| First Author | Dolev I | Year | 2013 |
| Journal | Nat Neurosci | Volume | 16 |
| Issue | 5 | Pages | 587-95 |
| PubMed ID | 23563578 | Mgi Jnum | J:197603 |
| Mgi Id | MGI:5494174 | Doi | 10.1038/nn.3376 |
| Citation | Dolev I, et al. (2013) Spike bursts increase amyloid-beta 40/42 ratio by inducing a presenilin-1 conformational change. Nat Neurosci 16(5):587-95 |
| abstractText | Accumulated genetic evidence suggests that attenuation of the ratio between cerebral amyloid-beta Abeta40 and Abeta42 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 Abeta40/42 an enigma. Here we explored regulation of Abeta40/42 ratio by temporal spiking patterns in the rodent hippocampus. Spike bursts boosted Abeta40/42 through a conformational change in presenilin1 (PS1), the catalytic subunit of gamma-secretase, and subsequent increase in Abeta40 production. Conversely, single spikes did not alter basal PS1 conformation and Abeta40/42. 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 Abeta40/42 facilitation by bursts in the hippocampus. Thus, burst probability and transfer properties of synapses represent fundamental features regulating Abeta40/42 by experience and may contribute to the initiation of the common, sporadic Alzheimer's disease. |
