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1.
Article in English | WPRIM | ID: wpr-922254

ABSTRACT

To investigate the effects of on behavior and blood brain barrier (BBB) in Alzheimer's disease mice. Thirty-eight 4-month-old APP/PS1 double transgenic mice were randomly divided into three groups: model group, low-dose group and high-dose group. Saline, and 12 g·kg·d were given to each group by continuous gavage once a day for respectively. The changes in activities of daily live and fear conditioning memory behavior of mice were examined by nesting behavior test and fear conditioning test, respectively. The β-amyloid protein (Aβ) depositions in cortex and hippocampal CA1 area of mice were detected by thioflavin T staining. The CD34 and activities fibrinogen (Fib) immunofluorescence double staining were used to determine the vascular endothelial integrity and BBB exudation. Compared with model mice, activities of daily live were significantly improved in low-dose and high-dose groups (both <0.01), the fear memory ability was significantly increased in high-dose group (<0.01). The amount of Aβ deposition in cortex and hippocampal CA1 decreased significantly in high-dose group, the area ratio decreased significantly; the area ratio of Aβ deposition in hippocampal CA1 region in low-dose group also decreased (all <0.05). The proportions of CD34 positive area of cortex in low and high dose groups increased, the percentage of fibrinogen positive area decreased (all <0.05). The proportion of CD34 positive area in hippocampal CA1 region in high-dose group was significantly increased, the percentage of fibrinogen positive area decreased significantly (both <0.05). especially high-dose can improve the activities of daily live and fear conditioning memory function of APP/PS1 mice, reduce the deposition of Aβ in brain. The mechanism may be related to the reduction of BBB permeability and the protection of the integrity of BBB.


Subject(s)
Alzheimer Disease , Amyloid beta-Protein Precursor , Animals , Blood-Brain Barrier/metabolism , Disease Models, Animal , Hippocampus/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic
2.
Chinese Acupuncture & Moxibustion ; (12): 1231-1235, 2021.
Article in Chinese | WPRIM | ID: wpr-921037

ABSTRACT

OBJECTIVE@#To compare the clinical efficacy of abdominal acupoint thread embedding therapy based on "brain-intestinal connection" combined with donepezil hydrochloride tablets and oral donepezil hydrochloride tablets alone for mild-to-moderate Alzheimer's disease (AD) and observe its effects on amyloid precursor protein (APP) and β-amyloid protein@*METHODS@#Sixty patients with AD were randomly divided into an observation group (30 cases, 3 cases dropped off) and a control group (30 cases, 3 cases dropped off). The patients in the control group were treated with donepezil hydrochloride tablets (5 mg per day); based on the treatment in the control group, the patients in the observation group were treated with abdominal acupoint thread embedding therapy at Zhongwan (CV 12), Xiawan (CV 10), Huaroumen (ST 24), Wailing (ST 26), Daheng (SP 15), etc., once every 10 days. Both groups were treated for 2 months. The mini-mental state examination (MMSE), Alzheimer's disease assessment scale-cognitive subscale (ADAS-Cog), activity of daily living scale (ADL), neuropsychiatric inventory questionnaire (NPI) as well as the serum levels of APP and Aβ@*RESULTS@#After treatment, the MMSE scores in the two groups were higher than those before treatment (@*CONCLUSION@#The abdominal acupoint thread embedding therapy based on the theory of "brain-intestinal connection" combined with donepezil hydrochloride tablets can improve cognitive function, self-care ability of daily life and mental behavior, and reduce the serum levels of APP and Aβ


Subject(s)
Acupuncture Points , Alzheimer Disease/drug therapy , Amyloid beta-Peptides , Amyloid beta-Protein Precursor , Brain , Donepezil , Humans , Peptide Fragments
3.
Acta Physiologica Sinica ; (6): 471-481, 2021.
Article in Chinese | WPRIM | ID: wpr-887682

