Spike bursts increase amyloid-β 40/42 ratio by inducing a presenilin-1 conformational change

Iftach Dolev, Hilla Fogel, Hila Milshtein, Yevgeny Berdichevsky, Noa Lipstein, Nils Brose, Neta Gazit, Inna Slutsky*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)587-595
Number of pages9
JournalNature Neuroscience
Issue number5
StatePublished - May 2013


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