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. Author manuscript; available in PMC: 2021 Sep 1.
Published in final edited form as: Sci Transl Med. 2020 Aug 26;12(558):eaaz5677. doi: 10.1126/scitranslmed.aaz5677

Fig. 4. A second X chromosome confers resilience against AD-related cognitive impairments in XY (male) and XO (female) hAPP mice.

Fig. 4.

(A) Strategy to identify whether the sex chromosome effect depends on the X or Y chromosome. (B) Diagram of mouse cross used in this experiment. hAPP females (XX, hAPP) were crossed with XY* males that harbored an altered pseudoautosomal region on the Y chromosome, allowing abnormal crossover with the X chromosome during meiosis (33, 34). The cross resulted in offspring of eight genotypes, each of the sex chromosome genotypes, with or without hAPP. The equivalent number of X and Y chromosomes for each genotype is shown. (C) Experimental strategy: All mice underwent gonadectomy at 2.5 months of age followed by behavioral testing and survival studies between 3 and 6 months of age. (D to G) In the Kaplan-Meier survival curves in (D), all hAPP mice show (E) a main effect of X chromosome dose on mortality (2X, HR 0.2, P < 0.01, CI 0.12 to 0.75) and (F) no main effect of a Y chromosome on mortality (P = 0.53). (G) An interaction between X and Y chromosomes showed lower mortality in the presence of Y (or male gonadal type) when X dose = 1 (XY versus XO, HR 0.23, P < 0.01, CI 0.08 to 0.64). Analyses were by Cox proportional hazards for all groups (XY: n = 79, XX: n = 88; XO: n = 10; XXY: n = 15 mice). (H to J) Shown is testing of mice in the passive avoidance task, measured by latency to enter the dark chamber 1 and 7 days after a foot shock (age 3 to 5 months; n = 4 to 16 per group). (H) Abnormal loss of fear memory in hAPP mice of XY and XO genotypes is shown. Two-way repeated measures ANOVA: X dose effect, P < 0.05. The dashed line represents latency to enter the dark chamber during training, which did not differ among the groups. (I) Greater loss of fear memory in hAPP mice with 1X compared to 2X chromosomes is presented. (J) Percent loss of fear memory in hAPP mice with 1X compared to 2X chromosomes is shown. *P < 0.05 as indicated by bracket (Bonferroni-Holm). Data are presented as means ± SEM.