The Mechanism Of The Improvement Of Alzheimer Disease-like Lesions With Unsaturated Fatty Acids And Neuroimmune Network Related Factors

Alzheimer disease(AD)is one of the most deadly diseases,which is characterized by the loss of memory and cognition,with depressive and mania symptoms.Because of its unknown etiology,there is no ideal treatment for this disease.Recently,neuroinflammation has been found to play a key role in the onset and progression of Dementia.Previous studys proved that proinflammatory factors such as interleukin(IL)-1b and activated glial cells were increased in the brain of Dementia.Glial cells can not only induce inflammation in the brain,but also secrete neurotrophic factors(NTFs),both of which can affect the survival of neurons.The anti-inflammatory content of omega-3 polyunsaturated fatty acids(n-3 PUFAs)in the brain of Dementia was decreased.Clinical and experimental results show that n-3 PUFA can protect neurons by regulating the nervous system and immune system.The aim of the present study is 1)to compare the neuroprotective role of pure n-3 PUFAs and their different proportion combinations;2)to explore whether and how the marine unsaturated fatty acid play a neuroprotective role through antioxidation,anti-inflammatory and neurotrophic regulation;3)by intervention with regulating factors on the pathway of dementia,to comfirm the effect of anti-inflammation,blocking GC and supplement with NTFs on the prevention of Dementia.The following 6 experiments were included in the present study.1)NMR,HPLC and GC assays showed that the extract 4-2A obtained from shrimp Pandalus borealis industry processing wastes contained 67.19 % monounsaturated FAs and 16.83 % polyunsaturated FAs.The treatment with 4-2A significantly attenuated the A?25-35-induced changes in cell viability,ROS,GSH,NGF,Trk A,TNF-? the Bax/Bcl-2 ratio and Caspase-3,except for nitric oxide,BDNF and Tr KB.2)It was found that the LPS significantly induced BV2 cells to increase the expression of nuclear transcription factor(NF-k B/p65)and increase the levels of IL-1b,IL-6,TNF-alpha and ROS,and the conditioned medium from BV2 cells pretreated with LPS significantly decreased the viability of SH-SY5 Y cells.Pretreatment with eicosapentaenoic acid(EPA) significantly inhibited the above changes.3)We used amyloid-?(A?)25-35-treated differentiated SH-SY5 Y cells as a model of AD to compare the neuroprotective effect of DHA,EPA and their combination at various ratios.The results from our study indicate that DHA,EPA and their various ratios all could protect the viability of SH-SY5 Y cells from A?25-35 induced cellular damage in vary degrees by suppressing oxidative stress and TNF-?,regulating neurotrophin and their receptor expression and reducing neuron apoptosis.Moreover,pure EPA or higher ratio of EPA is more effective in exerting anti-oxidative effects than DHA,while pure DHA or combinations containing more DHA is stronger than EPA to promote the expression of neurotrophins and their receptors.Two n-3 PUFAs have distinct but synergistic anti-inflammatory effects on AD,especially at 1:1 DHA/EPA ratio.Furthermore,both DHA and EPA attenuate apoptosis and improve cell viability,but DHA is more effective than EPA.4)IL-10 significantly decreased the IL-1?-induced changes of learning and memory ability in the Morris water maze,anxiety behavior in open field test and sucrose preference test,microglial activation,the level of IL-1?,IL-6 and TNF-Alpha,and proliferation of peripheral lymphocyte in rats.5)It was proved that GC receptor antagonist RU486 significantly decreased the IL-1?-induced changes of anxiety behavior in elevated maze and open field test and the level of IL-1?,IL-6,TNF-Alpha,NGF,BDNF,Tr K A and Tr K B in rats.6)It was proved that BDNF significantly decreased the IL-1?-induced changes of learning and memory ability in the Morris water maze,microglial activation,the levels of inflammatory cytokines IL-1?,IL-6,IL-10,TNF-alpha,INF-gamma and the expression of p75,APP,GFAP,NGF,BDNF Tr K A and Tr K B in rats.In summary,the results from the present study confirmed that 1)marine unsaturated fatty acids play a neuroprotective function by exerting anti-inflammatory,antioxidant effect and regulating neurotrophic factor;2)the effects of DHA and EPA are proved to be different in neuroprotective function and the optimal proportion was found;3)the interventions by anti-inflammation,blocking GC and supplement with NTFs are proved to be effective on the prevention of Dementia.The present study is helpful to further improve the theory of mental-brain-immunity,and to shed light on the development of anti-AD drugs,as well to provide the evidence for the development of UFAs into clinical medicine and nutrition.