ABSTRACT

Sleep exerts important functions in the regulation of cognition and emotion. Recent studies have found that sleep disorder is one of the important risk factors for Alzheimer's disease (AD), but the effects of chronic sleep deprivation on the cognitive functions of AD model mice and its possible mechanism are still unclear. In the present study, 8-month-old male APP/PS1/tau triple transgenic AD model (3xTg-AD) mice and wild type (WT) mice (n = 8 for each group) were subjected to chronic sleep deprivation by using the modified multiple platform method, with 20 h of sleep deprivation each day for 21 days. Then, open field test, elevated plus maze test, sugar water preference test, object recognition test, Y maze test and conditioned fear memory test were performed to evaluate anxiety- and depression-like behaviors, and multiple cognitive functions. In addition, the immunohistochemistry technique was used to observe pathological characteristics in the hippocampus of mice. The results showed that: (1) Chronic sleep deprivation did not affect anxiety- (P = 0.539) and depression-like behaviors (P = 0.874) in 3xTg-AD mice; (2) Chronic sleep deprivation exacerbated the impairments of object recognition memory (P < 0.001), working memory (P = 0.002) and the conditioned fear memory (P = 0.039) in 3xTg-AD mice; (3) Chronic sleep deprivation increased amyloid β (Aβ) deposition (P < 0.001) and microglial activation (P < 0.001) in the hippocampus of 3xTg-AD mice, without inducing abnormal tau phosphorylation and neurofibrillary tangles. These results indicate that chronic sleep deprivation exacerbates the impairments of recognition memory, working memory and conditioned fear memory in 3xTg-AD mice by aggravating Aβ deposition and the excessive activation of microglia in the hippocampus.


Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Amyloid beta-Protein Precursor/genetics , Animals , Cognition , Disease Models, Animal , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Presenilin-1 , Sleep Deprivation , tau Proteins
4.
Article in Chinese | WPRIM | ID: wpr-826727

ABSTRACT

OBJECTIVE@#To compare the therapeutic effect of electroacupuncture (EA) combined with donepezil hydrochloride and donepezil hydrochloride alone on improving learning-memory ability in patients with Alzheimer's disease (AD), and to explore its action mechanism.@*METHODS@#Sixty patients of AD were randomly divided into an observation group and a control group, 30 cases in each group. The patients in the observation group were treated with EA at governor vessel (GV) combined with donepezil hydrochloride. EA was applied at Baihui (GV 20) and Fengfu (GV 16) with dilatational wave (10 Hz/50 Hz of frequency, 0.5 to 5.0 mA of intensity), and the needles were kept for 40 min, EA was given once a day; the donepezil hydrochloride tablet was taken orally, 5 mg, once a day, and after 4 weeks the dosage might be increased to 10 mg per day according to the specific situation. All the treatment was given for 8 weeks. The patients in the control group were only treated with donepezil hydrochloride with the identical procedure as the observation group. The Montreal cognitive assessment (MoCA) and Alzheimer's disease assessment scale cognitive part (ADAS-Cog) were evaluated before and after treatment; P300 (latency and amplitude of N2 and P3) was detected by EEG/ERP system brain event related potential instrument, and amyloid precursor protein (APP) and β-amyloid protein 1-42 (Aβ) were detected by ELISA.@*RESULTS@#Compared before treatment, the MoCA scores were increased after treatment in the two groups (<0.05), and the MoCA score in the observation group was higher than that in the control group (<0.05). Compared before treatment, the ADAS-Cog scores were decreased after treatment in the two groups (<0.05), and the ADAS-Cog score in the observation group was lower than that in the control group (<0.05). Compared before treatment, the latency of N2 and P3 was shortened and the amplitude was increased after treatment in the two groups (<0.05); after treatment, the latency of N2 and P3 in the observation group was shorter than that in the control group and the amplitude was higher than that in the control group (<0.05). Compared before treatment, the serum levels of APP and Aβ were lower after treatment in the two groups (<0.05), and the serum levels of APP and Aβ in the observation group were lower than those in the control group (<0.05).@*CONCLUSION@#EA at Baihui (GV 20) and Fengfu (GV 6) combined with donepezil hydrochloride can effectively reduce the serum levels of APP and Aβ and improve the scores of MoCA and ADAS-Cog and the levels of N2 and P3 of P300 in AD patients, which has superior effect to donepezil hydrochloride alone in improving the learning-memory of AD patients.


Subject(s)
Alzheimer Disease , Blood , Therapeutics , Amyloid beta-Peptides , Blood , Amyloid beta-Protein Precursor , Blood , Cognition , Donepezil , Therapeutic Uses , Electroacupuncture , Humans , Learning , Memory , Peptide Fragments , Blood
5.
Article in Chinese | WPRIM | ID: wpr-776570

