Marginal Vitamin A Deficiency Exacerbates Memory Deficits Following Aβ1-42 Injection in Rats

Jiaying Zeng, Tingyu Li, Ming Gong, Wei Jiang, Ting Yang, Jie Chen, Youxue Liu, Li Chen, Jiaying Zeng, Tingyu Li, Ming Gong, Wei Jiang, Ting Yang, Jie Chen, Youxue Liu, Li Chen

Abstract

Background: Although clinical vitamin A deficiency (VAD), which is a public health problem developing throughout the world, has been well controlled, marginal vitamin A deficiency (MVAD) is far more prevalent, especially among pregnant women and preschool children in China. Increasing evidence suggests that VAD is involved in the pathogenesis of Alzheimer's disease (AD). However, whether MVAD, beginning early in life, increases the risk of developing AD has yet to be determined.

Objective: The goal of this study was to investigate the long-term effects of MVAD on the pathogenesis of AD in rats.

Method: An MVAD model was generated from maternal MVAD rats and maintained with an MVAD diet after weaning. The males were bilaterally injected with aggregated amyloid β (Aβ)1-42 into the CA3 area of the hippocampus, and the AD-associated cognitive and neuropathological phenotypes were examined.

Results: We found that MVAD feeding significantly aggravated Aβ1-42-induced learning and memory deficits in the Morris water maze test. MVAD did not induce the mRNA expression of retinoic acid receptors (RARs), a disintegrin and metalloprotease 10 (ADAM10) or insulin-degrading enzyme (IDE) in Aβ1-42-injected rats. Moreover, RARα and RARγ mRNA were positively correlated with ADAM10 mRNA, whereas RARβ mRNA was positively correlated with IDE mRNA.

Conclusion: Our study suggests that MVAD beginning from the embryonic period perturbs the ADassociated genes, resulting in an enhanced risk of developing AD.

Keywords: ADAM10; Alzheimer’s disease; IDE; amyloid β; marginal vitamin A deficiency; memory deficits; retinoic acid receptors; vitamin A.

Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Figures

Fig. (1)
Fig. (1)
MVAD reduces serum retinol levels during all life stages and at post-injection of Aβ1-42 in rats. (A) At preconception, the serum retinol levels of the maternal rats in the MVAD group were significantly lower than those in the control group. n=6, *P<0.05 by Student’s t test. (B) At 24 hours, 4 weeks, 8 weeks and 12 weeks postnatal, the serum retinol levels of the pups in the MVAD group were significantly reduced compared with those of the control group. n=5 or 6, *P<0.05 and **P<0.01 at the same age by Student’s t test. (C) After vehicle PBS, 1/2Aβ or Aβ injection, the serum retinol levels of the pups in the MVAD group at 18 weeks, 22 weeks and 26 weeks postnatal were significantly reduced compared with those of the control group. n=5 or 6, ▽significant effects (P<0.05 in all cases), *P<0.05 at the same age by two-way ANOVA. (D) At 80 days post-injection of vehicle PBS, 1/2Aβ or Aβ, the rats were sacrificed immediately after behavioral tests, and the retinol levels in the serum were measured. The serum retinol levels of the MVAD pups after vehicle PBS, 1/2Aβ or Aβ injection were significantly lower than those of the control group. Control group: nvehicle=8, n1/2Aβ=12, and nAβ=15; MVAD group: nvehicle=8, n1/2Aβ=12, and nAβ=10; ▽significant effects (P<0.05 in all cases), ***P<0.001 by two-way ANOVA with Bonferroni post hoc tests. (E) The serum retinol levels in the combined groups of MVAD pups were significantly decreased compared with those in the combined groups of control pups. nControl=22, nMVAD=17, **P<0.01 by Student’s t test. All values indicate means ± SEMs. 1/2Aβ, half dose of aggregated Aβ1-42; Aβ, full dose of aggregated Aβ1-42; MVAD, marginal vitamin A deficiency.
Fig. (2)
Fig. (2)
MVAD with Aβ1-42 injection exacerbates memory deficits in rats. Both the MVAD and control rats were subjected to the Morris water maze test at 18 weeks of age and at 30 and 80 days after vehicle PBS, 1/2Aβ or Aβ injection. (A) At 18 weeks of age, prior to Aβ1-42 injectionat baseline, the MVAD pups showed similar escape latencies relative to those of the control group. nControl=21, nMVAD=21, P>0.05 by two-way ANOVA with repeated measures. (B) At 30 days post-injection of vehicle PBS (left) or 1/2Aβ (middle), no significant differences in escape latencies were observed between the MVAD and control rats; however, the MVAD rats showed a prolonged escape latency compared with the control rats at 30 days post-injection of Aβ (right). (C) At 80 days post-injection of vehicle PBS (left) or 1/2Aβ (middle), the MVAD rats showed a longer escape latency than the control rats, whereas similar escape latencies were found between the MVAD and control rats after the Aβ injection (right). Control group: nvehicle=5, n1/2Aβ=6, and nAβ=10; MVAD group, nvehicle=6, n1/2Aβ=9, and nAβ=6; *P<0.05 and **P<0.01 by two-way ANOVA with repeated measures. All values are expressed as the means ± SEMs. 1/2Aβ, half dose of aggregated Aβ1-42; Aβ, full dose of aggregated Aβ1-42; MVAD, marginal vitamin A deficiency.
Fig. (3)
Fig. (3)
MVAD suppresses the Aβ-induced mRNA levels of RARα/β/γ, ADAM10 and IDE in the hippocampus of rats. The rats were sacrificed immediately after behavioral tests at 80 days post-injection of vehicle PBS, 1/2Aβ or Aβ, and the mRNA levels of RARα (A), RARβ (D), RARγ (B), ADAM10 (C) and IDE (E) were detected in the hippocampus of both the MVAD and control groups. (A-C) Aβ injection dramatically induced RARα (A), RARγ (B) and ADAM10 (C) mRNA levels in the control group, whereas the increased levels of these mRNAs induced by Aβ were not significant in the MVAD group. (D and E) RARβ (D) and IDE (E) mRNA levels were increased by 1/2Aβ and decreased by Aβ in control rats; however, no significant difference was observed in these mRNA levels among the vehicle PBS, 1/2Aβ and Aβ groups with regard to the MVAD rats. Control group: nvehicle=8, n1/2Aβ=8, and nAβ=10; MVAD group: nvehicle=8, n1/2Aβ=9, and nAβ=8; ▽significant effects (P<0.05 in all cases), *P<0.05, **P<0.01 and ***P<0.001 by two-way ANOVA with Bonferroni post hoc tests. Values indicate means ± SEMs. 1/2Aβ, half dose of aggregated Aβ1-42; Aβ, full dose of aggregatedAβ1-42; ADAM10, a disintegrin and metalloprotease 10; IDE, insulin degrading enzyme; RARα, retinoic acid receptor α; RARβ, retinoic acid receptor β; RARγ, retinoic acid receptor γ.
Fig. (4)
Fig. (4)
Pearson’s correlations between ADAM10/IDE mRNA and RARα/β/γ mRNA in the hippocampus of rats. Both the MVAD and control rats were sacrificed immediately after behavioral tests at 80 days post-injection of vehicle PBS, a half dose (1/2Aβ) or full dose (Aβ) of aggregated Aβ1-42, and the mRNA levels of RARα, RARβ, RARγ, ADAM10 and IDE were detected in their hippocampus. n=39 total: nvehicle=4, n1/2Aβ=8, and nAβ=10 in Control group; nvehicle=3, n1/2Aβ=9, and nAβ=5 in MVAD group. Pearson’s correlation analysis was performed. (A and B) ADAM10 mRNA levels were positively correlated with both RARα (A) and RARγ (B) mRNA levels. rRARα*ADAM10=0.9946, rRARγ*ADAM10=0.9964, P<0.0001. (C) RARα mRNA levels were positively correlated with RARγ mRNA levels. rRARα*RARγ=0.9951, P<0.0001. (D) A positive correlation was found between IDE and RARβ mRNA levels. rRARβ*IDE=0.6780, P<0.0001. (E and F) IDE mRNA levels were negatively correlated with both RARα (E) and RARγ (F) mRNA levels. rRARα*IDE=-0.5118, rRARγ*IDE=-0.5152, P<0.001. ADAM10, a disintegrin and metalloprotease 10; IDE, insulin degrading enzyme; RARα, retinoic acid receptor α; RARβ, retinoic acid receptor β; RARγ, retinoic acid receptor γ.

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