Effects of γ-secretase cleavage-region mutations on APP processing and Aβ formation: interpretation with sequential cleavage and α-helical model

• Published in: Journal of neurochemistry 2008-11, Vol.107 (3), p.722-733
• Main Authors: Tan, Jianxin, Mao, Guozhang, Cui, Mei-Zhen, Kang, Shin-Chung, Lamb, Bruce, Wong, Boon-Seng, Sy, Man-Sun, Xu, Xuemin
• Format: Article
• Language: English
• Subjects: Alzheimer disease; Alzheimer’s disease; amyloid; amyloid precursor protein processing
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/j.1471-4159.2008.05643.x

Overwhelming evidence supports the amyloid hypothesis of Alzheimer's disease that stipulates that the relative level of the 42 amino acid β-amyloid peptide (Aβ₄₂) in relationship to Aβ₄₀ is critical to the pathogenesis of the disease. While it is clear that the multi-subunit gamma secretase is responsible for cleavage of the amyloid precursor protein (APP) into Aβ₄₂ and Aβ₄₀, the exact molecular mechanisms regulating the production of the various Aβ species remain elusive. To elucidate the underlying mechanisms, we replaced individual amino acid residues from positions 43 to 52 of Aβ with phenylalanine to examine the effects on the production of Aβ₄₀ and Aβ₄₂. All mutants, except for V50F, resulted in a decrease in total Aβ with a more prominent reduction in Aβ for residues 45, 48, and 51, following an every three residue repetition pattern. In addition, the mutations with the strongest reductions in total Aβ had the largest increases in the ratio of Aβ₄₂/Aβ₄₀. Curiously, the T43F, V44F, and T48F mutations caused a striking decrease in the accumulation of membrane bound Aβ₄₆, albeit by a different mechanism. Our data suggest that initial cleavage of APP at the ε site is crucial in the generation of Aβ. The implicated sequential cleavage and an α-helical model may lead to a better understanding of the γ-secretase-mediated APP processing and may also provide useful information for therapy and drug design aimed at altering Aβ production.