ABSTRACT

OBJECTIVE@#To study the effect of β-sheet blocking peptide H102 on the expression of AMPK-mTOR autophagy pathway-related protein in APP/PS1 double transgenic AD mice.@*METHODS@#Thirty male APP/PS1 transgenic male AD mice of 6 months old were randomly divided into AD group and H102 intervention group, and C57BL/6J male mice of the same age were used as control group (n=15). The mice in the HF group were administered with 5 μl (5.8 mg/kg) of H102 polypeptide solution through the nasal cavity at the same time period, and the mice in the control group and the AD group were given the same amount of blank adjuvant solution daily. The memory recognition ability was tested by a new object recognition experiment 30 days after continuous administration. Immunohistochemistry and Western blot were used to detect the expressions of phosphorylated AMP-activated protein kinase(P-AMPK),phosphorylated mammalian target of rapamycin (P-mTOR) and ratio of LC32to LC31(LC3II/I )in brain tissue.@*RESULTS@#Compared with the control group, the new object recognition index (RI) of the AD group was significantly lower (P<0.05), and the P-AMPK and LC3II/I ratios in the brain of the mice were significantly lower (P<0.05). The expression of P-mTOR protein was increased significantly (P<0.05). Compared with the AD group, the RI of the H102 intervention group was increased significantly (P<0.05), and the P-AMPK and LC3II/I ratios in the brain tissue of the mice were increased significantly (P<0.05). The expression of P-mTOR protein was decreased significantly (P<0.05).@*CONCLUSION@#H102 can improve the recognition and memory ability of AD mice by activating the AMPK-mTOR autophagy-related pathway.


Subject(s)
AMP-Activated Protein Kinases , Alzheimer Disease , Amyloid beta-Protein Precursor , Animals , Autophagy , Disease Models, Animal , Male , Memory , Mice , Mice, Inbred C57BL , Mice, Transgenic , Peptides , Pharmacology , Random Allocation , TOR Serine-Threonine Kinases
6.
Neuroscience Bulletin ; (6): 912-920, 2018.
Article in English | WPRIM | ID: wpr-775500

ABSTRACT

Astrocytes are closely associated with Alzheimer's disease (AD). However, their precise roles in AD pathogenesis remain controversial. One of the reasons behind the different results reported by different groups might be that astrocytes were targeted at different stages of disease progression. In this study, by crossing hAPP (human amyloid precursor protein)-J20 mice with a line of GFAP-TK mice, we found that astrocytes were activated specifically at an early stage of AD before the occurrence of amyloid plaques, while microglia were not affected by this crossing. Activation of astrocytes at the age of 3-5 months did not affect the proteolytic processing of hAPP and amyloid plaque loads in the brains of hAPP-J20 mice. Our data suggest that early activation of astrocytes does not affect the deposition of amyloid β in an animal model of AD.


Subject(s)
Aldehyde Dehydrogenase , Metabolism , Alzheimer Disease , Genetics , Metabolism , Pathology , Amyloid beta-Peptides , Metabolism , Amyloid beta-Protein Precursor , Genetics , Metabolism , Animals , Astrocytes , Metabolism , Brain , Pathology , Calcium-Binding Proteins , Metabolism , Cell Proliferation , Disease Models, Animal , Gene Expression Regulation , Genetics , Glial Fibrillary Acidic Protein , Glutamine , Metabolism , Green Fluorescent Proteins , Genetics , Metabolism , Humans , Ki-67 Antigen , Metabolism , Mice , Mice, Transgenic , Microfilament Proteins , Metabolism , Mutation , Genetics , Nerve Tissue Proteins , Metabolism
7.
Neuroscience Bulletin ; (6): 736-746, 2018.
Article in English | WPRIM | ID: wpr-775492

ABSTRACT

Alzheimer's disease (AD) is the most common form of dementia among the elderly, characterized by amyloid plaques, neurofibrillary tangles, and neuroinflammation in the brain, as well as impaired cognitive behaviors. A sex difference in the prevalence of AD has been noted, while sex differences in the cerebral pathology and relevant molecular mechanisms are not well clarified. In the present study, we systematically investigated the sex differences in pathological characteristics and cognitive behavior in 12-month-old male and female APP/PS1/tau triple-transgenic AD mice (3×Tg-AD mice) and examined the molecular mechanisms. We found that female 3×Tg-AD mice displayed more prominent amyloid plaques, neurofibrillary tangles, neuroinflammation, and spatial cognitive deficits than male 3×Tg-AD mice. Furthermore, the expression levels of hippocampal protein kinase A-cAMP response element-binding protein (PKA-CREB) and p38-mitogen-activated protein kinases (MAPK) also showed sex difference in the AD mice, with a significant increase in the levels of p-PKA/p-CREB and a decrease in the p-p38 in female, but not male, 3×Tg-AD mice. We suggest that an estrogen deficiency-induced PKA-CREB-MAPK signaling disorder in 12-month-old female 3×Tg-AD mice might be involved in the serious pathological and cognitive damage in these mice. Therefore, sex differences should be taken into account in investigating AD biomarkers and related target molecules, and estrogen supplementation or PKA-CREB-MAPK stabilization could be beneficial in relieving the pathological damage in AD and improving the cognitive behavior of reproductively-senescent females.


