As a common sleep disorder disease, OSAS is characterized by sudden pauses of breathing during sleep (Li et al., 2018). Resulting from repeated obstructions of the pharyngeal airway, CIH is a cardinal feature of OSAS, which induces degrease of cognitive performance. Our research found that the ability of social memory and spatial memory was damaged in C57BL/6 mouse after CIH treatment. Further study discovered that the hippocampal neurocytes of those mice were severely injured. It is thought that hippocampus is crucial for encoding new memory (Suh et al., 2011). Therefore, the injury of hippocampus by CIH finally gave rise to behavioral deficits. Until now, researchers consider that the mechanism of those neuro damage is related to the inflammation and the oxidative stress. In response to CIH, immune receptors initiate chronic neuroinflammation, such as TLR 2 and TLR 4. Those receptors upregulate the expression of inflammation cytokines, including IL-1β, IL-6 and TNF-α via TLR 2/TLR 4-MyD88 signal pathway (Li et al., 2020; Lu et al., 2019). In this process, microRNA (Ren et al., 2019), histone modifications and DNA methylation (Kiernan et al., 2016) have also been involved in. Besides, hypoxia-reoxygenation injures cell organs by promoting ROS generation. Targeting mitochondrial protein OPA1, ROS induces mitochondrial fission and disturbs mitochondrial membrane potential (Rovira-Llopis et al., 2017). Also, ROS initials apoptosis through triggering ER stress and ER calcium release (Ding et al., 2016).
Recently, LDs accumulation is closely related to a variety of human diseases (Maxfield, 2005). In peripheral system, LDs-associated protein cell death-inducing DFF45-like effector (CIDE), which is crucial for the formation and fusion of LDs, regulates the occurrence of type II diabetes (Dahlman et al., 2005). The depletion of perilipin 2 prevents hepatic steatosis via downregulating triglyceride synthesis and LDs accumulation (Carr et al., 2014). In nervous system, LDs accumulation enhances the formation of oligomeric α-synuclein, a major component of the pathological hallmarks in Parkinson's disease (Ruipérez and Darios, 2010). Knocking out HSP-related genes leads to LDs accumulation in neurons (Klemm et al., 2013). LDs accumulation also disrupts energy homeostasis (Konige and Wang, 2014), impairs the folding and clearance of proteins in neurons (Inloes et al., 2018), and breaks neuron-glia metabolic coupling (Schmitt et al., 2014). All these studies have shown that LDs accumulation is closely related to neurodegeneration diseases. Contradictorily, some studies support that LDs accumulation is helpful for neural protection. In the glial niche of Drosophila larvae, LDs accumulation keeps neural stem cells away from oxidative damage (Moldavski et al., 2015). Some fatty acids are vulnerable to peroxidation, and they are diverted into LDs to protect from ROS under hypoxia condition (Welte et al., 2017). Therefore, exploring the molecular mechanisms of altered lipid metabolism in brain injury, will help to reveal the cause of neurodegenerative changes, including CIH-induced cognitive dysfunction.
PDP1/PDHA1 pathway is an essential regulatory for de novo lipid synthesis. PDHA1 is activated by dephosphorylation of PDP1 and phosphorylation of pyruvate dehydrogenase kinases (PDK) (Shan et al., 2014). PDHA1 is one of the most important components of the PDC (Zhong et al., 2017), which oxidates pyruvate to Acetyl-CoA. As a major and central precursor in metabolism, Acetyl-CoA candidates in the synthesis and decomposition of biomacromolecules, especially for lipid biosynthesis (Kuerschner et al., 2008). It has been reported that PDP1/PDHA1 was related to a variety of diseases by affecting lipid metabolism. Inactivation of PDHA1 suppresses tumourigenesis by decreasing Acetyl-CoA levels in prostate cancer. However, knocking out PDK4 alleviates the hepatic steatosis by regulating the activity of PDC in nonalcoholic steatohepatitis mouse models (Zhang et al., 2017). In this study, experimental data showed that the activity of PDC and the production of Acetyl-CoA did not noticeable change after CIH exposure, which suggested the de novo lipid synthesis regulated by PDP1/PDHA1 might not be the main source of the abnormal increased lipids and LDs after CIH exposure. Therefore, the relevant mechanism still needs to be further studied.
ROS production and oxidative stress participate in neuro injuries and neurodegeneration. In Parkinson disease, ROS induces missense mutation by damaging DNA and inevitably causing neural cell damage (Pignataro et al., 2017). ROS also evokes Alzheimer's disease through active NLRP3, which promotes IL-1β-mediated inflammation (Pignataro et al., 2017). Recently, studies found that ROS is capable to promote lipid synthesis and LDs accumulation (Liu et al., 2015). Increased level of ROS exerts harmful effects by causing oxidative damage to biological macromolecules and disrupting various signaling pathways including the lipid metabolism (Fransen et al., 2011). In the development of fatty liver, redox cellular state especially the high level of ROS activates lipid biosynthesis gene SREBP and speeds up the disease process (Pan et al., 2017). Reports show that ROS triggers SREBP activity in fruit fly neurons leading to LDs accumulation (Liu et al., 2015). SREBP regulates the expression of several genes, such as ACC and fatty acid synthase (FAS), which is the candidate of cellular fatty acid synthesis (Nogalska et al., 2005). ACC is a rate-limiting enzyme in de novo fatty acid synthesis, catalyzing ATP-dependent carboxylation of Acetyl-CoA to form malonyl-CoA (an intermediate in fatty acid biosynthesis) (Hunkeler et al., 2018). We found that high level of ROS triggered JNK/SREBP/ACC pathway activated in neurons, thus more Acetyl-CoA were converted into fatty acid after CIH exposure. The excessive increase of lipid synthesis promoted abnormal LDs accumulation, which severely injured neurocytes in hippocampus. In addition, lipid peroxidation further aggravated neuro damage.
SMND-309 is a degradation production of Salvia miltiorrhiza, which has been widely used for neuroprotection (Su et al., 2015). SMND-309 inhibits apoptosis by upregulating the ratio of Bcl-2/Bax (Yang et al., 2010) and promotes neuron survival by increasing the content of brain-derived neurotrophic factor via activating the phosphatidylinositol 3-kinase/Akt/cAMP-response element-binding (CREB) signaling pathway (Wang et al., 2016). Consistent with the results of previous studies, SMND-309 treatment improved the behavioral performance of CIH mice by reducing the accumulation of LDs in neurocytes of the DG area. These findings might be helpful to provide a novel potential neuroprotective therapy.
In this study, CIH-induced hippocampal damaging was triggering by LDs accumulation in NBs, neurons and glia cells. The generation of LDs could be regulated via JNK/SREBP/ACC pathway. And these damages were alleviated by SMND-309 treatment. Until now, the role of LDs in neurocyte is controversial. The mechanism of lipid synthesis disorder and LDs abnormal accumulation is also unclear. All these questions need to be further investigated.