This study aims to investigate the therapeutic effect and mechanism of Daotan Xixin Decoction on APP/PS1 mice. Twelve APP/PS1 male mice were randomized into four groups: APP/PS1 and low-, medium-, and high-dose Daotan Xixin Decoction. Three C57BL/6 wild-type mice were used as the control group. The learning and memory abilities of mice in each group were examined by the Morris water maze test. The pathological changes of hippocampal nerve cells were observed by hematoxylin-eosin staining and Nissl staining. Immunohistochemistry was employed to detect the expression of β-amyloid(Aβ)_(1-42) in the hippocampal tissue. The high-dose Daotan Xixin Decoction group with significant therapeutic effects and the model group were selected for high-throughput sequencing. The differentially expressed gene(DEG) analysis, Gene Ontology(GO) analysis, Kyoto Encyclopedia of Genes and Genomes(KEGG) pathway enrichment analysis, and Gene Set Variation Analysis(GSVA) were performed on the sequencing results. RT-qPCR and Western blot were conducted to determine the mRNA and protein levels, respectively, of some DEGs. Compared with the APP/PS1 group, Daotan Xixin Decoction at different doses significantly improved the learning and memory abilities of APP/PS1 mice, ameliorated the neuropathological damage in the CA1 region of the hippocampus, increased the number of neurons, and decreased the deposition of Aβ_(1-42) in the brain. A total of 1 240 DEGs were screened out, including 634 genes with up-regulated expression and 606 genes with down-regulated expression. The GO analysis predicted the biological processes including RNA splicing and protein folding, the cellular components including spliceosome complexes and nuclear spots, and the molecular functions including unfolded protein binding and heat shock protein binding. The KEGG pathway enrichment analysis revealed the involvement of neurodegenerative disease pathways, amyotrophic lateral sclerosis, and splicing complexes. Further GSVA pathway enrichment analysis showed that the down-regulated pathways involved nuclear factor-κB(NF-κB)-mediated tumor necrosis factor-α(TNF-α) signaling pathway, UV response, and unfolded protein response, while the up-regulated pathways involved the Wnt/β-catenin signaling pathway. The results of RT-qPCR and Western blot showed that compared with the APP/PS1 group, Daotan Xixin Decoction at different doses down-regulated the mRNA and protein levels of signal transducer and activator of transcription 3(STAT3), NF-κB, and interleukin-6(IL-6) in the hippocampus. In conclusion, Daotan Xixin Decoction can improve the learning and memory abilities of APP/PS1 mice by regulating the STAT3/NF-κB/IL-6 signaling pathway.
Animals ; Drugs, Chinese Herbal/administration & dosage* ; Mice ; Male ; Alzheimer Disease/metabolism* ; Computational Biology ; Mice, Inbred C57BL ; High-Throughput Nucleotide Sequencing ; Amyloid beta-Protein Precursor/metabolism* ; Hippocampus/metabolism* ; Mice, Transgenic ; Presenilin-1/metabolism* ; Humans ; Memory/drug effects* ; Maze Learning/drug effects* ; Amyloid beta-Peptides/genetics* ; Disease Models, Animal

