lipstein, Noa
AU - Brose, Nils
AU - Gazit, Neta
AU - Slutsky, Inna
N1 - Funding Information:
We thank B. De Strooper for discussions, O. Berezovska (Harvard Medical School) for providing GFP-PS1-RFP cDNA, S. Frere for comments on the manuscript, Y. Amitai for suggestions on an early version of the manuscript and all laboratory members for discussions. This work was supported by European Research Council (281403), Legacy Heritage Biomedical Program of the Israel Science Foundation (1925/08), Alzheimer’s Association (NIRG-10-172308) and Israel Science Foundation (993/08 and 170/08) grants to I.S. and EUROSPIN and SynSys Consortia (FP7-HEALTH-F2-2009-241498 and FP7-HEALTH-F2-2009-242167) grants to N.B. I.D. is grateful to the Center for Nanoscience and Nanotechnology of Tel Aviv University and Azrieli Foundation for the award of doctoral fellowships.
PY - 2013/5
Y1 - 2013/5
N2 - Accumulated genetic evidence suggests that attenuation of the ratio between cerebral amyloid-β Aβ40 and Aβ42 isoforms is central to familial Alzheimer's disease (FAD) pathogenesis. However, FAD mutations account for only 1-2% of Alzheimer's disease cases, leaving the experience-dependent mechanisms regulating Aβ40/42 an enigma. Here we explored regulation of Aβ40/42 ratio by temporal spiking patterns in the rodent hippocampus. Spike bursts boosted Aβ40/42 through a conformational change in presenilin1 (PS1), the catalytic subunit of γ-secretase, and subsequent increase in Aβ40 production. Conversely, single spikes did not alter basal PS1 conformation and Aβ40/42. Burst-induced PS1 conformational shift was mediated by means of Ca 2+-dependent synaptic vesicle exocytosis. Presynaptic inhibition in vitro and visual deprivation in vivo augmented synaptic and Aβ40/42 facilitation by bursts in the hippocampus. Thus, burst probability and transfer properties of synapses represent fundamental features regulating Aβ40/42 by experience and may contribute to the initiation of the common, sporadic Alzheimer's disease.
AB - Accumulated genetic evidence suggests that attenuation of the ratio between cerebral amyloid-β Aβ40 and Aβ42 isoforms is central to familial Alzheimer's disease (FAD) pathogenesis. However, FAD mutations account for only 1-2% of Alzheimer's disease cases, leaving the experience-dependent mechanisms regulating Aβ40/42 an enigma. Here we explored regulation of Aβ40/42 ratio by temporal spiking patterns in the rodent hippocampus. Spike bursts boosted Aβ40/42 through a conformational change in presenilin1 (PS1), the catalytic subunit of γ-secretase, and subsequent increase in Aβ40 production. Conversely, single spikes did not alter basal PS1 conformation and Aβ40/42. Burst-induced PS1 conformational shift was mediated by means of Ca 2+-dependent synaptic vesicle exocytosis. Presynaptic inhibition in vitro and visual deprivation in vivo augmented synaptic and Aβ40/42 facilitation by bursts in the hippocampus. Thus, burst probability and transfer properties of synapses represent fundamental features regulating Aβ40/42 by experience and may contribute to the initiation of the common, sporadic Alzheimer's disease.
UR - http://www.scopus.com/inward/record.url?scp=84876926688&partnerID=8YFLogxK
U2 - 10.1038/nn.3376
DO - 10.1038/nn.3376
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AN - SCOPUS:84876926688
SN - 1097-6256
VL - 16
SP - 587
EP - 595
JO - Nature Neuroscience
JF - Nature Neuroscience
IS - 5
ER -