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. 2016 Sep 9;8(9):556.
doi: 10.3390/nu8090556.

Effects of Folic Acid on Secretases Involved in Aβ Deposition in APP/PS1 Mice

Tian Tian  1 , Dong Bai  2 , Wen Li  3 , Guo-Wei Huang  4 , Huan Liu  5
Affiliations

Effects of Folic Acid on Secretases Involved in Aβ Deposition in APP/PS1 Mice

Tian Tian et al. Nutrients. .

Abstract

Alzheimer's disease (AD) is the most common type of dementia. Amyloid-β protein (Aβ) is identified as the core protein of neuritic plaques. Aβ is generated by the sequential cleavage of the amyloid precursor protein (APP) via the APP cleaving enzyme (α-secretase, or β-secretase) and γ-secretase. Previous studies indicated that folate deficiency elevated Aβ deposition in APP/PS1 mice, and this rise was prevented by folic acid. In the present study, we aimed to investigate whether folic acid could influence the generation of Aβ by regulating α-, β-, and γ-secretase. Herein, we demonstrated that folic acid reduced the deposition of Aβ42 in APP/PS1 mice brain by decreasing the mRNA and protein expressions of β-secretase [beta-site APP-cleaving enzyme 1 (BACE1)] and γ-secretase complex catalytic component-presenilin 1 (PS1)-in APP/PS1 mice brain. Meanwhile, folic acid increased the levels of ADAM9 and ADAM10, which are important α-secretases in ADAM (a disintegrin and metalloprotease) family. However, folic acid has no impact on the protein expression of nicastrin (Nct), another component of γ-secretase complex. Moreover, folic acid regulated the expression of miR-126-3p and miR-339-5p, which target ADAM9 and BACE1, respectively. Taken together, the effect of folic acid on Aβ deposition may relate to making APP metabolism through non-amyloidogenic pathway by decreasing β-secretase and increasing α-secretase. MicroRNA (miRNA) may involve in the regulation mechanism of folic acid on secretase expression.

Keywords: Alzheimer’s disease; Aβ generation; folic acid; microRNAs; secretase.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Folate reduced hippocampal amyloid plaque loads in APP/PS1 (amyloid precursor protein)/(presenilin 1) mice. With bam-10 immunohistochemical staining following the administration, compared with the control group, the deposition of Aβ was significantly decreased in both 120 μg/kg and 600 μg/kg groups (A,B); scale bar = 100 μm. Enzyme-linked immuno sorbent assay (ELISA) was used to measure Aβ levels in brain tissues. Compared with the control group, folic acid administration decreased Aβ42 deposition, but not Aβ40 (C,D). The Aβ42 level was further decreased in the 600 μg/kg group compared to the 120 μg/kg group. After eight weeks, the folate deficiency diet reduced serum folate. Folic acid administration increased serum folate compared with the control group (E). The data were expressed as means ± SD values, n = 6 animals/group. a: p < 0.05 versus the Control group; b: p < 0.05 versus the 120 μg/kg group.
Figure 2
Figure 2
Folate stimulated ADAM9 and ADAM10 expression in APP/PS1 mice. The mRNA/protein levels of ADAM9 and ADAM10 in the brains of APP/PS1 mice were detected by qRT-PCR/Western blot analysis. Representative immunoblotting images of ADAM9 and ADAM10 are shown. Quantitative analysis revealed that the 120 μg/kg folic acid treatment led to up-regulation of ADAM9 (A–C) and ADAM10 (D–F). Folate deficiency led to down-regulation of ADAM9 and ADAM10. The 600 μg/kg folic acid treatment only up-regulated ADAM9, but did not change ADAM10 level; total α-secretase activity was reduced in the deficiency group and was increased in both 120 μg/kg and 600 μg/kg groups (G). The data were expressed as means ± SD values, n = 6 animals/group. a: p < 0.05 versus the control group.
Figure 3
Figure 3
Folate inhibited BACE1 expression in APP/PS1 mice. BACE1 mRNAs and proteins in the brains of APP/PS1 mice were evaluated by qRT-PCR and Western blot analysis. The β-secretase activity was determined by ELISA. Representative bands and quantitative analysis revealed that folic acid treatment led to down-regulation of mRNA (A) and protein (B,C) expression of BACE1 and its activity (D). Folate deficiency led to up-regulation of BACE1 expression and activity. The data were expressed as means ± SD values, n = 6 animals/group. a: p < 0.05 versus the control group.
Figure 3
Figure 3
Folate inhibited BACE1 expression in APP/PS1 mice. BACE1 mRNAs and proteins in the brains of APP/PS1 mice were evaluated by qRT-PCR and Western blot analysis. The β-secretase activity was determined by ELISA. Representative bands and quantitative analysis revealed that folic acid treatment led to down-regulation of mRNA (A) and protein (B,C) expression of BACE1 and its activity (D). Folate deficiency led to up-regulation of BACE1 expression and activity. The data were expressed as means ± SD values, n = 6 animals/group. a: p < 0.05 versus the control group.
Figure 4
Figure 4
Folate inhibited PS1 expression, but not NCT (nicastrin), in APP/PS1 mice. PS1 mRNAs and proteins in the brains of APP/PS1 mice were determined by qRT-PCR and Western blot analysis. Folic acid treatment inhibited PS1 mRNA and protein expression. Folate deficiency led to up-regulation of PS1. No difference in PS1 expression was showed between 120 μg/kg and 600 μg/kg groups (A–C); However, Western blot analysis revealed that folic acid did not change NCT protein levels (D,E). The data were expressed as means ± SD values, n = 6 animals/group. a: p < 0.05 versus the Control group.
Figure 5
Figure 5
Folate regulated miR-126-3p and miR-339-5p expression in APP/PS1 mice brains. Two miRNA expression levels in the brains of APP/PS1 mice were confirmed by qRT-PCR. (A) miR-126-3p was expressed at lower level in both 120 μg/kg and 600 μg/kg groups, it was expressed at higher levels in the deficiency group compared to the control group; (B) miR-339-5p was expressed at higher level in both the 120 μg/kg and 600 μg/kg groups, it was expressed at lower level in the deficiency group compared to the control group; and (C) predicted miR-126-3p and miR-339-5p target sites in the 3′-UTR of ADAM9 or BACE1. Schematic representation of base pair matching between miRNAs and the 3-UTR of ADAM 9 and BACE1. The seed region of the miRNAs is indicated. The data were expressed as means ± SD values, n = 6 animals/group. a: p < 0.05 versus the control group.
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