PURPOSE: To investigate the effects of hyperbaric oxygen (HBO) pretreatment on cognitive decline and neuronal damage in an Alzheimer’s disease (AD) rat model. MATERIALS AND METHODS: Rats were divided into three groups: normal saline (NS), AD, and HBO+AD. In the AD group, amyloid β peptide (Aβ)₁₋₄₀ was injected into the hippocampal CA1 region of the brain. NS rats received NS injection. In the HBO+AD group, rats received 5 days of daily HBO therapy following Aβ₁₋₄₀ injection. Learning and memory capabilities were examined using the Morris water maze task. Neuronal damage and astrocyte activation were evaluated by hematoxylin-eosin staining and immunohistochemistry, respectively. Dendritic spine density was determined by Golgi-Cox staining. Tumor necrosis factor-α, interleukin-1β, and interleukin-10 production was assessed by enzyme-linked immunosorbent assay. Neuron apoptosis was evaluated by terminal deoxynucleotidyl transferase dUTP nick end labeling. Protein expression was examined by western blotting. RESULTS: Learning and memory dysfunction was ameliorated in the HBO+AD group, as shown by significantly lower swimming distances and escape latency, compared to the AD group. Lower rates of neuronal damage, astrocyte activation, dendritic spine loss, and hippocampal neuron apoptosis were seen in the HBO+AD than in the AD group. A lower rate of hippocampal p38 mitogen-activated protein kinase (MAPK) phosphorylation was observed in the HBO+AD than in the AD group. CONCLUSION: HBO pretreatment improves cognition and reduces hippocampal damage via p38 MAPK in AD rats.
Alzheimer Disease/*therapy ; Amyloid beta-Peptides/*administration & dosage ; Animals ; Apoptosis ; *Cognition/drug effects ; Disease Models, Animal ; Enzyme-Linked Immunosorbent Assay ; Hippocampus/*enzymology ; *Hyperbaric Oxygenation ; In Situ Nick-End Labeling ; Interleukin-10/biosynthesis ; Interleukin-1beta/biosynthesis ; Learning/drug effects ; Male ; Memory/drug effects ; Neurons ; Peptide Fragments/*administration & dosage ; Rats ; Rats, Sprague-Dawley ; Sodium Chloride/administration & dosage ; Tumor Necrosis Factor-alpha/biosynthesis ; p38 Mitogen-Activated Protein Kinases/*metabolism

Cranberry extract (CBE) rich in polyphenols are potent to delay paralysis induced by alleviating β-amyloid (Aβ) toxicity in C. elegans model of Alzheimer's disease (AD). In order to better apply CBE as an anti-AD agent efficiently, we sought to deterrmine whether preventive or therapeutic effect contributes more prominently toward CBE's anti-AD activity. As the level of Aβ toxicity and memory health are two major pathological parameters in AD, in the present study, we compared the effects of CBE on Aβ toxicity and memory health in the C. elegans AD model treated with preventive and therapeutic protocols. Our results revealed that CBE prominently showed the preventive efficacy, providing a basis for further investigation of these effects in mammals.
Alzheimer Disease ; drug therapy ; genetics ; metabolism ; psychology ; Amyloid beta-Peptides ; metabolism ; toxicity ; Animals ; Caenorhabditis elegans ; drug effects ; metabolism ; Dietary Supplements ; analysis ; Disease Models, Animal ; Female ; Fruit ; chemistry ; Humans ; Male ; Memory ; drug effects ; Plant Extracts ; administration & dosage ; Vaccinium macrocarpon ; chemistry

Tongluo Xingnao effervescent tablet (TLXNET) is a patented prescription, which comes from modified Xionggui decoction and can improve cognitive function. However, its effect on the urine metabolites and anti-dementia mechanism in the dementia model rats induced by hippocampal injection with Aβ25-35 remains unclear. The experiment focused on the changes in trajectory and inter-relationship among the urinary metabolite of rats in the blank group, Aβ25-35 hippocampal injection dementia model group and the TLXNET intervention group, in order to determine theirs characteristic metabolic markers and explain the anti-dementia effect of TLX-NET base on the change of metabolic trajectory of these bio-markers. According to the experimental results, 5, 6-indolequinone, 4-hydroxyphenyl pyruvic acid (4-HPPA), cortisol and 3-thiosulfate lactic were preliminarily identified as the characteristic metabolic markers. They mainly participate in dopamine system, glucocorticoids and energy metabolic pathways. TLXNET can apparently downregulate the disturbances of metabolic trajectory of the four bio-markers. The experiment indicates that the dementia model induced by injecting Aβ25-3 into hippocampus has its characteristic endogenous metabolic markers in urine, and ELXNET can ameliorate dementia by down-regulating the disturbances of metabolic trajectory.
Amyloid beta-Peptides ; metabolism ; toxicity ; Animals ; Biomarkers ; urine ; Dementia ; drug therapy ; urine ; Drugs, Chinese Herbal ; administration & dosage ; Female ; Hippocampus ; drug effects ; metabolism ; Humans ; Male ; Metabolomics ; Peptide Fragments ; metabolism ; toxicity ; Rats ; Rats, Sprague-Dawley ; Tablets ; administration & dosage ; Urine ; chemistry

