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

Accumulated genetic evidence suggests that attenuation of the ratio between cerebral amyloid-beta A beta 40 and A beta 42 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 A beta 40/42 an enigma. Here we explored regulation of A beta 40/42 ratio by temporal spiking patterns in the rodent hippocampus. Spike bursts boosted A beta 40/42 through a conformational change in presenilin1 (PS1), the catalytic subunit of gamma-secretase, and subsequent increase in A beta 40 production. Conversely, single spikes did not alter basal PS1 conformation and A beta 40/42. Burst-induced PS1 conformational shift was mediated by means of Ca2+-dependent synaptic vesicle exocytosis. Presynaptic inhibition in vitro and visual deprivation in vivo augmented synaptic and A beta 40/42 facilitation by bursts in the hippocampus. Thus, burst probability and transfer properties of synapses represent fundamental features regulating A beta 40/42 by experience and may contribute to the initiation of the common, sporadic Alzheimer's disease.