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Spike bursts increase amyloid-β 40/42 ratio by inducing a presenilin-1 conformational change.
- Source :
-
Nature neuroscience [Nat Neurosci] 2013 May; Vol. 16 (5), pp. 587-95. Date of Electronic Publication: 2013 Apr 07. - Publication Year :
- 2013
-
Abstract
- 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.
- Subjects :
- Animals
Animals, Newborn
Calcium Channel Blockers pharmacology
Cells, Cultured
Dark Adaptation physiology
Dose-Response Relationship, Drug
Excitatory Postsynaptic Potentials drug effects
Excitatory Postsynaptic Potentials physiology
Female
Hippocampus cytology
In Vitro Techniques
Intracellular Signaling Peptides and Proteins genetics
Intracellular Signaling Peptides and Proteins metabolism
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Nerve Tissue Proteins genetics
Nerve Tissue Proteins metabolism
Neurotransmitter Agents pharmacology
Presenilin-1 chemistry
Presenilin-1 genetics
Protein Conformation
Rats
Rats, Wistar
Visual Cortex cytology
Amyloid beta-Peptides metabolism
Peptide Fragments metabolism
Presenilin-1 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1546-1726
- Volume :
- 16
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Nature neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 23563578
- Full Text :
- https://doi.org/10.1038/nn.3376