ABSTRACT
Fructo-oligosaccharides (FOS), an important prebiotic, have been proved to have a beneficial effect on Alzheimer's disease (AD); however, the specific mechanism remains to be confirmed. Senile plaques are one of the main neuropathological features of AD and the core of senile plaques mainly consists of extracellular beta-amyloid (Aß). Reducing Aß accumulation in the brain is an important therapeutic strategy for AD. Neprilysin (NEP), a major Aß-degrading enzyme, has been found to be decreased in the AD brain. Evidence has shown that the expression of NEP is associated with histone acetylation levels. Histone deacetylases (HDACs) are the key enzymes in the modulation of histone acetylation modification. Importantly, several metabolites of FOS have been demonstrated to be pan-HDAC inhibitors. In this study, we demonstrate that FOS ameliorate cognitive impairment and alleviate Aß accumulation in the brain of AD model mice. The regulation of HDAC2 on NEP plays an important role in the anti-AD effect of FOS.
Subject(s)
Alzheimer Disease/drug therapy , Neprilysin/pharmacology , Oligosaccharides/pharmacology , Amyloid beta-Peptides/metabolism , Animals , Body Weight , Brain/metabolism , Disease Models, Animal , Female , Histone Deacetylase 2/genetics , Histone Deacetylase 2/metabolism , Humans , Male , Mice , Mice, Transgenic , Neprilysin/genetics , Neprilysin/metabolism , Oligosaccharides/metabolism , Up-RegulationABSTRACT
Progressive accumulation of amyloid-ß (Aß) plaques in the brain is a characteristic pathological change in Alzheimer's disease (AD). We previously found the expression of lipoprotein lipase (LPL) was increased in SH-SY5Y cells exposed to low-dose Aß and decreased in cells with high-dose Aß exposure, but the molecular mechanism is still unclear. Based on previous studies, the opposite regulation of histone deacetylase2 (HDAC2) and HDAC3 on LPL expression probably explain the above molecular mechanism, in which microRNA-29a and peroxisome proliferator-activated receptor γ (PPARγ) may be involved. This study further revealed the mechanism of HDAC2 and HDAC3 on conversely regulating LPL expression. The results showed that HDAC2 down-regulated microRNA-29a by decreasing histone acetylation (Ace-H3K9) level in its promoter region, subsequently increasing LPL expression directly or through PPARγ/LPL pathway; HDAC3 decreased LPL expression through inhibiting Ace-H3K9 levels in LPL and PPARγ promoter regions and up-regulating microRNA-29a. This study also found that with increasing concentrations of Aß in cells, HDAC2 and HDAC3 expression were gradually increased, and Ace-H3K9 levels in LPL and PPARγ promoter region regulated by HDAC3 were decreased correspondingly, while Ace-H3K9 levels in microRNA-29a promoter region modulated by HDAC2 were not decreased gradually but presented a U-shaped trend. These may lead to the results that a U-shaped alteration in microRNA-29a expression, subsequently leading to an inverse U-shaped alteration in PPARγ or LPL expression. In conclusion, HDAC2 and HDAC3 at least partly mediate LPL expression variations in different concentrations of Aß exposed SH-SY5Y cells, in which microRNA-29a and PPARγ are involved, and the histone acetylation level in microRNA-29a promoter region plays a key role.
