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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

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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nutrients-08-00556-f005: 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.

Mentions: miR-126-3p has already been identified as a miRNA which targets ADAM9 and can be regulated by DNA methyltransferases (DNMTs). miR-339-5p possibly target the seed same region on 3′-UTR of BACE1. In our study, miR-126-3p was up-regulated in the deficiency group and was down-regulated in both the 120 μg/kg and 600 μg/kg groups compared to the control group (F[3,20] = 84.41, p < 0.05; Figure 5A). On the contrary, miR-339-5p was down-regulated in the deficiency group and was up-regulated in both 120 μg/kg and 600 μg/kg groups compared to the control group (F[3,20] = 138.1, p < 0.05; Figure 5B). No significant difference was observed between the 120 μg/kg and 600 μg/kg groups.


Effects of Folic Acid on Secretases Involved in A β Deposition in APP/PS1 Mice
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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Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC5037541&req=5

nutrients-08-00556-f005: 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.
Mentions: miR-126-3p has already been identified as a miRNA which targets ADAM9 and can be regulated by DNA methyltransferases (DNMTs). miR-339-5p possibly target the seed same region on 3′-UTR of BACE1. In our study, miR-126-3p was up-regulated in the deficiency group and was down-regulated in both the 120 μg/kg and 600 μg/kg groups compared to the control group (F[3,20] = 84.41, p < 0.05; Figure 5A). On the contrary, miR-339-5p was down-regulated in the deficiency group and was up-regulated in both 120 μg/kg and 600 μg/kg groups compared to the control group (F[3,20] = 138.1, p < 0.05; Figure 5B). No significant difference was observed between the 120 μg/kg and 600 μg/kg groups.

View Article: PubMed Central - PubMed

ABSTRACT

Alzheimer&rsquo;s disease (AD) is the most common type of dementia. Amyloid-&beta; protein (A&beta;) is identified as the core protein of neuritic plaques. A&beta; is generated by the sequential cleavage of the amyloid precursor protein (APP) via the APP cleaving enzyme (&alpha;-secretase, or &beta;-secretase) and &gamma;-secretase. Previous studies indicated that folate deficiency elevated A&beta; 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 A&beta; by regulating &alpha;-, &beta;-, and &gamma;-secretase. Herein, we demonstrated that folic acid reduced the deposition of A&beta;42 in APP/PS1 mice brain by decreasing the mRNA and protein expressions of &beta;-secretase [beta-site APP-cleaving enzyme 1 (BACE1)] and &gamma;-secretase complex catalytic component&mdash;presenilin 1 (PS1)&mdash;in APP/PS1 mice brain. Meanwhile, folic acid increased the levels of ADAM9 and ADAM10, which are important &alpha;-secretases in ADAM (a disintegrin and metalloprotease) family. However, folic acid has no impact on the protein expression of nicastrin (Nct), another component of &gamma;-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 A&beta; deposition may relate to making APP metabolism through non-amyloidogenic pathway by decreasing &beta;-secretase and increasing &alpha;-secretase. MicroRNA (miRNA) may involve in the regulation mechanism of folic acid on secretase expression.

No MeSH data available.


Related in: MedlinePlus