. 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.

  2. Yet another fascinating report from the Ashe laboratory is published in PNAS. Here, Karen Ashe and colleagues demonstrate that BACE1 cleavage of APP is needed for the enhancement of memory and the activity-dependent synaptic plasticity. A mouse model is used that overexpresses wild-type human APP at six times the endogenous level. These mice do not produce Aβ oligomers, or plaques, and exhibit enhanced spatial memory. Biochemically, these mice have more Aβ, APPsα, and AICD when compared to non-transgenic controls. So, which of the APP fragments is responsible for the enhanced memory? Ma et al. provide evidence that the enhanced synaptic plasticity is diminished by the lack of one or two copies of BACE1. Ablation of BACE1 leads to a parallel decrease in AICD but not to changes in APP or other APP fragments including Aβ and APPsα. The major novel conclusions of the paper are as follows:

    1. AICD plays an important role in synaptic plasticity and, thus, memory.

    2. The beneficial effects are not caused by Aβ or APPsα, as previously reported.

    3. We need to exercise caution when designing BACE1 inhibitors to reduce Aβ load in AD patients.

    These are exciting findings that could be open to additional interpretations. For example, BACE1 also cleaves neuregulin, and that has been shown to affect synaptic plasticity and myelination (Harrison and Law, 2006; Willem et al. 2006; Hu et al., 2006). In addition, the increased levels of APPsα in the WT APP mice suggest that the αCTF fragment levels are increased. These are the substrates for γ-secretase to produce AICD by cleaving at the ε site. So, why then would lack of BACE1 affect the γ-secretase cleavage of αCTF fragments? As always, an intriguing article opens many more stimulating questions.

    View all comments by Carmela Abraham
  3. I wonder why there is no mention of the neuropathology, including neuritic plaques and neurofibrillary tangles, that develops in most, but not all (see Argellati et al., 2006) individuals afflicted with Down syndrome. BACE1 and BACE2 levels have been reported to be elevated in the brains of Down's patients (Sun et al., 2006; Motonaga et al., 2002). Duplication of the APP locus has been found in families that lack clinical features of DS, but develop EOAD (see Cabrejo et al., 2006). This is an interesting paper, but it again reveals that the value of mice as models to study human disease is limited.

    AICD signaling to the nucleus, although frequently compared to NICD nuclear signaling, is still a matter of debate. This is largely due to the number of conflicting reports throughout the literature, including on AICD stabilizing proteins and the expression of putative AICD-targeted genes. In keeping with this, adaptor proteins (e.g., Fe65) can apparently activate transcription without the need of AICD (see Hebert et al., 2006; Cao and Sudhof, 2004).

    So what is it about AICD? Could it primarily function as a scaffolding protein or recruitment factor for APP-binding proteins? Kinases? Phosphatases? Cytoskeleton? Proteins that have such an incredibly short half-life are typically the most critical to the health of the cell. As such, they contribute to the control of signal transduction pathways, cell-cycle control, apoptosis, antigen processing, differentiation, and surface receptor desensitization, to name just a few. Maybe AICD is a nuclear signaling molecule with dual functionality, and we just haven't looked hard enough or in the right spot. Maybe AICD is one of many protein by-products involved in nuclear signaling within neurons, and is rapidly destroyed in order to maintain a mitotic block through gene repression or expression. A second role would still require rapid degradation in proliferating cells to allow for growth. Either way, it would make it an elusive molecule to detect. In a scenario where AICD generation from mAPP is no longer tightly regulated by α- or β-secretase activities (e.g., in FAD mutants), the genes would become deregulated and the neurons begin to slowly cycle into an abyss.

    I imagine this scenario: deregulated secretase activities such that a cell cycle checkpoint is breached into G1/S phase, expression of cell cycle proteins in the affected neurons increases, recruitment of microglia and increased ROS's, Aβ levels slowly increase, the neuron reaches G2 where it needs to prepare for division and so microtubules and MAPs increase, G2 continues very slowly, tau phosphorylation and NFTs increase, but the neuron is genetically programmed not to be in this predicament. It cannot reach M phase. Cell cycle markers accumulate and trigger apoptotic pathways. And that's it. The neuron has no choice but to die, leaving behind a dark hole full of protein aggregates, where a memory once lived.

    I recommend this paper.

    View all comments by Michael Myre

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