Figure 1.

Genetic construct, phenotypic hallmarks, and Aβ/pE3–Aβ levels in TBA2.1 and TBA2.1/2.2 mice. In the construct of TBA2.1 and TBA2.2, Aβ(Q3–42) is fused to pre-pro-TRH for product liberation within the secretory pathway. After prohormone convertase cleavage, the N-terminally truncated Aβ peptide is transported into the trans-Golgi and secretory vesicles, in which the N terminus is available to QC for cyclization (A). Transgene expression levels (B) in both lines are gene-dosage dependent, with TBA2.2 expressing ∼80% of transgene compared with HOM TBA2.1 and double HET TBA2.1/TBA2.2 animals expressing ∼90% of transgene. HOM TBA2.1 mice aged 3 months are severely affected in hanging behavior and righting reflex paradigms (C). Both HOM TBA2.1 (D) and double HET TBA2.1/TBA2.2 (D, inset) mice show significantly slower body weight gain over time compared with WT (interaction, p < 0.001); data were analyzed by two-way repeated-measures ANOVA and represent means ± SEM; n ≥ 9 animals per group. Quantification of protein levels by ELISA (E) reveals differential kinetics of Aβ and pE3–Aβ in TBA2.1, with pE3–Aβ peaking at 4 weeks and decreasing to levels of ∼30 ng/g brain at the age of 7 months, whereas Aβ levels increase continuously over time. Significant loss of pE3–Aβ is seen after genetic deletion of QC activity (F, left), whereas a similar deletion of isoQC enzymatic activity has no effect on pE3–Aβ levels (F, right); values expressed as percentage of TBA2.1 HOM/QC-ko WT or isoQC-ko WT, respectively; *p = 0.0101; data were analyzed by one-way ANOVA followed by Newman–Keuls post hoc test and represent means ± SEM; n ≥ 6 animals per group.