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

Robert Tamayev, Shuji Matsuda, Ottavio Arancio, Luciano D'Adamio

Research output: Contribution to journalArticle

77 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)171-179
Number of pages9
JournalEMBO Molecular Medicine
Volume4
Issue number3
DOIs
StatePublished - Mar 2012

Fingerprint

Amyloid Precursor Protein Secretases
Amyloid beta-Protein Precursor
Memory Disorders
Proteolysis
Dementia
Poisons
Alzheimer Disease
Serum Amyloid A Protein
Amyloid
Familial Danish dementia
Mutation
Therapeutics

Keywords

  • Alzheimer disease
  • BACE1
  • BRI2
  • Familial Danish dementia
  • Mouse models

ASJC Scopus subject areas

  • Molecular Medicine

Cite this

β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia. / Tamayev, Robert; Matsuda, Shuji; Arancio, Ottavio; D'Adamio, Luciano.

In: EMBO Molecular Medicine, Vol. 4, No. 3, 03.2012, p. 171-179.

Research output: Contribution to journalArticle

Tamayev, Robert ; Matsuda, Shuji ; Arancio, Ottavio ; D'Adamio, Luciano. / β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia. In: EMBO Molecular Medicine. 2012 ; Vol. 4, No. 3. pp. 171-179.
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