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

EMBO Molecular Medicine

Robert Tamayev¹  Shuji Matsuda¹  Ottavio Arancio² 

[1]Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA

[2]Department of Pathology and Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY, USA

关键词: Alzheimer disease;    BACE1;    BRI2;    familial Danish dementia;    mouse models;   

DOI  :  10.1002/emmm.201100195

来源: Wiley

【 摘 要 】

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

【 授权许可】

Unknown   
Copyright © 2012 EMBO Molecular Medicine