title: β- but not γ-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-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.
authors.affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Tamayev
authors.forename: Shuji
authors.initials: S
authors.lastname: Matsuda
authors.forename: Ottavio
authors.initials: O
authors.lastname: Arancio
authors.forename: Luciano
authors.initials: L
authors.lastname: D'Adamio
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002386:Cataract / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000523:psychology*; D002524:Cerebellar Ataxia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000523:psychology*; D003638:Deafness / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000523:psychology*; D003704:Dementia / Q000201:enzymology* / Q000235:genetics / Q000503:physiopathology / Q000523:psychology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008568:Memory; D051379:Mice; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D059748:Proteolysis; D013569:Synapses / Q000502:physiology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D016229:Amyloid beta-Peptides; D004791:Enzyme Inhibitors; C492300:Itm2b protein, mouse; D008565:Membrane Proteins; D053829:Amyloid Precursor Protein Secretases