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

Tamayev R, Matsuda S, Arancio O, D'Adamio L - EMBO Mol Med (2012)

Bottom Line: Processing of β-CTF by γ-secretase releases amyloid-β (Aβ), which is assumed to cause AD.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.

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Mapping the BRI2 domain that binds APP and inhibits APP processingA. APP is cleaved by β-secretase into sAPPβ and β-CTF. γ-cleavage of β-CTF yields Aβ and AID/AICD peptides. Alternatively, α-secretase clips APP into sAPPα and α-CTF. α-CTF is cut by γ-secretase into P3 and AID.B-C. BRI2 binds APP and inhibits processing by α- and β-secretases. Binding of BRI2 to β-CTF inhibits cleavage by γ-secretase.D. Constructs and domains [cytoplasmic (Cyt), transmembrane (TM), extracellular (Lumen), brichos (B) and convertases-cleavage site, myc-tag]. Lysates (L) and α-myc immunoprecipitates (myc-IP) from transfected cells were analysed by Western blot (WB) for α-Tubulin, BRI2, APP and APP-CTFs. Supernatants (SN) were analysed for sAPPα and sAPPβ. *Indicates an APP-CTF larger than β-CTF, which is routinely observed when BRI2 is over-expressed. This band, whose origin is unknown, also binds to BRI2.E. APP-Gal4, AID-Gal4, Gal4-depended promoter, luciferase reporter, cytoplasm (Cyt) and nucleus (Nc) are schematically indicated. Luciferase activity is expressed as % of the activity in cells transfected with APP-Gal4, luciferase reporter and empty vector (vec). Overall, our analysis shows that BRI2 residues comprised between amino acids 102 and 134 retained APP-binding properties and inhibitory effects on APP processing.
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fig01: Mapping the BRI2 domain that binds APP and inhibits APP processingA. APP is cleaved by β-secretase into sAPPβ and β-CTF. γ-cleavage of β-CTF yields Aβ and AID/AICD peptides. Alternatively, α-secretase clips APP into sAPPα and α-CTF. α-CTF is cut by γ-secretase into P3 and AID.B-C. BRI2 binds APP and inhibits processing by α- and β-secretases. Binding of BRI2 to β-CTF inhibits cleavage by γ-secretase.D. Constructs and domains [cytoplasmic (Cyt), transmembrane (TM), extracellular (Lumen), brichos (B) and convertases-cleavage site, myc-tag]. Lysates (L) and α-myc immunoprecipitates (myc-IP) from transfected cells were analysed by Western blot (WB) for α-Tubulin, BRI2, APP and APP-CTFs. Supernatants (SN) were analysed for sAPPα and sAPPβ. *Indicates an APP-CTF larger than β-CTF, which is routinely observed when BRI2 is over-expressed. This band, whose origin is unknown, also binds to BRI2.E. APP-Gal4, AID-Gal4, Gal4-depended promoter, luciferase reporter, cytoplasm (Cyt) and nucleus (Nc) are schematically indicated. Luciferase activity is expressed as % of the activity in cells transfected with APP-Gal4, luciferase reporter and empty vector (vec). Overall, our analysis shows that BRI2 residues comprised between amino acids 102 and 134 retained APP-binding properties and inhibitory effects on APP processing.

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).


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

Tamayev R, Matsuda S, Arancio O, D'Adamio L - EMBO Mol Med (2012)

Mapping the BRI2 domain that binds APP and inhibits APP processingA. APP is cleaved by β-secretase into sAPPβ and β-CTF. γ-cleavage of β-CTF yields Aβ and AID/AICD peptides. Alternatively, α-secretase clips APP into sAPPα and α-CTF. α-CTF is cut by γ-secretase into P3 and AID.B-C. BRI2 binds APP and inhibits processing by α- and β-secretases. Binding of BRI2 to β-CTF inhibits cleavage by γ-secretase.D. Constructs and domains [cytoplasmic (Cyt), transmembrane (TM), extracellular (Lumen), brichos (B) and convertases-cleavage site, myc-tag]. Lysates (L) and α-myc immunoprecipitates (myc-IP) from transfected cells were analysed by Western blot (WB) for α-Tubulin, BRI2, APP and APP-CTFs. Supernatants (SN) were analysed for sAPPα and sAPPβ. *Indicates an APP-CTF larger than β-CTF, which is routinely observed when BRI2 is over-expressed. This band, whose origin is unknown, also binds to BRI2.E. APP-Gal4, AID-Gal4, Gal4-depended promoter, luciferase reporter, cytoplasm (Cyt) and nucleus (Nc) are schematically indicated. Luciferase activity is expressed as % of the activity in cells transfected with APP-Gal4, luciferase reporter and empty vector (vec). Overall, our analysis shows that BRI2 residues comprised between amino acids 102 and 134 retained APP-binding properties and inhibitory effects on APP processing.
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Related In: Results  -  Collection

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fig01: Mapping the BRI2 domain that binds APP and inhibits APP processingA. APP is cleaved by β-secretase into sAPPβ and β-CTF. γ-cleavage of β-CTF yields Aβ and AID/AICD peptides. Alternatively, α-secretase clips APP into sAPPα and α-CTF. α-CTF is cut by γ-secretase into P3 and AID.B-C. BRI2 binds APP and inhibits processing by α- and β-secretases. Binding of BRI2 to β-CTF inhibits cleavage by γ-secretase.D. Constructs and domains [cytoplasmic (Cyt), transmembrane (TM), extracellular (Lumen), brichos (B) and convertases-cleavage site, myc-tag]. Lysates (L) and α-myc immunoprecipitates (myc-IP) from transfected cells were analysed by Western blot (WB) for α-Tubulin, BRI2, APP and APP-CTFs. Supernatants (SN) were analysed for sAPPα and sAPPβ. *Indicates an APP-CTF larger than β-CTF, which is routinely observed when BRI2 is over-expressed. This band, whose origin is unknown, also binds to BRI2.E. APP-Gal4, AID-Gal4, Gal4-depended promoter, luciferase reporter, cytoplasm (Cyt) and nucleus (Nc) are schematically indicated. Luciferase activity is expressed as % of the activity in cells transfected with APP-Gal4, luciferase reporter and empty vector (vec). Overall, our analysis shows that BRI2 residues comprised between amino acids 102 and 134 retained APP-binding properties and inhibitory effects on APP processing.
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).

Bottom Line: Processing of β-CTF by γ-secretase releases amyloid-β (Aβ), which is assumed to cause AD.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.

Show MeSH
Related in: MedlinePlus