title: Spike bursts increase amyloid-β 40/42 ratio by inducing a presenilin-1 conformational change.
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.
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Iftach
authors.initials: I
authors.lastname: Dolev
authors.forename: Hilla
authors.initials: H
authors.lastname: Fogel
authors.forename: Hila
authors.initials: H
authors.lastname: Milshtein
authors.forename: Yevgeny
authors.initials: Y
authors.lastname: Berdichevsky
authors.forename: Noa
authors.initials: N
authors.lastname: Lipstein
authors.forename: Nils
authors.initials: N
authors.lastname: Brose
authors.forename: Neta
authors.initials: N
authors.lastname: Gazit
authors.forename: Inna
authors.initials: I
authors.lastname: Slutsky
mesh_terms: D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D002121:Calcium Channel Blockers / Q000494:pharmacology; D002478:Cells, Cultured; D003623:Dark Adaptation / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D005260:Female; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism*; D053764:Presenilin-1 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D051381:Rats; D017208:Rats, Wistar; D014793:Visual Cortex / Q000166:cytology
chemical_list: D016229:Amyloid beta-Peptides; D002121:Calcium Channel Blockers; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D018377:Neurotransmitter Agents; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; C503321:Unc13a protein, mouse; C485549:Unc13b protein, mouse; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42)
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