Intermittent fasting has been demonstrated to protect against Alzheimer's disease (AD), however, the mechanism is unclear. Histone acetylation and lipoprotein lipase (LPL) are involved in AD progression. Importantly, LPL has been documented to be regulated by histone deacetylases (HDACs) inhibitors (increase histone acetylation level) in adipocyte and mesenchymal stem cells, or by fasting in adipose and muscle tissues. In brain, however, whether histone acetylation or fasting regulates LPL expression is unknown. This study was designed to demonstrate intermittent fasting may protect against AD through increasing β-hydroxybutyrate, a HDACs inhibitor, to regulate LPL. We also investigated microRNA-29a expression associating with regulation of LPL and histone acetylation. The results showed LPL mRNA expression was increased and microRNA-29a expression was decreased in the cerebral cortex of AD model mice (APP/PS1), which were alleviated by intermittent fasting. No significant differences were found in the total expression of LPL protein (brain-derived and located in capillary endothelial cells from peripheral tissues) in the cerebral cortex of APP/PS1 mice. Further study indicated that LPL located in capillary endothelial cells was decreased in the cerebral cortex of APP/PS1 mice, which was alleviated by intermittent fasting. LPL and microRNA-29a expression were separately increased and down-regulated in 2 μM Aβ25−35-exposed SH-SY5Y cells, but respectively decreased and up-regulated in 10 μM Aβ25−35-exposed cells, which were all reversed by β-hydroxybutyrate. The increase of HDAC2/3 expression and the decrease of acetylated H3K9 and H4K12 levels were alleviated in APP/PS1 mice by intermittent fasting treatment, as well in 2 or 10 μM Aβ25−35-exposed cells by β-hydroxybutyrate treatment. These findings above suggested the results from APP/PS1 mice were consistent with those from cells treated with 2 μM Aβ25−35. Interestingly, LPL expression was reduced (0.2-folds) and microRNA-29a expression was up-regulated (1.7-folds) in HDAC2-silenced cells, but respectively increased (1.3-folds) and down-regulated (0.8-folds) in HDAC3-silenced cells. Furthermore, LPL expression was decreased in cells treated with microRNA-29a mimic and increased with inhibitor treatment. In conclusion, intermittent fasting inhibits the increase of brain-derived LPL expression in APP/PS1 mice partly through β-hydroxybutyrate-mediated down-regulation of microRNA-29a expression. HDAC2/3 may be implicated in the effect of β-hydroxybutyrate on microRNA-29a expression.

The impairment of amyloid-β (Aβ) clearance in the brain plays a causative role in Alzheimer’s disease (AD). Polarity distribution of aquaporin-4 (AQP4) is important to remove Aβ from brain. AQP4 polarity can be influenced by the ratio of two AQP4 isoforms M1 and M23 (AQP4-M1/M23), however, it is unknown whether the ratio of AQP4-M1/M23 changes in AD. Histone deacetylase 3 has been reported to be significantly increased in AD brain. Moreover, evidence indicated that microRNA-130a (miR-130a) possibly mediates the regulation of histone deacetylase 3 on AQP4-M1/M23 ratio by repressing the transcriptional activity of AQP4-M1 in AD. This study aimed to investigate whether intermittent fasting (IF), increasing the level of an endogenous histone deacetylases inhibitor β-hydroxybutyrate, restores AQP4 polarity via miR-130a mediated reduction of AQP4-M1/M23 ratio in protection against AD. The results showed that IF ameliorated cognitive dysfunction, prevented brain from Aβ deposition, and restored the AQP4 polarity in a mouse model of AD (APP/PS1 double-transgenic mice). Additionally, IF down-regulated the expression of AQP4-M1 and histone deacetylase 3, reduced AQP4-M1/M23 ratio, and increased miR-130a expression in the cerebral cortex of APP/PS1 mice. In vitro, β-hydroxybutyrate was found to down-regulate the expression of AQP4-M1 and histone deacetylase 3, reduce AQP4-M1/M23 ratio, and increase AQP4-M23 and miR-130a expression in 2 μM Aβ-treated U251 cells. Interestingly, on the contrary to the result observed in 2 μM Aβ-treated cells, AQP4 expression was obviously decreased in cells exposed to 10 μM Aβ. miR-130a mimic decreased the expression of AQP4-M1 and the ratio of AQP4-M1/M23, as well as silencing histone deacetylase 3 caused the up-regulation of AQP4 and miR-130a, and the reduction of AQP4-M1/M23 ratio in U251 cells. In conclusion, IF exhibits beneficial effects against AD. The mechanism may be associated with recovery of AQP4 polarity, resulting from the reduction of AQP4-M1/M23 ratio. Furthermore, β-hydroxybutyrate may partly mediate the effect of IF on the reduction of AQP4-M1/M23 ratio in AD, in which miR-130a and histone deacetylase 3 may be implicated.

