ABSTRACT
Aim To investigate the effect of ellagic acid (EA) on cognitive function in APP/PS 1 double- transgenic mice, and to explore the regulatory mechanism of ellagic acid on the level of oxidative stress in the hippocampus of double-transgenic mice based on the phosphatidylinositol 3-kinase/protein kinase B/glycogen synthase kinase-3 (PI3K/AKT/GSK-3 β) signaling pathway. Methods Thirty-two SPF-grade 6-month-old APP/PS 1 double transgenic mice were randomly divided into four groups, namely, APP/PS 1 group, APP/PS1 + EA group, APP/PS1 + LY294002 group, APP/PS 1 + EA + LY294002 group, with eight mice in each group, and eight SPF-grade C57BL/6J wild type mice ( Wild type) were selected as the blank control group. The APP/PS 1 + EA group was given 50 mg · kg
ABSTRACT
Objective::To study whether long-term administration of Gastrodiae Rhizoma powder can improve the learning and memory ability of APPswe/PSldE9 double transgenic (APP/PS1) Alzheimer' s disease(AD) model mice and delay the progress of AD whether these effects are related to the regulation of antioxidant stress pathway in Kelch-like epoxylopropylamine-related protein 1(Keap1)-nuclear factor E2 related factor 2 (Nrf2)/heme oxygenase(HO)-1, and further explore the neuroprotective mechanism of Gastrodiae Rhizoma powder and its role in the prevention and treatment of AD. Method::APP/PS1 double transgenic mice model, the mice consisted of five groups: normal, normal administration group, model group, Gastrodiae Rhizoma powder prevention group, Gastrodiae Rhizoma powder treatment group.The mice in the normal administration group and the Gastrodiae Rhizoma powder prevention group were given the same dose of Gastrodiae Rhizoma powder (1.5 g·kg-1) daily at the age of 8 weeks.The normal group and model group were given the same amount of normal saline at the same time, until 24 weeks old, Morris water maze was used to test the learning and memory ability of mice, and the treatment group was treated with Gastrodiae Rhizoma powder at 22 weeks old.The mice were given the same dose of Gastrodiae Rhizoma powder (1.5 g·kg-1) every day for 2 weeks.The number of crossing platform, escape latency and platform residence time of mice were detected by Morris water maze from 24 weeks old to 24 weeks old.RNA, Real-time PCR was extracted from mouse hippocampus to detect the mRNA level of Nrf2, HO-1, Keap1, and Western blot was used to detect the expression of Nrf2, HO-1, Keap1 protein in mouse hippocampus. Result::Compared with normal group, the water maze test showed that the learning and memory ability of model group was lower than that of the model group (P<0.01), and the learning and memory ability of Gastrodiae Rhizoma powder prevention group and Gastrodiae Rhizoma powder treatment group was significantly higher than that of model group (P<0.01). Compared with normal group, the levels of Nrf2, HO-1 and protein in the hippocampus in model group decreased in varying degrees (P<0.05). Compared with model group, Gastrodiae Rhizoma powder prevented Nrf2, in the hippocampus of mice in model group.The level of HO-1 in mRNA and protein increased in different degrees (P<0.05, P<0.01). Levels of Nrf2, HO-1 mRNA in Gastrodiae Rhizoma powder treatment group was significantly higher than that in Gastrodiae Rhizoma powder group (P<0.05). There was no significant difference in the expression of Nrf2, HO-1 protein.There was no significant difference in mRNA and protein levels of Keap1 among different groups. Conclusion::Morris water maze test and other results showed that Gastrodiae Rhizoma powder could improve the learning and memory ability of APP/PS1 mice, and it may enhance the expression of downstream antioxidant genes by regulating Keap1-Nrf2/HO-1 pathway.And then improve the learning and memory ability of APP/PS1 mice.