BACKGROUND/OBJECTIVES: Alzheimer's disease (AD) is characterized by deficits in memory and cognitive functions. The accumulation of amyloid beta peptide (Abeta) and oxidative stress in the brain are the most common causes of AD. MATERIALS/METHODS: Caffeic acid (CA) is an active phenolic compound that has a variety of pharmacological actions. We studied the protective abilities of CA in an Abeta25-35-injected AD mouse model. CA was administered at an oral dose of 10 or 50 mg/kg/day for 2 weeks. Behavioral tests including T-maze, object recognition, and Morris water maze were carried out to assess cognitive abilities. In addition, lipid peroxidation and nitric oxide (NO) production in the brain were measured to investigate the protective effect of CA in oxidative stress. RESULTS: In the T-maze and object recognition tests, novel route awareness and novel object recognition were improved by oral administration of CA compared with the Abeta25-35-injected control group. These results indicate that administration of CA improved spatial cognitive and memory functions. The Morris water maze test showed that memory function was enhanced by administration of CA. In addition, CA inhibited lipid peroxidation and NO formation in the liver, kidney, and brain compared with the Abeta25-35-injected control group. In particular, CA 50 mg/kg/day showed the stronger protective effect from cognitive impairment than CA 10 mg/kg/day. CONCLUSIONS: The present results suggest that CA improves Abeta25-35-induced memory deficits and cognitive impairment through inhibition of lipid peroxidation and NO production.
Administration, Oral ; Alzheimer Disease* ; Amyloid beta-Peptides ; Animals ; Brain ; Kidney ; Lipid Peroxidation ; Liver ; Memory ; Memory Disorders ; Mice ; Nitric Oxide ; Oxidative Stress ; Phenol ; Water

BACKGROUNDThe advent of brain stimulation techniques to treat movement disorders and psychiatric diseases has shown potential to decode the neural mechanism that underlies the cognitive process by modulating the interrupted circuit. Here, the present investigation aimed at evaluating the influence of deep brain stimulation of the anterior nucleus thalamus (ANT-DBS) on memory.

METHODSThirty-two rats were randomized into phosphate buffer saline (PBS) group (n = 8, rats received PBS injections without implantation of electrodes into the ANT), Alzheimer's dementia (AD) group (n = 8, rats received Aβ1-40 injections without implantation of electrodes into the ANT), ANT sham stimulation group (n = 8, rats received Aβ1-40 injections with implantation of electrodes into the ANT but without stimulation) and ANT stimulation group (n = 8, rats received Aβ1-40 injections with implantation of electrodes into the ANT and stimulation). A Morris maze test was used for determining the effect of electrical stimulation on cognitive function in rats. The data were assessed statistically with one-way analysis of variance (ANOVA) followed by Tukey's tests for multiple post hoc comparisons.

RESULTSThe data showed that in the training test, PBS group and AD group managed to learn the hidden-platform faster and faster while AD group needed a significantly longer time to reach the platform than PBS group (P < 0.05). Meanwhile, ANT stimulation group demonstrated a significantly shorter time to reach the platform (P < 0.05) compared to the AD group, while there was no significant difference between the ANT sham stimulation group and the AD group (P > 0.05). On the probe test, the AD group spent less time ((10.15 ± 2.34) seconds) in the target quadrant than the PBS group ((28.20 ± 2.75) seconds) (P < 0.05). And the times of platform-traversing of the AD group (3.35 ± 1.12) significantly decreased compared with the PBS group (8.69 ± 2.87) (P < 0.05). However, the times of platform-traversing and the time spent in the target quadrant of the ANT stimulation group significantly increased compared to the AD group (P < 0.05), while times of platform-traversing or the time spent in the target quadrant was not significantly different between the ANT sham stimulation group and the AD group (P > 0.05).

