| Alzheimer’s Disease (AD) is a neurodegenerative disorder, which is characterized by the loss of neurons and the impairment of cognitive function. The presence of neurofibrillary tangles and the increased senile plaque in brain are regarded as the pathological hallmarks of AD. Although the mechanism of AD remains unclear, the increasing evidence has implicated P-amyloid, which is an important component in senile plaque, plays a critical role in the progress of AD. Sea cucumber is well known as traditional seafood for a long time in East Asia, which contains many bioactive substances, including saponins, polysaccharides, phospholipids and cerebrosides. Recent studies proved that the phospholipids from sea cucumber could improve the learning and memory deficits in dementia mice via antioxidant ability. However, till now no study has examined whether the polar lipids have the neuroprotective effect against Aβ-induced neuron damage and dementia.In this study, it was testified the protective effect of the polar lipids, obtained from the sea cucumber, against Aβ-induced cytotoxicities, based on in vitro study of PC 12 cell line and APP/PS1 cell line. Also the underlying molecular mechanisms were elucidated. Besides, the effect of the lipids on neurite growth of PC12 cells was investigated. Furthermore, the effect of the cerebrosides on S AMP8 mice in vivo was also tested. The main results are listed below:The neuro-protectional effect and its mechanism of the polar lipids were tested in vitro using two kinds of dementia model. First, Aβ was used to induce PC12 cells damage. The results showed that Aβ made PC 12 cells damaged significantly, while the cerebrosides increased the survival rate of PC12 cells, decreased the leakage of LDH, recoverd the cellular morphology, down-regulated the amount of caspase-3, caspase-9 and bax and up-regulated the level of GSK-3β, all of which indicated that the cerebrosides could inhibit Aβ-induced cell apoptosis by regulating the mitochondria-dependent apoptotic pathway. In the APP/PS1 transgenic cells, we found the phospholipids could decrease the secretion of Aβ1-40 and Aβ1-42 and the protein level of APP, suggesting their neuroprotective abilities.Then, PC 12 cells were cultured in the low nutrition conditions to explore the roles of the polar lipids in the neurite growth. The results showed the lipids could promote the neurite growth, which perhaps depend on the up-regulated expression levels of synapses and GAP-43 that were related to the synaptic growth.On top of the in vitro study, the effects of the cerebrosides on SAMP8 mice were studied by open-field test, based on Barnes maze and Morris water maze model. In this study, SAMP8 mice displayed learning and memory deficit significantly. In Barnes maze test, it showed shorter escape latency and less error time in cerebrosides group mice compared to that in SAMP8 mice. In Morris water maze test, the cerebrosides could increase the frequency of crossing the platform and residence time in the target quadrant, decrease the escape latency obviously. These results suggested that cerebrosides could improve the learning and memory deficits of dementia mice.Moreover, the levels of Aβ and GAP-43, along with the oxidative stress conditions in SAMP8 mice’s brain, liver and serum were evaluated to further research the mechanisms of cerebrosides on the brain function. The results showed that SAMP8 mice’s brain tissue had excess Ap accumulation, less GAP-43 content and severe oxidative stress response. Nontheless, pre-treatment of cerebrosides decreased the level of Ap, dropped the content of MDA,8-OHdG,8-oxo-G and NO, and enhanced the SOD activity significantly. These results implied that cerebrosides could inhibit the peroxidation of lipids, DNA and RN A, regulate the oxidative stress balance, decline the cytotoxicity of NO and the level of AP to improve the learning and memory deficits, which was also in consistent with the in vitro study.In conclusion, it is the first time to study the neuroprotective effect of the polar lipids from sea cucumber against AP-induced dementia. The cerebrosides were proved to have the protective effect on AP-induced damage of PC12 cells while the phospholipids could decrease the Aβ level in APP/PS1 cells. These two kinds of polar lipids both could promote the neurite growth obviously. The protective effects of cerebrosides against the learning and memory deficits of AD mice model and their mechanisms were also clarified. This study may provide a new insight for developing functional foods for ameliorating learning and memory deficits and neuronal damage. |
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