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

Accumulated genetic evidence suggests that attenuation of the ratio between cerebral amyloid-ß Aß40 and Aß42 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 Aß40/42 an enigma. Here we explored regulation of Aß40/42 ratio by temporal spiking patterns in the rodent hippocampus. Spike bursts boosted Aß40/42 through a conformational change in presenilin1 (PS1), the catalytic subunit of γ-secretase, and subsequent increase in Aß40 production. Conversely, single spikes did not alter basal PS1 conformation and Aß40/42. 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 Aß40/42 facilitation by bursts in the hippocampus. Thus, burst probability and transfer properties of synapses represent fundamental features regulating Aß40/42 by experience and may contribute to the initiation of the common, sporadic Alzheimer's disease.