. Gamma-secretase inhibition reduces spine density in vivo via an amyloid precursor protein-dependent pathway. J Neurosci. 2009 Aug 19;29(33):10405-9. PubMed.

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  1. Bittner and colleagues succinctly describe the effects of gamma-secretase inhibition on dendritic spine density in the neocortex using in vivo, two-photon imaging in mice. The authors report that chronic, independent administration of two different gamma-secretase inhibitors reduces the density of synaptic spines in a focal region of neocortex, and that this effect requires the presence of APP.

    These intriguing findings will certainly stimulate further research on this topic, as synapse loss could impair cognitive function in people treated with gamma secretase inhibitors, thus neutralizing potential benefits of the therapy in Alzheimer patients. This report raises several questions:
    1) Is the anatomical distribution of the effect widespread or focal in the brain? (this issue might be addressed by biochemical or stereological analysis of synapse-associated markers);
    2) what is the dose-response relationship between gamma secretase inhibition and synapse depletion, and is this phenomenon separable from the effect of the inhibitors on Aβ levels? and
    3) a key issue, noted in the paper's Discussion, is whether chronic gamma secretase inhibition influences cognition, and whether the predicted behavioral changes persist following discontinuation of the drugs. The outcome of follow-up studies could influence strategic approaches to lowering Aβ in Alzheimer disease.