The Protective Effect And Mechanism Of PF11 On LPS And A?-induced Learning And Memory Impairment In Mice

Alzheimer's disease(AD)is a progressive neurodegenerative disease commonly found in old people and characterized by amyloid ?(A?)deposits,neruofibril tangle,neuronal loss and neuro-inflammation.The etiology of AD is complex.Historically,various hypotheses have been proposed,such as A? hypothesis,genic mutation hypothesis,tau hypothesis,cholinergic hypothesis,excitatory amino acids hypothesis,oxidative stress hypothesis and neuroinflammation hypothesis.Pseudoginsenoside-F11(PF11),a component of Panax quinquefolium(American ginseng),has been demonstrated to antagonize the learning and memory deficits induced by scopolamine,morphine and methamphetamine in mice,but the neuroprotective mechanism of PF11 is needed further research.Based on the neuro-inflammation hypothesis,amyloid hypothesis and genic mutation hypothesis,several studies were done in this paper to investigate the protective effects of PF11 on cognition impairment induced by lipopolysaccharides(LPS)and Ap:1.The learning and memory impairment and neuro-inflammation induced by LPSNeuro-inflammation is an important contributor to pathogenesis of age-related neuro-degenerative disorders,such as AD.LPS is always used to induce neruo-inflammatory models.The deficits of nest building,working memory and spatial reference memory were induced by single intrahippocampal administration of LPS 40 ?g bilaterally in mice.Furthermore,long-term and chronic activation of microglia and astrocyte appeared after LPS treatment.The activation of microglia was faster than astrocyte.The expression of CX3CL1 and CX3CR1 in hippocampus was increased and decreased repectively after LPS treatment.The activation of TLR4-NF?B and MAPKs pathways in hippocampus might be involved in the neuro inflammation induced by LPS.The results suggested chronic and aggravated neuro-inflammation was initiated by LPS in mice,which might be involved in the learning and memory deficits induced by LPS.2.Protective effects of PF11 on learning and memory impairment induced by LPSPF11 obviously mitigated the working memory and spatial reference memory impairment in LPS-treated mice,which might be attritable to the alleviation of microglia activation in cortex and hippocampus as well as astrocyte activation in hippocampus.Furthermore,PF11 significantly inhibited the activation of TLR4-NF?B and MAPKs pathway as well as the up-regulated expression of COX-2 and iNOS.What is more,the expression of CX3CR1,MAP-2 and synaptophysin was enhanced by PF11 too.The results suggested that the protective effects of PF11 on learning and memory deficits induced by LPS in mice might be attributed to the inhibitory effects on neuro-inflammation and beneficial effects on CX3CL1-CX3CR1 signaling and neuronal functions.3.Distinct neurotoxic effects induced by three conformaitons of A?1-42A?1-42 is responsible for AD for its hydrophibility,aggregation and toxicity.The working memory and novel object recognition ability were impaired obviously in mice treated with oA?1-42,aA?1-42 and fA?1-42(i.c.v.).The deficits of spatial reference and working memory were also induced by oA?1-42 and fA?1-42.Furthermore,activation of microglia,decreased expression of synaptophysin,MAP-2,BDNF and TrkB and increased expression of iNOS and COX2 were induced by the three conformations of A?1-42 in cortex and hippocampus significantly,as well as reduced expression of NeuN in cortex.In vitro,the three conformations of A?1-42 decreased the viability of primary mice cortex neurons and SH-SY5Y cells and increased the production of NO,PGE-2,IL-1?,IL-6 and TNF-a in N9 microglia dose-dependently.The conditioned medium from N9 microglia incubated with oA?1-42,aA?1-42,and fA?1-42 for 24 h significantly reduced the viability of primary mice cortex neurons in a dose-dependent manner.The data suggested different conformations of A?1-42 might possess different toxic effect on learning and memory via different mechanisms,both the direct neurotoxicity to neurons and indirect neurotoxicity by activating microglia to produce toxic pro-inflammatory mediators contributed to the pathogenic role of A?1-42 in AD.Combing the learning and memory deficits with Iba-1 expression in CA1 of hippocampus and NeuN expression in cortex,the neuro-toxic effects of oA?1-42 were most serious compared with aA?1-42 and fA?1-42,so oA?1-42 might be responsible for the AD pathogenesis,and most suitable for the induction of AD in mice.4.Protective effect of PF11 on learning and memory impairment induced by oA?1-42In oA?1-42-treated mice,the impaired nest building,working memory,novel object recognition and spatial reference memory ability were significantly improved by PF11.The loss of NeuN positive neurons in cortex and activation of microglia in cortex and CA1 of hippocampus were mitigated by PF11.PF11 also strengthened the BDNF-TrkB-PI3K/ERK signaling and reduced the expression of p-JNK,caspase 3 and Bax in cortex and hippocampus.What is more,PF11 significantly protected the neurons by increasing the expression MAP-2 and synaptophysin in cortex.The results suggested that the inhibition of neuro-inflammation and apoptosis as well as enhancement of BDNF-TrkB singling might contributed to the protective effects of PF11 on learning and memory deficits in mice treated with oA?1-42.5.PF11 improved the recognition function in APP/PS1 miceAPP/PS1 mice expressing both APP695swe and PS1dE9 transgenes is a reliable AD model for its pathological characters at 4-6 month old,such as A? deposits,neuro-inflammation and recognition impairment.PF11 8 mg/kg significantly alleviated the deficits of nest building,working memory,recognition memory,spatial reference memory and passive avoidance ability in 7-mon and 12-mon old APP/PS1 mice.PF11 also inhibited expression of APP and A?1-40 and deposits of A?1-42,mitigated activation of microglia and astrocyte significantly.The decreased activity of SOD and GSH-Px and increased levels of MDA in cortex were antagonized by PF11.Furthermore,the dysfunction of BDNF-TrkB-PI3K/ERK signaling and reduced expression of p-JNK,caspase 3,p53 and Bax were restored by PF11 obviously.More importantly,the expression of synaptophysin in hippocampus was significantly increased by PF11.These findings suggested that the inhibitory effect on amyloidogenesis,neuro-inflammation,oxidative stress and apoptosis,beneficial effects on BDNF-TrkB signaling and synapse might contribute to the recognition improvement effect of PF11 in APP/PS1 mice.Cumulatively,long-term and chronic neuro-inflammation and recognition deficits were induced by intrahippocampal administration of LPS in mice.Many behavioral and pathological changes in AD could be induced by three conformations of A?1-42,but the oA?1-42?was most toxic and suitable for preparation of AD-like models.PF11 exhibited protective effects on learning and memory deficits in mice induced by LPS and oA?1-42 as well as APP/PS1 mice significantly via the inhibitory effects on amyloidogenesis,neuro-inflammation,oxidative stress and apoptosis,and beneficial effects on BDNF-TrkB signaling and synapse,suggesting PF11 might be a valuable therapy for AD.