Longer Forms of Amyloid β Protein: Implications for the Mechanism of Intramembrane Cleavage by γ-Secretase

By Yue Qi-Takahara, M. Morishima-kawashima, Y. Tanimura, G. Dolios, N. Hirotani, Y. Horikoshi, F. Kametani, M. Maeda, T. Saido, Rong Wang and 1 more. Journal of Neuroscience, 2005

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γ-Cleavage of β-amyloid precursor protein (APP) in the middle of the cell membrane generates amyloid β protein (Aβ), and ϵ-cleavage, ∼10 residues downstream of the γ-cleavage site, releases the APP intracellular domain (AICD). A significant link between generation of Aβ and AICD and failure to detect AICD41-99 led us to hypothesize that ϵ-cleavage generates longer Aβs, which are then processed to Aβ40/42. Using newly developed gel systems and an N-end-specific monoclonal antibody, we have identified the longer Aβs (Aβ1-43, Aβ1-45, Aβ1-46, and Aβ1-48) within the cells and in brain tissues. The production of these longer Aβs as well as Aβ40/42 is presenilin dependent and is suppressed by {1S-benzyl-4R-[1S-carbamoyl-2-phenylethylcarbamoyl-1S-3-methylbutylcarbamoyl]-2R-hydroxy-5-phenylpentyl}carbamic acid tert-butyl ester, a transition state analog inhibitor for aspartyl protease. In contrast, N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester, a potent dipeptide γ-secretase inhibitor, builds up Aβ1-43 and Aβ1-46 intracellularly, which was also confirmed by mass spectrometry. Notably, suppression of Aβ40 appeared to lead to an increase in Aβ43, which in turn brings an increase in Aβ46, in a dose-dependent manner. We therefore propose an α-helical model in which longer Aβ species generated by ϵ-cleavage is cleaved at every three residues in its carboxyl portion.

Subfields: Molecular Biology, Oncology, Physiology

View Paper: https://www.semanticscholar.org/paper/eb917cb46409bc7144414b2f7e76e44d58d8d3e2

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Citations in the corpus

Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide (2007, background): “It seems that the remaining membrane-anchored fragment undergoes an intermediate scission ∼3 residues N-terminal to the e-cut at the so-called ζ-sit”
The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism (2009, background): “Once NEXT enters the active site of γ-secretase, its transmembrane domain is sequentially cleaved starting near the cytosolic plasma membrane leaflet (Qi-Takahara et al., 2005; Zhao et al., 2005).”
The amyloid hypothesis of Alzheimer's disease at 25 years (2016, background): “Subsequent studies have begun to illuminate how presenilin mediates intramembrane proteolysis (Qi-Takahara et al, 2005; Takami et al, 2009; Chavez-Gutierrez et al, 2012; Okochi et al, 2013; Fernandez et al, 2014): an initial endopeptidase cleavage of APP near the transmembrane/cytoplasmic interface…”
Trafficking and proteolytic processing of APP. (2012, background): “Cleavages at the so-called 1-, z-, and g-sites that are separated by approximately three amino acids are postulated (Fig. 3; Sastre et al. 2001; Weidemann et al. 2002; Qi-Takahara et al. 2005; Takami et al. 2009).”