Subject(s)
Alzheimer Disease , Metabolism , Pathology , Psychology , Amyloid beta-Protein Precursor , Genetics , Metabolism , Animals , Cyclic AMP Response Element-Binding Protein , Metabolism , Cyclic AMP-Dependent Protein Kinases , Metabolism , Disease Models, Animal , Female , Hippocampus , Metabolism , Pathology , Humans , Inflammation , Metabolism , Pathology , Psychology , Male , Maze Learning , Physiology , Mice, Inbred C57BL , Mice, Transgenic , Neurofibrillary Tangles , Metabolism , Pathology , Plaque, Amyloid , Metabolism , Pathology , Psychology , Presenilin-1 , Genetics , Metabolism , Sex Characteristics , Spatial Memory , Physiology , p38 Mitogen-Activated Protein Kinases , Metabolism , tau Proteins , Genetics , Metabolism
8.
Article in Chinese | WPRIM | ID: wpr-775291

ABSTRACT

OBJECTIVE@#To investigate the effect of osthole on the expression of amyloid precursor protein (APP) in Alzheimer's disease (AD) cell model and its mechanism.@*METHODS@#The SH-SY5Y cell with over expression of APP was established by transfection by liposome 2000. The cells were treated with different concentrations of osthole, and the cell viability was determined by MTT and lactate dehydrogenase (LDH) assay. The differentially expressed miRNAs with and without osthole treatment were detected by miRNA array, and the target genes binding to the differentially expressed miRNAs were identified and verified by databases and Cytoscape. After the inhibitor of the differentially expressed miRNA was transduced into cells, the changes of APP and amyloid β (Aβ) protein were determined by immunofluorescence cytochemistry, and the mRNA expression of APP was determined by RT-PCR.@*RESULTS@#The AD cell model with over expression of APP was established successfully. The results of MTT and LDH assay showed that osthole had a protective effect on cells and alleviated cell damage. miR-101a-3p was identified as the differentially expressed miRNA, which was binding to the 3'-UTR of APP. Compared with APP group, the expression of APP and Aβ protein and APP mRNA increased in the miR-101a-3p inhibitor group (all <0.01), while the expression of APP and Aβ protein and APP mRNA decreased in the cells with osthole treatment (all <0.01).@*CONCLUSIONS@#Osthole inhibits the expression of APP by up-regulating miR-101a-3p in AD cell model.


Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Amyloid beta-Protein Precursor , Genetics , Cell Line , Coumarins , Pharmacology , Gene Expression Regulation , Genetics , Humans , MicroRNAs , Genetics , Metabolism
9.
Article in Chinese | WPRIM | ID: wpr-773792

ABSTRACT

OBJECTIVES@#To identify the genotype of (APP/PS1) transgenic mice and evaluate the changing of cognitive and behavioral fu nctions, provide an effective animal model for the Alzheimer's disease (AD) research.@*METHODS@#Male APP/PS1 transgenic mice mated with female APP/PS1 transgenic mice, and the genotype of their filial mice was identified by PCR. The APP +/PS1 + mice were assigned into AD model group (AD group, =8), and the APP/PS1 mice were assigned into control group (CT group, =8). The Morris water maze test was carried out to detect the capacity of learning and memory of mice. After that, the mice were sacrificed and the brain tissues were sampled and stained by HE and congo red for the pathological examination.@*RESULTS@#①A APP/PS1 genome DNA about 360 bp size was detected. The methods of feeding and breeding were successful to attain APP/PS1 transgenic mice.②Statistical significance was found in the differences of the capacity of learning and memory between 7-month-old APP/PS1 positive mice and negative mice (<0.05).③The results of HE stain showed that the structure and cellular morphology of hippocampus of AD mice were obviously abnormal. The results of congo red stain showed that positive amyloid plaque was observed in brains of AD mice.@*CONCLUSIONS@#APP/PS1 transgenic mice present typical symptoms and behaviors of Alzheimer's disease. The transgenic mouse is an effective tool for the research and prevention of AD.


Subject(s)
Alzheimer Disease , Amyloid beta-Protein Precursor , Genetics , Animals , Disease Models, Animal , Female , Genotype , Hippocampus , Pathology , Male , Maze Learning , Mice , Mice, Inbred C57BL , Mice, Transgenic , Plaque, Amyloid , Pathology , Presenilin-1 , Genetics
10.
Article in Chinese | WPRIM | ID: wpr-773774

