. Spike bursts increase amyloid-β 40/42 ratio by inducing a presenilin-1 conformational change. Nat Neurosci. 2013 May;16(5):587-95. PubMed.


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  1. This is a wonderful study by Dolev et al. that underscores why we need more experts in synapse biology to turn their attention to AD. In a remarkable paper, they show that the Aβ40/42 ratio depends on temporal spike bursting and synaptic facilitation. Moreover, they show that modulating these parameters regulates the Aβ40/42 ratio by altering the open/closed conformation of presenilin 1. The authors point out a literature of reduced synaptic facilitation and spike bursts with aging, and thus provide a novel explanation for how aging can promote AD by reducing Aβ40.

    The study also raises many questions. The authors show that spike bursts and synaptic facilitation only affect Aβ40 and not Aβ42. It isn’t clear here why changing the PS1 conformation doesn’t also impact Aβ42(43). Moreover, the mechanism by which age-related reduction in Aβ40 is then translated into elevation and aggregation of Aβ in the brain in AD still needs to be sorted out.

    In a supplementary figure, the authors show reductions in synaptic facilitation and in the burst-associated Aβ40 release in APP/PS1 mutant transgenic AD mice. The mechanism of how presumably elevated Aβ42 impairs synaptic facilitation in these mice needs to be uncovered. In addition, one wonders why the APP Swedish mutation, which increases Aβ40 and 42 similarly, is pathogenic, although one could hypothesize that Aβ42 effects are dominant over the protective effects of Aβ40. Other critical questions include how and why synaptic bursting and facilitation change with aging to promote AD. One looks forward to following this group as they make more advances in our understanding of the role of Aβ at synapses and how this becomes a problem in AD.

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