ß- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia.

A mutation in the BRI2/ITM2b gene causes loss of BRI2 protein leading to familial Danish dementia (FDD). BRI2 deficiency of FDD provokes an increase in amyloid-ß precursor protein (APP) processing since BRI2 is an inhibitor of APP proteolysis, and APP mediates the synaptic/memory deficits in FDD. APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias. We show that inhibition of APP cleavage by ß-secretase rescues synaptic/memory deficits in a mouse model of FDD. ß-cleavage of APP yields amino-terminal-soluble APPß (sAPPß) and ß-carboxyl-terminal fragments (ß-CTF). Processing of ß-CTF by γ-secretase releases amyloid-ß (Aß), which is assumed to cause AD. However, inhibition of γ-secretase did not ameliorate synaptic/memory deficits of FDD mice. These results suggest that sAPPß and/or ß-CTF, rather than Aß, are the toxic species causing dementia, and indicate that reducing ß-cleavage of APP is an appropriate therapeutic approach to treating human dementias. Our data and the failures of anti-Aß therapies in humans advise against targeting γ-secretase cleavage of APP and/or Aß.