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

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

SUBMITTER: Tamayev R 

PROVIDER: S-EPMC3376850 | biostudies-other | 2012 Mar

REPOSITORIES: biostudies-other

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

Tamayev Robert R   Matsuda Shuji S   Arancio Ottavio O   D'Adamio Luciano L   D'Adamio Luciano L  

EMBO molecular medicine 20120123 3

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-β 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  ...[more]