CONCLUSIONBilateral high-frequency stimulation of the ANT may be useful as a potential therapeutic modality for cognitive dysfunction in AD.

Amyloid beta-Peptides ; administration & dosage ; toxicity ; Animals ; Anterior Thalamic Nuclei ; drug effects ; Cognition ; drug effects ; Cognition Disorders ; chemically induced ; therapy ; Deep Brain Stimulation ; methods ; Hippocampus ; drug effects ; Male ; Peptide Fragments ; administration & dosage ; toxicity ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo observe the changes in A&beta;40, A&beta;42 and ADDLs in brains of 3 month-old APPswe/PS1dE9 double transgenic mice after six-month intervention with curcumin, in order to discuss the neuroprotective effect of curcumin.

METHODAPPswe/PS1dE9dtg mice were randomly divided into the model group, the Rosiglitazone group (10 mg x kg(-1) x d(-1)) and curcumin high (400 mg x kg9-1) x d(-1)), medium (200 mg x kg(-1) x d(-1)) and low (100 mg x kg(-1) x d(-1)) dosage groups, with C57/BL6J mice of the same age and the same background in the normal control group. After 6 months, the immunohistochemical staining (IHC) and the Western blot method were used to observe the changes in positive cell of A&beta;40, A&beta;42 and ADDLs in hippocampal CA1 area, their distribution and protein expressions.

RESULTBoth of the immunohistochemical staining and the Western blot method showed more positive cell of A&beta;40, A&beta;42 and ADDLs in hippocampal CA1 area and higher protein expressions in the model group than the normal group (P < 0.01). IHC showed a lower result in the Rosiglitazone group than the model group (P < 0.05), while Western blot showed a much lower result (P < 0.01). The number of A&beta;40, A&beta;42 and ADDLs positive cells and the protein expressions decreased in the curcumin high group, the medium group showed a significant decrease (P < 0.01), and the low dose group also showed reductions in the protein expressions of A&beta;40 and A&beta;42.

CONCLUSIONThe six-month intervention with curcumin can significantly reduce the expressions of hippocampal A&beta;40, A&beta;42 and ADDLs in brains of APPswe/PS1dE9 double transgenic mice. Whether curcumin can impact A&beta; cascade reaction by down-regulating expressions of A&beta;40, A&beta;42 and ADDLs and show the neuroprotective effect needs further studies.

Alzheimer Disease ; drug therapy ; genetics ; metabolism ; Amyloid beta-Peptides ; genetics ; metabolism ; Animals ; Brain ; drug effects ; metabolism ; Curcumin ; administration & dosage ; Disease Models, Animal ; Hippocampus ; drug effects ; metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Neuroprotective Agents ; administration & dosage ; Plant Extracts ; administration & dosage

OBJECTIVETo study the effect of qingxin kaiqiao formula and saponin on the learning and memory ability and the expression of the apoptosis signal transducers Abeta and betaAPP in AD rat brain.

METHODThe comparative observation method was adopted for the animal test. Forty male SD rats were randomly divided into five groups, namely the normal group, the model group, the aricept group, the qingxin kaiqiao formula group and the saponin group, with eight rats in each group. Abeta(25-35) (10 g x L(-1)) was injected into their bilateral amygdala to establish the AD rat model. Since the next day, they were intragastrically administered with Aricept (1.67 mg x kg(-1)), Qingxin Kaiqiao decoction (12.67 mL x kg(-1)), saponin (6.30 mg x kg(-1)) and double distilled water filling for 2 weeks to observe their spatial memory ability in a Morris water maze and study the expression of Caspase-3, Abeta and betaAPP in brain tissues by immunohistochemistry.

RESULTEach traditional Chinese medicine groups showed significant improvement in the learning and memory ability of AD rats and notable differences (P < 0.05, P < 0.01) compared with the control group. The qingxin kaiqiao formula group and the saponin group showed a decrease in the expressions of Caspase-3, Abeta and betaAPP in cerebral cortex and hippocampus area, displaying notable differences (P < 0.01, P < 0.05) compared with the control group.

