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. 2021 Apr 23;12:2421. doi: 10.1038/s41467-021-22624-z

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© The Author(s) 2021

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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Fig. 1 — a Strategy for production of hAβ-KI mice. b Schematic representation of humanized Aβ in hAβ-KI mice. c Breeding strategy to produce App^hAβ-KI/+; UBC-Cre-ERT2 hemizygous mice (green box = exon 14, red triangle = loxP sequence, yellow and blue box = UBC-Cre-ERT2). d Western-blot analysis showing that Tamoxifen treatment reduces APP expression (22C11 antibody) in brains of App^hAβ-KI/+; UBC-Cre-ERT2 hemizygous mice compared to PBS-treated animals. The hAβ specific product (6E10 antibody) expressed by the floxed hAβ-KI allele is depleted following Tamoxifen treatment. e qPCR analysis of App expression shows decrease in Tamoxifen-treated App^hAβ-KI/+; UBC-Cre-ERT2 hemizygous mice (green) versus PBS-treated mice (pink) (PBS n = 4 and tamoxifen n = 3; unpaired, two-tailed t-test, *p = 0.035). f No difference in App expression in CNS of WT and hAβ-KI homozygous mice at 2 and 22 month of age (transcript level normalized to 2 mo-WT animals; n = 6 in hAβ-KI 22 mo, n = 7 in WT 2 mo and n = 8 in WT 22 mo and hAβ-KI 2 mo) (blue = WT 2 mo, light-blue = WT 22 mo, green = hAβ-KI 2 mo and light-green = hAβ-KI 22 mo). g–i Immunoblot analysis of APP recognized by C-terminal APP (CT-20 antibody) (dark-gray) and 6E10 (hAβ-specific) (black) antibody in hippocampal homogenates of hAβ-KI from 2 to 22 months of age (n = 4/genotype/age) shows no differences in APP expression. Representative immunoblot analysis of APP holoprotein using APP-CT20 (detect both mouse and human APP) and 6E10 (recognize only human Aβ) in hippocampal (j), cortical (k) and cerebellar (l) homogenates of WT (blue), hAβ-KI (het) (yellow) and hAβ-KI (homo) (green) (n = 8/genotype). m Quantification of j, k and l shows no difference in APP steady-state level between groups and brain areas. n Quantification of j, k and l by 6E10 antibody shows dose-dependent expression of APP in hAβ-KI homozygous mice in the hippocampus (One-way ANOVA, F_2,21 = 124.0, Tukey’s post hoc test, ****p < 0.0001), cortex (One-way ANOVA, F_2,21 = 53.43, Tukey’s post hoc test, ****p < 0.0001) and cerebellum (One-way ANOVA, F_2,21 = 26.83, Tukey’s post hoc test, **p < 0.01 and ****p < 0.0001) compared to WT mice and hAβ-KI heterozygous mice. Data are presented as mean values ± SEM.