ABSTRACT
AIM:To explore the therapeutic effect of a novel Rho kinase inhibitor FSD-C10 onβ-amyloid pro-tein precursor (APP)/presenilin-1 (PS1) double transgenic mice.METHODS: The transgenic mice overexpressing hu-man APP with the Swedish mutation (695) and human PS1 with ΔE9 mutation at the age of 8 months were used in this study.The mice were randomly divided into model group and FSD-C10 intervention group, and wild-type mice at the same age served as normal controls .The mice in FSD-C10 intervention group were treated with FSD-C10 (25 mg· kg-1 · d-1 ) for 2 months by intraperitoneal injection .The mice in model group and the wild-type mice were injected with saline in the similar manner.Morris water maze (MWM) test was applied to examine the capacity of learning and memory .The Aβ1-42 deposition, Tau protein phosphorylation , and the expression of β-site APP-cleaving enzyme ( BACE) as well as inflammato-ry molecules, such as TLR-4 and NF-Κb, and M1/M2 microglial markers, such as Inos and Arg-1, were determined by the methods of immunohistochemistry and Western blot .RESULTS: Compared with model group , FSD-C10 significantly improved the learning and memory abilities of APP/PS1 double transgenic mice , accompanied by reduced Aβ1-42 deposi-tion, Tau protein phosphorylation and BACE expression in the hippocampus .The intervention of FSD-C10 decreased the protein levels of TLR-4 and p-NF-Κb, reduced the expression of Inos and increased the expression of Arg-1 in the brain tissues.CONCLUSION:The novel Rho kinase inhibitor FSD-C10 improves the capacity of spatial learning and memory in APP/PS1 double transgenic mice , which may be related to the inhibition of TLRs/NF-Κb signaling pathway , the reduction of the secretion of inflammatory molecules and the polarization of anti-inflammatory M2 microglia, thus improving the in-flammatory microenvironment of the brain in APP/PS1 double transgenic mice .
ABSTRACT
AIM:To explore the therapeutic effect of a novel Rho kinase inhibitor FSD-C10 onβ-amyloid pro-tein precursor (APP)/presenilin-1 (PS1) double transgenic mice.METHODS: The transgenic mice overexpressing hu-man APP with the Swedish mutation (695) and human PS1 with ΔE9 mutation at the age of 8 months were used in this study.The mice were randomly divided into model group and FSD-C10 intervention group, and wild-type mice at the same age served as normal controls .The mice in FSD-C10 intervention group were treated with FSD-C10 (25 mg· kg-1 · d-1 ) for 2 months by intraperitoneal injection .The mice in model group and the wild-type mice were injected with saline in the similar manner.Morris water maze (MWM) test was applied to examine the capacity of learning and memory .The Aβ1-42 deposition, Tau protein phosphorylation , and the expression of β-site APP-cleaving enzyme ( BACE) as well as inflammato-ry molecules, such as TLR-4 and NF-Κb, and M1/M2 microglial markers, such as Inos and Arg-1, were determined by the methods of immunohistochemistry and Western blot .RESULTS: Compared with model group , FSD-C10 significantly improved the learning and memory abilities of APP/PS1 double transgenic mice , accompanied by reduced Aβ1-42 deposi-tion, Tau protein phosphorylation and BACE expression in the hippocampus .The intervention of FSD-C10 decreased the protein levels of TLR-4 and p-NF-Κb, reduced the expression of Inos and increased the expression of Arg-1 in the brain tissues.CONCLUSION:The novel Rho kinase inhibitor FSD-C10 improves the capacity of spatial learning and memory in APP/PS1 double transgenic mice , which may be related to the inhibition of TLRs/NF-Κb signaling pathway , the reduction of the secretion of inflammatory molecules and the polarization of anti-inflammatory M2 microglia, thus improving the in-flammatory microenvironment of the brain in APP/PS1 double transgenic mice .
ABSTRACT
This study was aimed to investigate the effects of Bu-Yang Huan-Wu (BYHW) decoction to the learning and memory ability of APP/PS1 double transgenic mice through two behavior tests,in order to observe the Alzheimer's disease (AD) treatment effect of BYHW decoction.A total of 60 APP/PS1 double transgenic mice were randomly divided into five groups,which were the model group,the hydrochloride group,the high-,middle-,and low-dose BYHW decoction group,with ten rats in each group.The C57BL/6J mice were used as the control group.After 30 days of drug administration,all mice were subjected to behavior tests,including new object recognition experiment and step-through task.Western blot was used to detect changes of inflammatory factors,including IL-6 and TNF-α,in hippocampus of mice.The results showed that compared with the model group,the high-and middle-dose BYHW decoction can significantly decrease inflammatory factors of IL-6 and TNF-α expression in hippocampus of APP/PS1 mice.It can also obviously improve the learning and memory ability of APP/PS1 mice.It was concluded that BYHW decoction can significantly decrease the inflammatory factor expression in APP/PS 1 double transgenic AD model mice.It can obviously improve its learning and memory ability,which can be used in the treatment of AD.
