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
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Mentions: We tested if peptides spanning this domain duplicated BRI2's function. Two overlapping peptides N3 and N8 strongly reduced β-cleavage and moderately decreased α-processing of APP (Fig 2A). Mutagenesis of N3 showed that replacing any of amino acids 3–10 with Alanine reduced the inhibitory activity of N3 on β-cleavage of APP, showing the functional importance of these residues. However, replacing either the first or second residue (N3-1A/N3-2A) actually resulted in a stronger inhibitor of APP processing by β-secretase (Fig 2B). Notably, α-cleavage of APP is inhibited by N3, unaffected by N3-2A and, probably, increased by N3-1A. It is possible that these three peptides bind APP differently thereby reducing (N3), unaffecting (N3-2A) or increasing (N3-1A) access of α-secretase to the APP-docking/cleavage site. However, the mechanism underlying this potentially useful difference remains to be investigated.
Affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA.