ß- but not ?-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-beta 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 beta-secretase rescues synaptic/memory deficits in a mouse model of FDD. beta-cleavage of APP yields amino-terminal-soluble APP beta (sAPP beta) and beta-carboxyl-terminal fragments (beta-CTF). Processing of beta-CTF by gamma-secretase releases amyloid-beta (A beta), which is assumed to cause AD. However, inhibition of gamma-secretase did not ameliorate synaptic/memory deficits of FDD mice. These results suggest that sAPP beta and/or beta-CTF, rather than A beta, are the toxic species causing dementia, and indicate that reducing beta-cleavage of APP is an appropriate therapeutic approach to treating human dementias. Our data and the failures of anti-A beta therapies in humans advise against targeting gamma-secretase cleavage of APP and/or A beta.