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


Dolev I, Fogel H, Milshtein H, Berdichevsky Y, Lipstein N, Brose N, Gazit N, Slutsky I.

Nat Neurosci. 2013 May;16(5):587-95. doi: 10.1038/nn.3376. Epub 2013 Apr 7.

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.

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