The Protective Effects And Mechanism Of PLTP Overexpression On AD Induced By ?-amyloid Based On The Foxred2 Gene

ObjectiveAlzheimer's disease?AD?is the most common neurodegenerative disease in the elder dementia.To date,its etiology remains still unknown.However,abnormal accumulation of extracellular amyloid-?protein?A??peptide in the formation of senile plaques in the brain is a pathological hallmark of AD.So A?plays a central role in mediating neurotoxicity in AD.Phospholipid transfer protein?PLTP?belongs to a family of lipid transfer proteins.Increased expression of PLTP was observed in the brains of AD patients.However,the role of PLTP in the progress of AD is still poorly understood.The animal experiments showed PLTP deficiency impairs learning and memory capabilities partially due to alteration of A?metabolism in old mice.The gene of FAD-dependent oxidoreductase domain containing2?FOXRED2?was down-regulated in PLTP-Tg mice by the microarray.The latest research shows that FOXRED2 could mediate A?neurotoxicity.To explore the protective effects of PLTP overexpression on AD induced by A?and its mechanisms based on the foxred2 gene,we designed the following experiments:Methods1.Animals experiments?1?Animals were housed in a temperature and humidity controlled conditions?20²2?,50%⁶0%?with a 12/12h light-dark cycle.?2?AD models:Mice were anesthetized by intraperitoneal injection of 10%Chloral hydrate.A midline sagittal incision was made in the scalp.Hypodermic needle was inserted perpendicularly through the skull into the brain.2.Learning and memory capabilities were assessed using the Morris water maze?MWM?.Briefly,the mice were putted into water and the mice will look for an unlabeled underwater platform.We assessed the hidden platform test?the probe test repetitively.3.We analyzed the level of A?_1⁴0 and A?_1⁴2 in hippocampus and cerebral cortex by ELISA kits,according to the manufacturer`s protocol.4.We examined the protective effect of PLTP overexpression on SP which were stained by thioflavin S5.In order to investigate the protective mechanism of PLTP overexpression,Western blot were performed to detect the expressions of protein levels of APP?BACE1?PS1,which were related to the generation of A?,as well as the expression of Foxred2?Capase12 and GRP78 related to ERS,respectively.Results1.The results of Morris water maze showed that the ability of study and memory were significantly improved in PLTP-Tg mice,whether ICV with A?or not.2.The results of ELISA showed that PLTP overexpression decreased the level of the A?_1⁴0 and A?_1⁴2,and increased the active of 20S protease protein in both cerebral cortex and hippocampus.3.The results of Thioflavin S showed that PLTP overexpression decreased the number of the SP in both cerebral cortex and hippocampus.4.The results of Western blot showed that the expression of APP?PS1and GRP78 in hippocampus was significantly decreased in PLTP-Tg mice compared with WT mice,and PLTP overexpression decreased the level of Capase12 protein in the cortex of mice.The expression of foxred2 and BACE1 in both cerebral cortex and hippocampus was significantly decreased in PLTP-Tg mice compared with C57 mice.Conclusion1.PLTP overexpression could improve learning and memory capabilities in AD models.2.PLTP overexpression could improve learning and memory capabilities in AD models,which was related to induce generation enzyme of A?.3.The underlying mechanisms of PLTP's protective effects on?-amyloid-induced AD,might be attributed to the down-regulation of foxred2,and improve active of the proteasome as well as the attenuate of ERS.