ABSTRACT
AIM:To investigate the protective effects of astrocyte protein phosphatase 2A (PP2A) up-regula-tion on APP/PS1 double transgenic mice.METHODS:An eGFP-wtPP2A lentivirus with glial fiber acidic protein promoter was constructed to specifically increase PP2A expression in the astrocytes.The mice were divided into wild -type mice +vector virus group (Con), APP/PS1 transgenic mice +vector virus group (APP/PS1) and APP/PS1 transgenic mice +eGFP-wtPP2A lentivirus group (PP2A) by lateral ventricular injection of the lentivirus.Four weeks after injection of the vi-rus, the immunofluorescence of brain slices were used to detect the level of β-amyloid protein ( Aβ) .Golgi staining was used to detect the changes of dendritic spine density and morphology.Electron microscopy was applied to detect the thickness of postsynaptic density (PSD).The Morris water maze test was applied to examine the learning and memory abilities of the mice.RESULTS: Up-regulation of PP2A in the astrocytes attenuated Aβlevel increasing in APP/PS1 group.Up-regulation of PP2A in the astrocytes significantly attenuated both decreases in the dendritic spine density and the percentage of mushroom-like dendritic spines in the hippocampal CA3 region of APP/PS1 mice.Up-regulation of PP2A in the astrocytes significantly attenuated the reduced thickness of PSD in APP/PS1 group.Up-regulation of PP2A in the astro-cytes attenuated the escape latency extending in APP/PS1 group .CONCLUSION: Up-regulation of PP2A in the astro-cytes reduces AD-like pathological changes, and attenuates synaptic impairment, synaptic plasticity deficits and cognitive impairment in the APP/PS1 double transgenic mice.
ABSTRACT
Objective To investigate the effects of Abnormal Phlegmatic Temperament Granules on spatial learning and memory, histopathology morphological change in hippocampus CA1 zone; To discuss its mechanism of action.Methods Three-month-old APP/PS1 transgenic mice were randomly divided into 5 groups: model control group, positive control (donepezil 0.92 mg/kg) group, Abnormal Phlegmatic Temperament Granules high-, medium-, and low-dose groups (3, 2, 1.5 g/kg), 18 mice in each group. Another 18 three-month-old C57BL/ 6J mice were chosen as normal control group. All administration groups received relevant medicine for successive 6 months. Then the changes in learning and memory ability of mice were detected by Morris water maze test; pathomorphism in hippocampus CA1 zone was detected by HE staining method; changes of myelin sheath, microtubule, and microfilament in myelinated nerve of hippocampus CA1 zone were detected by electron microscope. Results Morris water maze test results showed that escape incubation period of APP/PS1 transgenic mice was significantly longer than the normal control group (P<0.01), and the original platform time was significantly shorter than normal control group (P<0.01); compared with model control group, Abnormal Phlegmatic Temperament Granules treatment groups escape latency time was significantly reduced (P<0.05, P<0.01). Space experiments and escape incubation period of Abnormal Phlegmatic Temperament Granules high-, medium-, low-dose groups were significantly shortened (P<0.05, P<0.01), and spatial searching test showed that the times of mice in Abnormal Phlegmatic Temperament Granules high-, medium-, low-dose groups passing through effective area increased (P<0.01). The integrity of HE staining pyramidal cell layer in the hippocampus CA1 zones of Abnormal Phlegmatic Temperament Granules high-, medium-, and low-dose groups was relatively good; cells arranged orderly; distribution was normal. Electron microscopic observation showed that compared with model control group, the hippocampus neurons nuclear had irregular shape; nuclear membrane was clear and complete; chromatin was clear; nucleolus was obvious; cell matrix was uniform; organelles were abundant; mitochondrial cristae was obvious; endoplasmic reticulum and free ribosomes were obvious. Conclusion Abnormal Phlegmatic Temperament Granules can improve spatial learning and memory in APP/PS1 mice, alleviate neuronal ultrastructure damage and ultimately improve cognitive function.