ABSTRACT

OBJECTIVE@#To observe the gait changes of Alzheimer's disease PS1M146V/APPswe/tauP301L triple-transgenic (3xTg-AD) mice and to investigate the improvement effect of single chain variable domain antibody fragment 17 (scFv17) on the gait.@*METHODS@#In the present study, a selection of 6-month-old 3xTg-AD mice (=18) and C57BL/6 wild-type mice (=24) was performed. First, we observed their gait changes and found that the gait of 12-month-old 3xTg-AD mice was severely damaged. Then, the two groups of mice were randomly divided into four groups:WT+PBS(=12), WT+scFv17(=12), 3xTg-AD+PBS(=9) and 3xTg-AD+scFv17(=9). The gait behavior test and pathological test were performed after 12 weeks'continuous administration of scFv17 (1.5 mg/kg) or an equal volume of PBS (0.01 mol/L) by nasal gavage twice a week.@*RESULTS@#Compared with the same month old wild type mice, the rear track width of 12 month old 3xTg-AD mice was increased(<0.01), swing time percent was decreased (<0.01), stance time percent was increased(<0.01), so the ability of movement coordination and balance was seriously damaged. ScFv17 could improve the coordination and balance ability of 12 month old 3xTg-AD mice(<0.01). The morphological structure of 3xTg-AD mice cerebellar Purkinje cells was improved. The treatment of scFv17 increased the Nissl body number of the cerebellar Purkinje cells of 3xTg-AD mice (<0.01). scFv17 reduced the amyloid β protein (Aβ) plaques in the cerebellar cortex of 3xTg-AD mice (<0.01), and scFv17 reduced the intracellular neurofibrillary tangles (NFT) of the cerebellar Purkinje cells of the 3xTg-AD mice (<0.01).@*CONCLUSIONS@#The coordination and balance ability of 3xTg-AD mice was significantly impaired. ScFv17 can improve gait behaviour in the 3xTg-AD significantly.The mechanism may be related to the improvement of the structure and protein function of cerebellar Purkinje cells, and the eliminating of the Aβ plaques and the neurofibrillary tangles.


Subject(s)
Alzheimer Disease , Amyloid beta-Peptides , Amyloid beta-Protein Precursor , Animals , Disease Models, Animal , Gait , Mice , Mice, Inbred C57BL , Mice, Transgenic , tau Proteins
11.
Article in English | WPRIM | ID: wpr-327203

ABSTRACT

<p><b>OBJECTIVE</b>To observe the effects of Huannao Yicong Formula (, HYF) on learning and memory and it's regulating effect on γ-secretase related anterior pharynx defective 1 (APH-1), presenilin enhancer-2 (PEN-2) signaling pathway, so as to discuss and further clarify the mechanism of HYF on Alzheimer's disease.</p><p><b>METHODS</b>Sixty APP/PS1 transgenic mice, randomly allocated into 4 groups, the model group, the donepezil group (0.65 mg/kg), HYF low-dose group (HYF-L, 5.46 g/kg) and HYF high-dose group (HYF-H, 10.92 g/kg), 15 for each group. Another 15 C57BL/6J mice with the same age and same genetic background were allocated into the control group, proper dosage of drugs or distilled water were given by intragastric administration once daily for 12 weeks. After 12 weeks of administration, the learning and memory abilities of mice in each group was evaluated by the morris water maze test, amyloid precursor protein (APP), Aβand Aβlevels in hippocampus were detected by enzyme-linked immunosorbent assay, γ-secretase was detected by dual luciferase assaying, the levels of APH-1a, hypoxia-inducible factor 1α (HIF-1α), cAMP response element-binding protein (CREB) and PEN-2 and their mRNA expression was measured by Western blot and real-time polymerase chain reaction.</p><p><b>RESULTS</b>HYF can ameliorate learning and memory deficits in APP/PS1 transgenic mice by decreasing the escape latency, improving the number of platform crossing and swimming speed (P<0.01, P<0.05). HYF can decrease the levels of APP, Aβ, Aβand the activity of γ-secretase in hippocampus of Alzheimer's disease model mice. HYF can down-regulate the levels of CREB and PEN-2 and the expression of their mRNA.</p><p><b>CONCLUSION</b>HYF can improve the learning and memory ability by inhibiting the activity of γ-secretase through the CREB/PEN-2 signaling pathway, and this may be one of the therapeutic mechanisms of HYF in Alzheimer's disease.</p>


Subject(s)
Amyloid Precursor Protein Secretases , Metabolism , Amyloid beta-Protein Precursor , Metabolism , Animals , Cyclic AMP Response Element-Binding Protein , Genetics , Metabolism , Drugs, Chinese Herbal , Pharmacology , Therapeutic Uses , Endopeptidases , Genetics , Metabolism , Enzyme-Linked Immunosorbent Assay , Female , Gene Expression Regulation , Hippocampus , Metabolism , Pathology , Hypoxia-Inducible Factor 1, alpha Subunit , Genetics , Metabolism , Immunohistochemistry , Learning , Male , Memory Disorders , Drug Therapy , Genetics , Mice, Inbred C57BL , Mice, Transgenic , Presenilin-1 , Metabolism , Presenilin-2 , Genetics , Metabolism , RNA, Messenger , Genetics , Metabolism , Signal Transduction
12.
Braz. j. med. biol. res ; 50(6): e6049, 2017. tab, graf
Article in English | LILACS | ID: biblio-839314

