β- but not γ-secretase proteolysis of APP causes synaptic and memory deficits in a mouse model of dementia.
Bottom Line: APP processing is linked to Alzheimer disease (AD) pathogenesis, which is consistent with a common mechanism involving toxic APP metabolites in both dementias.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.
Affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.Show MeSH
Related in: MedlinePlus
Mentions: Amyloid deposition of amyloid-β (Aβ) peptide characterises Alzheimer disease (AD). Aβ derives from sequential cleavage of amyloid-β precursor protein (APP) by β- and γ-secretases (Cole & Vassar, 2007; De Strooper et al, 2010; Fig 1A). Interestingly, mutations in either APP or the γ-secretase genes PSEN1 and PSEN2 cause familial AD (FAD; Bertram et al, 2010; St George-Hyslop & Petit, 2005). Mutation of BRI2/ITM2b causes familial Danish dementia (FDD), an AD-like familial dementia with amyloid deposits. In normal individuals the immature BRI2 precursor (imBRI2) is cleaved by convertases in the Golgi into mature BRI2 (mBRI2) and a carboxy-terminal 23 amino acid peptide (Bri23). mBRI2 is transported to the plasma membrane and Bri23 is secreted. In the Danish kindred, the presence of a 10-nt duplication one codon before the normal stop codon produces a frame-shift in the BRI2 sequence generating a larger-than-normal precursor protein called BRI2ADan. Cleavage by convertases releases the amyloid subunit that comprises the last 34 COOH-terminal amino acids (ADan) and mBRI2. ADan accumulates into amyloid plaques, which contain both Aβ and ADan (Choi et al, 2004; Vidal et al, 2000).
Affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.