Alzheimer's disease is an irreversible, progressive neurodegenerative disorder. The accumulation of Aβ in the brain is thought to play a causative role in the development of cognitive dysfunction in Alzheimer's disease. The p75 neurotrophin receptor is of great importance to protect against the Aβ burden and its expression is regulated by histone acetylation. This study investigated whether the phytochemical sulforaphane, a pan-histone deacetylase inhibitor, up-regulates the p75 neurotrophin receptor expression via affecting histone acetylation in protection against Alzheimer's disease. We found that sulforaphane ameliorated behavioral cognitive impairments and attenuated brain Aβ burden in Alzheimer's disease model mice. Additionally, sulforaphane reduced the expression of histone deacetylase1, 2, and 3, up-regulated p75 neurotrophin receptor, and increased levels of acetylated histone 3 lysine 9 and acetylated histone 4 lysine 12 in the cerebral cortex of Alzheimer's disease model mice as well as in Aβ-exposed SH-SY5Y cells. Furthermore, silencing of histone deacetylase1 and 3, but not histone deacetylase2, gene expression with small interfering RNA caused up-regulation of p75 neurotrophin receptor in SH-SY5Y cells. In conclusion, this study demonstrates that sulforaphane can ameliorate neurobehavioral deficits and reduce the Aβ burden in Alzheimer's disease model mice, and the mechanism underlying these effects may be associated with up-regulation of p75 neurotrophin receptor mediated, apparently at least in part, via reducing the expression of histone deacetylase1 and 3.

Pulmonary artery hypertension (PAH) is a severe disease characterized with progressive increase of pulmonary vascular resistance that finally causes right ventricular failure and premature death. Cigarette smoke (CS) is a major factor of Chronic Obstructive Pulmonary Disease (COPD) that can lead to PAH. However, the mechanism of CS-induced PAH is poorly understood. Mounting evidence supports that pulmonary vascular remodeling play an important role in the development of PAH. PDGF signaling has been demonstrated to be a major mediator of vascular remodeling implicated in PAH. However, the association of PDGF signaling with CS-induced PAH has not been documented. In this study, we investigated CS-induced PAH in rats and the expression of platelet derived growth factor (PDGF) and PDGF receptor (PDGFR) in pulmonary artery. Forty male rats were randomly divided into control group and three experimental groups that were exposed to CS for 1, 2, and 3 months, respectively. CS significantly increased right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI). Histology staining demonstrated that CS significantly increased the thickness of pulmonary artery wall and collagen deposition. The expression of PDGF isoform B (PDGF-B) and PDGF receptor beta (PDGFRβ) were significantly increased at both protein and mRNA levels in pulmonary artery of rats with CS exposure. Furthermore, Cigarette smoke extract (CSE) significantly increased rat pulmonary artery smooth muscle cell (PASMC) proliferation, which was inhibited by PDGFR inhibitor Imatinib. Thus, our data suggest PDGF signaling is implicated in CS-induced PAH.

Accumulating evidence suggests a direct role for cigarette smoke in pulmonary vascular remodeling, which contributes to the development of pulmonary hypertension. However, the molecular mechanisms underlying this process remain poorly understood. Platelet-derived growth factor (PDGF) is a potential mitogen and chemoattractant implicated in several biological processes, including cell survival, proliferation, and migration. In this study, we investigated the effect of cigarette smoke extract (CSE) on cell proliferation of rat pulmonary artery smooth muscle cells (rPASMCs). We found that stimulation of rPASMCs with CSE significantly increased cell proliferation and promoted cell cycle progression from G1 phase to the S and G2 phases. CSE treatment also significantly upregulated the mRNA and protein levels of PDGFB and PDGFRβ. Our study also revealed that Rottlerin, an inhibitor of PKCδ signaling, prevented CSE-induced cell proliferation, attenuated the increase of S and G2 phase populations induced by CSE treatment, and downregulated PDGFB and PDGFRβ mRNA and protein levels in rPASMCs exposed to CSE. Collectively, our data demonstrated that CSE-induced cell proliferation of rPASMCs involved upregulation of the PKCδ-PDGFB pathway.