Effects of Folic Acid on Secretases Involved in Aβ Deposition in APP/PS1 Mice.
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.
Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China. tiantiantmu@126.com.
Tian
T
Tian
Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China. baidongtmu@126.com.
Dong
D
Bai
Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China. liwen828@163.com.
Wen
W
Li
Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China. huangguowei@tmu.edu.cn.
Guo-Wei
GW
Huang
Department of Nutrition and Food Science, School of Public Health, Tianjin Medical University, Tianjin 300070, China. liuhuan@tmu.edu.cn.
Huan
H
Liu
D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism; D000072197:ADAM10 Protein / Q000235:genetics / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy / Q000235:genetics; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics / Q000378:metabolism*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004195:Disease Models, Animal; D005492:Folic Acid / Q000097:blood / Q000494:pharmacology*; D005494:Folic Acid Deficiency / Q000188:drug therapy; D005786:Gene Expression Regulation; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D016229:Amyloid beta-Peptides; C000614039:MIRN-339 microRNA, mouse; C545201:MIRN126 microRNA, mouse; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D035683:MicroRNAs; D053764:Presenilin-1; D012333:RNA, Messenger; C413604:nicastrin protein; C580804:presenilin 1, mouse; D005492:Folic Acid; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509282:Bace1 protein, mouse; D051722:ADAM Proteins; C498316:Adam9 protein, mouse; D000072197:ADAM10 Protein; C491234:Adam10 protein, mouse
Alzheimer’s disease; Aβ generation; folic acid; microRNAs; secretase