ABSTRACT

Down syndrome cell adhesion molecule (DSCAM) is located within the Down syndrome critical region of chromosome 21. DSCAM is a broadly expressed neurodevelopmental protein involved in synaptogenesis, neurite outgrowth, and axon guidance. We previously demonstrated DSCAM overexpression in the cortex of amyloid precursor protein (APP) transgenic mice, suggesting possible regulatory interactions between APP and DSCAM. APP mice exhibit deficits in hippocampus-dependent learning and memory. In this preliminary study, we examined age-related changes in DSCAM expression within the hippocampus in 16 APP transgenic mice (1, 3, 6 and 12 months old). Hippocampus-dependent spatial memory was assessed in APP mice and age-matched wild type littermates (WTs) using the Morris water maze (MWM). The cellular distribution of hippocampal DSCAM and total expression at both mRNA and protein levels were measured by immunohistochemistry, qRT-PCR, and western blotting, respectively. APP mice exhibited spatial memory deficits in the MWM. Intense DSCAM immunoreactivity was observed in the dentate gyrus granule cell layer and hippocampal stratum pyramidale. Total hippocampal DSCAM mRNA and protein expression levels were substantially higher in APP mice than WTs at 1 and 3 months of age. Expression decreased with age in both groups but remained higher in APP mice. DSCAM is overexpressed in the hippocampus over the first 12 months of life in APP mice, but especially during maturation to adulthood. In conclusion, these results suggest an association between DSCAM and APP mice, which is characterized by neuropathology and behavioral deficits. These results provide some clues for future studies on the role of DSCAM overexpression in the precocious cognitive decline observed in APP transgenic mice.


Subject(s)
Animals , Amyloid beta-Protein Precursor/genetics , Cell Adhesion Molecules/metabolism , Hippocampus/metabolism , Age Factors , Brain/metabolism , Disease Models, Animal , Down Syndrome/metabolism , Genotype , Learning Disabilities/metabolism , Memory Disorders/metabolism , Mice, Inbred C57BL , Mice, Transgenic
13.
Chinese Medical Journal ; (24): 1835-1844, 2016.
Article in English | WPRIM | ID: wpr-251294

ABSTRACT

<p><b>BACKGROUND</b>Amyloid β (Aβ) has been established as a key factor for the pathological changes in the brains of patients with Alzheimer's disease (AD), and cellular senescence is closely associated with aging and cognitive impairment. However, it remains blurred whether, in the AD brains, Aβ accelerates the neuronal senescence and whether this senescence, in turn, impairs the cognitive function. This study aimed to explore the expression of senescence-associated genes in the hippocampal tissue from young to aged 5XFAD mice and their age-matched wild type (WT) mice to determine whether senescent neurons are present in the transgenic AD mouse model.</p><p><b>METHODS</b>The 5XFAD mice and age-matched wild type mice, both raised from 1 to 18 months, were enrolled in the study. The senescence-associated genes in the hippocampus were analyzed and differentially expressed genes (DEGs) were screened by quantitative real-time polymerase chain reaction. Cognitive performance of the mice was evaluated by Y-maze and Morris water maze tests. Oligomeric Aβ (oAβ) (1-42) was applied to culture primary neurons to simulate the in vivo manifestation. Aging-related proteins were detected by Western blotting analysis and immunofluorescence.</p><p><b>RESULTS</b>In 5XFAD mice, of all the DEGs, the senescence-associated marker p16 was most significantly increased, even at the early age. It was mainly localized in neurons, with a marginal expression in astrocytes (labeled as glutamine synthetase), nil expression in activated microglia (labeled as Iba1), and negatively correlated with the spatial cognitive impairments of 5XFAD mice. oAβ (1-42) induced the production of senescence-related protein p16, but not p53 in vitro, which was in line with the in vivo manifestation.</p><p><b>CONCLUSIONS</b>oAβ-accelerated neuronal senescence may be associated with the cognitive impairment in 5XFAD mice. Senescence-associated marker p16 can serve as an indicator to estimate the cognitive prognosis for AD population.</p>


Subject(s)
Alzheimer Disease , Metabolism , Amyloid Precursor Protein Secretases , Genetics , Metabolism , Amyloid beta-Peptides , Metabolism , Amyloid beta-Protein Precursor , Metabolism , Animals , Aspartic Acid Endopeptidases , Genetics , Metabolism , Brain , Metabolism , Cells, Cultured , Cellular Senescence , Genetics , Physiology , Cognition , Physiology , Cognition Disorders , Metabolism , Disease Models, Animal , Male , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons , Metabolism , Pathology , Real-Time Polymerase Chain Reaction
14.
Protein & Cell ; (12): 417-433, 2016.
Article in English | WPRIM | ID: wpr-757122