CONCLUSIONqingxin kaiqiao formula and saponin can obviously improve the learning and memory ability of AD rats with by decreasing the expression of Caspase-3, Abeta and betaAPP in cortex and hippocampus.

Alzheimer Disease ; drug therapy ; genetics ; Amyloid beta-Peptides ; genetics ; Animals ; Apoptosis ; drug effects ; Caspase 3 ; metabolism ; Cerebral Cortex ; drug effects ; metabolism ; Disease Models, Animal ; Drugs, Chinese Herbal ; administration & dosage ; pharmacology ; Hippocampus ; drug effects ; metabolism ; Learning ; drug effects ; Male ; Maze Learning ; drug effects ; Memory ; drug effects ; Rats ; Rats, Sprague-Dawley ; Saponins ; administration & dosage ; pharmacology ; Time Factors

To study the effect of Cu2+ and Zn2+ on amyloid-beta peptides (Abeta) aggregation, the morphology, size and cell toxicity of Abeta40 aggregates formed with the metal ions have been observed by the methods including ultraviolet spectroscopy, fluorescence spectroscopy and transmission electron microscopy. The results showed that Cu2+ and Zn2+ can accelerate Abeta40 aggregation, and both changed the morphology and size of Abeta40 aggregates. Zn2+ induced Abeta40 to form fibrous Abeta40 aggregates, while the amorphous and fibrous aggregates were produced by the interaction between Cu2+ and Abeta40. In addition, H2O2 was produced when Abeta40 reduced Cu2+. The relationship between metal ions and Abeta40 aggregates was analyzed, and the function of metal ions in Alzheimer's disease (AD) was illustrated in the research.
Amyloid beta-Peptides ; chemistry ; Cell Survival ; drug effects ; Copper ; administration & dosage ; chemistry ; toxicity ; Dose-Response Relationship, Drug ; HeLa Cells ; Humans ; Hydrogen Peroxide ; chemistry ; Ions ; chemistry ; Microscopy, Electron, Transmission ; Peptide Fragments ; chemistry ; Spectrometry, Fluorescence ; Spectrophotometry, Ultraviolet ; Zinc ; chemistry

OBJECTIVETo study the effects of immunization with the fusion protein CAC (a product of prokaryotic expression of recombinant HBcAg and &beta;-amyloid peptide fusion gene) against the toxicity induced by intrahippocampal injection of aggregated &beta;-amyloid peptide (A&beta;) in rats.

METHODSSD rats were immunized intraperitoneally with the fusion protein CAC, and the titer of anti-A&beta; antibody was evaluated by ELISA. When the titers of the anti-A&beta; antibody reached 1:3 000, aggregated A&beta; was injected into the CA1 region of the rat hippocampus. Two weeks after A&beta; injection, the rats underwent morris water maze test before sacrificed to prepare the brain slices with Congo red and haematoxylin staining.

RESULTSThe titer of anti-A&beta; antibody reached 1:3 000 after 5 immunizations with the fusion protein. After A&beta; injection, the saline-immunized rats showed a reduced cognitive behavior in the Morris water maze test compared to the CAC-immunized rats. In the saline-immunized rats, the neurons around the site of A&beta; injection exhibited obvious cell damages with A&beta; deposits and glial infiltration, whereas in CAC-immunized rats, A&beta; deposits were significantly reduced or even absent.

CONCLUSIONImmunization with the fusion protein CAC can inhibit the toxicity induced by intrahippocampal aggregated A&beta; injection.

Amyloid beta-Peptides ; administration & dosage ; biosynthesis ; genetics ; immunology ; Animals ; Antibodies ; blood ; Hepatitis B Core Antigens ; biosynthesis ; genetics ; Hippocampus ; metabolism ; Immunization ; Injections ; Male ; Peptide Fragments ; administration & dosage ; immunology ; Rats ; Rats, Sprague-Dawley ; Recombinant Fusion Proteins ; biosynthesis ; genetics ; immunology