Fig. 9: Enhanced δ secretase activity in the SORCS2-deficient mouse brain.
a Schematic presentation of APP processing pathways and the resulting cleavage products. (1) non-amyloidogenic processing initiated by α secretase, (2) amyloidogenic processing by β and γ secretases, (3) alternative amyloidogenic processing by sequential cleavage from δ, β, and γ secretases. CTFδ and sAPPδ are cleavage products unique to δ secretase action. b Levels of soluble (s)APPα and sAPPβ in cortex (cx) and hippocampus (hip) of 40 weeks old female PDAPP/WT and PDAPP/KO animals as determined by ELISA. Data are given as mean ± SEM from n = 10 (cx, WT), n = 11 (hip, WT), n = 12 (cx, sAPPβ KO), n = 14 (hip, sAPPα KO), n = 35 (cx and hip, sAPPα KO) animals per group (two-sided unpaired Mann-Whitney U test for cx, two-sided unpaired Student’s t-test for hip). Representative Western blot (c), and densitometric scanning of replicate blots (d), quantifying levels of APP, CTFβ, sAPP species, as well as full-length and cleaved forms of δ secretase in the cx lysates of 40 weeks old PDAPP/WT and PDAPP/KO females. Immunoreactive bands representing mature and immature forms of APP as well as APPα/β and sAPPδ are marked. Data are expressed as relative to WT (set to 100%) and given as mean ± SEM from n = 6 (WT CTFβ, APP mature, APP immature; KO CTFβ), n = 7 (KO APP mature, APP immature; WT and KO sAPPα/β, WT and KO sAPPδ), n = 14 (δ secretase WT and KO) animals per group (two-sided unpaired Mann-Whitney U test for APP, CTFβ, and sAPP; two-sided unpaired Student’s t-test for δ secretase). e, f Experiment as in (c, d), but testing hip extracts of 40 weeks old PDAPP females. Data are expressed as relative to WT (set to 100%) and given as mean ± SEM from n = 6 (WT CTFβ, APP mature, APP immature, sAPPδ), n = 7 (all other groups) animals per group (two-sided unpaired Student’s t-test for sAPPδ and two-sided unpaired Mann-Whitney U test for other comparisons). g Peptide sequence of proteolytic fragment produced from recombinant APP, following incubation with PDAPP/KO brain extracts, verifies APP cleavage after N58543. h Levels of truncated tau (tauN368) and ratio of tauN368/tautotal, in cortex and hippocampus of 40 weeks old female mice as determined by ELISA. Data are given as mean ± SEM from n = 4 (KO, hip tau and hip tauN368/tautotal), n = 10 (all other groups) animals per group (two-sided unpaired Mann-Whitney U test). i Activity of δ secretase in cx and hip lysates of 40 weeks old PDAPP/KO and PDAPP/WT females, as documented by activity assays using a fluorogenic substrate (see methods for details). Data are given as mean ± SEM from n = 6 (WT), n = 7 (KO) animals per group (repeated measures two-way ANOVA to test significance for genotypes). p-values for all statistically significant differences are indicated on the graphs. Source data are provided in the Source Data file.