ABSTRACT

Microglia play a pivotal role in clearance of Aβ by degrading them in lysosomes, countering amyloid plaque pathogenesis in Alzheimer's disease (AD). Recent evidence suggests that lysosomal dysfunction leads to insufficient elimination of toxic protein aggregates. We tested whether enhancing lysosomal function with transcription factor EB (TFEB), an essential regulator modulating lysosomal pathways, would promote Aβ clearance in microglia. Here we show that microglial expression of TFEB facilitates fibrillar Aβ (fAβ) degradation and reduces deposited amyloid plaques, which are further enhanced by deacetylation of TFEB. Using mass spectrometry analysis, we firstly confirmed acetylation as a previously unreported modification of TFEB and found that SIRT1 directly interacted with and deacetylated TFEB at lysine residue 116. Subsequently, SIRT1 overexpression enhanced lysosomal function and fAβ degradation by upregulating transcriptional levels of TFEB downstream targets, which could be inhibited when TFEB was knocked down. Furthermore, overexpression of deacetylated TFEB at K116R mutant in microglia accelerated intracellular fAβ degradation by stimulating lysosomal biogenesis and greatly reduced the deposited amyloid plaques in the brain slices of APP/PS1 transgenic mice. Our findings reveal that deacetylation of TFEB could regulate lysosomal biogenesis and fAβ degradation, making microglial activation of TFEB a possible strategy for attenuating amyloid plaque deposition in AD.


Subject(s)
Alzheimer Disease , Metabolism , Pathology , Amyloid beta-Peptides , Metabolism , Amyloid beta-Protein Precursor , Genetics , Metabolism , Animals , Basic Helix-Loop-Helix Leucine Zipper Transcription Factors , Chemistry , Genetics , Metabolism , Brain , Metabolism , Cells, Cultured , Chloride Channels , Genetics , Metabolism , Disease Models, Animal , HEK293 Cells , Humans , Lysosomes , Genetics , Metabolism , Mice , Mice, Transgenic , Microglia , Cell Biology , Metabolism , Mutagenesis, Site-Directed , Peptides , Chemistry , Protein Binding , RNA Interference , Sirtuin 1 , Genetics , Metabolism
15.
Rev. méd. Chile ; 143(1): 120-123, ene. 2015. ilus
Article in Spanish | LILACS | ID: lil-742561

ABSTRACT

We report a 37 years old male with a dermatomyositis treated with oral cyclophosphamide. He was admitted to the hospital due to a zone of skin necrosis with purulent exudate, located in the second left toe. A complete blood count showed a leukocyte count of 2,600 cells/mm³. A Chest CAT scan showed a pneumomediastinum with emphysema of adjacent soft tissue. Cyclophosphamide was discontinued and leukocyte count improved. The affected toe was amputated and a chest CAT scan showed a partial resolution of the pneumomediastinum. We discuss and review the pathogenesis, clinical presentation and management of pneumomediastinum and cutaneous necrosis in association with dermatomyositis.


Subject(s)
Animals , Female , Rats , Benzoxazines/therapeutic use , Cannabinoids/agonists , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Encephalomyelitis, Autoimmune, Experimental/pathology , Morpholines/therapeutic use , Naphthalenes/therapeutic use , Neurons/drug effects , Oligodendroglia/drug effects , Analysis of Variance , Amyloid beta-Protein Precursor/metabolism , Caspase 9/metabolism , /metabolism , Cell Count/methods , Central Nervous System/pathology , Cytokines/genetics , Cytokines/metabolism , Disease Models, Animal , Encephalomyelitis, Autoimmune, Experimental/complications , Macrophages/drug effects , Neurologic Examination , Nerve Degeneration/etiology , Nerve Degeneration/prevention & control , Poly(ADP-ribose) Polymerases/metabolism , Spinal Cord/drug effects , Spinal Cord/pathology , T-Lymphocytes/drug effects , Time Factors
16.
Article in English | WPRIM | ID: wpr-264612

