%0 Journal Article
%T Inhibition of ¦Ã-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia
%A Robert Tamayev
%A Luciano D'Adamio
%J Molecular Neurodegeneration
%D 2012
%I BioMed Central
%R 10.1186/1750-1326-7-19
%X Here, we have further analyzed the effect of ¦Ã-secretase inhibition. We show that treatment with a ¦Ã-secretase inhibitor (GSI) results in a worsening of the memory deficits of FDDKI mice. This deleterious effect on memory correlates with increased levels of the ¦Â/¦Á-CTFs APP fragments in synaptic fractions isolated from hippocampi of FDDKI mice, which is consistent with inhibition of ¦Ã-secretase activity.This harmful effect of the GSI is in sharp contrast with a pathogenic role for A¦Â, and suggests that the worsening of memory deficits may be due to accumulation of synaptic-toxic ¦Â/¦Á-CTFs caused by GSI treatment. However, ¦Ã-secretase cleaves more than 40 proteins; thus, the noxious effect of GSI on memory may be dependent on inhibition of cleavage of one or more of these other ¦Ã-secretase substrates. These two possibilities do not need to be mutually exclusive. Our results are consistent with the outcome of a clinical trial with the GSI Semagacestat, which caused a worsening of cognition, and advise against targeting ¦Ã-secretase in the therapy of AD. Overall, the data also indicate that FDDKI is a valuable mouse model to study AD pathogenesis and predict the clinical outcome of therapeutic agents for AD.
%U http://www.molecularneurodegeneration.com/content/7/1/19/abstract