. BACE overexpression alters the subcellular processing of APP and inhibits Abeta deposition in vivo. J Cell Biol. 2005 Jan 17;168(2):291-302. PubMed.

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  1. EB Lee and colleagues provide very interesting data indicating that
    high BACE overexpression paradoxically reduces Aβ levels and
    plaque pathology in Tg2576 transgenic mice harboring the APP Swedish
    mutation. They employ diverse methods to demonstrate that BACE
    overexpression reduces transport of mature and phosphorylated APP
    into axons. This publication underscores the importance of studying AD
    biology in neurons, especially their processes. Increasing evidence is
    placing the critical site of Aβ generation, and accumulation,
    within neurites and synapses. Disruption of the perforant path has
    previously been shown to reduce plaque pathology in synaptic terminal
    fields of the hippocampus. Aβ at synapses may even have a
    physiological role that as yet is poorly defined. A central but more
    controversial issue is how Aβ generation at synapses links to
    synaptic dysfunction and plaque formation.

    A topic not discussed in the paper is the growing literature on intraneuronal Aβ
    accumulation with AD pathogenesis. Indeed, the labs of Virginia Lee
    and John Trojanowski were pioneers in studies on intracellular Aβ.
    Their work raises the intriguing question of why the low BACE
    expressing APP mutant mice have reduced plaques in hippocampus but
    increased plaques in cortex. The authors speculate that differential
    effects of increased BACE in projection neurons with long axons
    compared to smaller interneurons with shorter axons may be involved.
    Despite the emphasis on axons and presynaptic compartments, one could
    also consider the potential involvement of dendrites and postsynaptic
    compartments, which are more difficult to study but also accumulate
    Aβ. Overall, this is exciting new work using rigorous analysis of
    APP/Aβ processing with elegant in vivo experiments that provide
    novel insights into the neurobiology of AD.

  2. I agree with Martin and Gouras that this paper deserves serious study since it is an ambitious attempt to explore whether cleavage of APP at different subcellular sites determines whether Abeta peptides are ultimately toxic to the neurons in which the are produced.

    The authors found that increased expression of beta secretase in mice has a paradoxical effect on Aβ levels and plaque development. High levels of beta secretase decrease Aβ levels and retard plaque formation, contrary to what might have been predicted. They propose that excessive beta secretase cleaves APP prematurely in the ER/Golgi regions of neurons, thereby reducing their translocation to distal segments where it is presumed that abeta peptides might be more toxic. While this is an interesting idea, I would look for deeper explanations.

    Other interesting effects are also described, such as a striking decrease in levels of phosphorylated C99, a product of beta cleavage, while non-phosphorylated C99 and other amino terminal fragments of APP accumulate inside cells. This makes one wonder whether high levels of beta secretase, or the peptides they generate, have as yet unsuspected actions that might influence other metabolic pathways including kinase/phosphatase actions and the PS1/gamma secretase complex.

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