Inhibition of γ-secretase worsens memory deficits in a genetically congruous mouse model of Danish dementia

Background: A mutation in the BRI2/ITM2b gene causes familial Danish dementia (FDD). BRI2 is an inhibitor of amyloid-beta precursor protein (APP) processing, which is genetically linked to Alzheimer's disease (AD) pathogenesis. The FDD mutation leads to a loss of BRI2 protein and to increased APP processing. APP haplodeficiency and inhibition of APP cleavage by beta-secretase rescue synaptic/memory deficits of a genetically congruous mouse model of FDD (FDDKI). beta-cleavage of APP yields the beta-carboxyl-terminal (beta-CTF) and the amino-terminal-soluble APP beta (sAPP beta) fragments. gamma-secretase processing of beta-CTF generates A beta, which is considered the main cause of AD. However, inhibiting A beta production did not rescue the deficits of FDDKI mice, suggesting that sAPP beta/beta-CTF, and not A beta, are the toxic species causing memory loss. Results: Here, we have further analyzed the effect of.-secretase inhibition. We show that treatment with a gamma-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 beta/alpha-CTFs APP fragments in synaptic fractions isolated from hippocampi of FDDKI mice, which is consistent with inhibition of gamma-secretase activity. Conclusion: This harmful effect of the GSI is in sharp contrast with a pathogenic role for A beta, and suggests that the worsening of memory deficits may be due to accumulation of synaptic-toxic beta/alpha-CTFs caused by GSI treatment. However, gamma-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 gamma-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 gamma-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.