. Involvement of beta-site APP cleaving enzyme 1 (BACE1) in amyloid precursor protein-mediated enhancement of memory and activity-dependent synaptic plasticity. Proc Natl Acad Sci U S A. 2007 May 8;104(19):8167-72. PubMed.

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  1. This intriguing study from Karen Ashe’s lab shows that mice overproducing wild-type human APP (TgAPP) display enhanced spatial memory in the Morris water maze. To determine which of the proteolytic products of APP plays a role in this process, the TgAPP mice were crossed with BACE1 knockout mice. TgAPP mice bearing a single targeted allele of BACE1 no longer displayed enhanced memory. The only APP fragment that was reduced in the TgAPP/BACE1 heterozygote mice when compared to TgAPP controls was AICD. These data clearly implicate BACE1 activity in APP-dependent enhanced memory and suggest that AICD plays a role in memory, thus providing the first physiological evidence for AICD function in vivo.

    Electrophysiology studies were also carried out to determine whether synaptic plasticity in the Schaffer collateral pathway of the hippocampus correlated with the respective behaviors of the mice in this spatial memory task. Primed long-term potentiation (P-LTP) was enhanced in TgAPP mice, but LTP was unchanged relative to non-transgenic controls. This suggests that the synaptic plasticity affected by APP overproduction was dependent on prior synaptic activity. These changes in primed LTP were no longer observed in mice bearing a single targeted allele of BACE1. The implication from these data is that AICD plays a role in this form of synaptic plasticity. We are left wondering whether AICD levels change in response to synaptic activity. Specifically, are AICD levels affected differently in primed LTP versus LTP, and does AICD modulate transcriptional events associated with memory? These are only a couple of the questions that arise from this fascinating report.

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