ABSTRACT

<p><b>OBJECTIVE</b>The inhalation anesthetic isoflurane has been shown to induce mitochondrial dysfunction and caspase activation, which may lead to learning and memory impairment. Ginsenoside Rg1 is reported to be neuroprotective. We therefore set out to determine whether ginsenoside Rg1 can attenuate isoflurane-induced caspase activation via inhibiting mitochondrial dysfunction.</p><p><b>METHODS</b>We investigated the effects of ginsenoside Rg1 at concentrations of 12.5, 25, and 50 μmol/L and pretreatment times of 12 h and 24 h on isoflurane-induced caspase-3 activation in H4 naïve and stably transfected H4 human neuroglioma cells that express full-length human amyloid precursor protein (APP) (H4-APP cells). For mitochondrial dysfunction, we assessed mitochondrial permeability transition pore (mPTP) and adenosine-5'-triphosphate (ATP) levels. We employed Western blot analysis, chemiluminescence, and flowcytometry.</p><p><b>RESULTS</b>Here we show that pretreatment with 50 µmol/L ginsenoside Rg1 for 12 h attenuated isoflurane-induced caspase-3 activation and mitochondrial dysfunction in H4-APP cells, while pretreatment with 25 and 50 µmol/L ginsenoside Rg1 for 24 h attenuated isoflurane-induced caspase-3 activation and mitochondrial dysfunction in both H4 naïve and H4-APP cells.</p><p><b>CONCLUSION</b>These data suggest that ginsenoside Rg1 may ameliorate isoflurane-induced caspase-3 activation by inhibiting mitochondrial dysfunction. Pending further studies, these findings might recommend the use of ginsenoside Rg1 in preventing and treating isoflurane-induced neurotoxicity.</p>


Subject(s)
Amyloid beta-Protein Precursor , Metabolism , Caspase 3 , Genetics , Metabolism , Cell Line, Tumor , Gene Expression Regulation, Enzymologic , Ginsenosides , Pharmacology , Glioma , Drug Therapy , Humans , Ionomycin , Pharmacology , Isoflurane , Pharmacology , Mitochondria , Metabolism
17.
Article in Chinese | WPRIM | ID: wpr-297378

ABSTRACT

<p><b>OBJECTIVE</b>To explore the mechanism of three kinds extracts (saponins, volatile components, polysaccharide components) of Qingxin Kaiqiao Recipe (QKR) in improving learning and memory capabilities of Alzheimer's disease (AD) rats.</p><p><b>METHODS</b>A controlled comparison method was used. Totally 56 male SD rats were randomly divided into seven groups, i.e., the normal control group, the sham-operation group, the model group, the Aricept group, the saponin group, the benzene group, and the polysaccharide group, 8 in each group. AD rat model was established by bilateral hippocampus injection of Aβ1-40 (2 µL, 2.5 µg/µL). The next day after modeling rats in the saponin group, the benzene group, and the polysaccharide group, the saponin group, the Aricept group were intragastrically administered with saponin (at the daily dose of 9 mL/kg, 2.1 g/mL) , benzene (at the daily dose of 3.33 mL/kg, 5.7 g/mL) , polysaccharide (at the daily dose of 8.33 mL/kg, 2.28 g/mL), Aricept (at the daily dose of 1.67 mg/kg), respectively, once a day for 2 consecutive weeks from 10 am every day. Equal volume of normal saline was intragastrically administered to rats in the normal control group and the model group. Learning and memory capabilities were detected using water maze 2 weeks later. Expression levels of synaptotagmin-1 (Syt-1), interleukin-1β (IL-1β), glia fibrillary acidic protein (GFAP), and β-amyloid precursor protein (βAPP) in the cortex and hippocampus of AD rats were detected using immunohistochemistry.</p><p><b>RESULTS</b>Learning and memory capabilities could be improved by three kinds extracts of QKR. There was no statistical difference in the escape latency between the polysaccharide group and the model group (P >0. 05). The escape lacency was shortened in the rest treatment groups (P < 0.05). The escape latency was obviously prolonged in three kinds extracts of QKR groups, when compared with the Aricept group (P < 0.05, P < 0.01). Compared with the model group, times for crossing platforms were significantly increased in the saponin group and the Aricept group (P < 0.05). Compared with the Aricept group, average times for crossing platforms were significantly lessened in three kinds extracts of QKR groups (P < 0.01). Compared with the sham-operation group, expression levels of Syt-1, IL-1β, GFAP, and βAPP in the cortex and hippocampus were increased in the model group (P < 0.01). Compared with the model group, the expression of cortical Syt-1 increased in the saponin group and the benzene group; the expression of cortical IL-1β increased in the benzene group and the polysaccharide group; the expression of hippocampal GFAP increased in the three kinds extracts of QKR groups; expression levels of Syt-1, IL-1β, GFAP, and β-APP in the cortex and hippocampus decreased in the rest treatment groups (all P < 0.05, P < 0.01). Compared with the Aricept group, expression levels of Syt-1, IL-1β, GFAP, and βAPP in the cortex and hippocampus were significantly increased in three kinds extracts of QKR groups (P < 0.05, P < 0.01).</p><p><b>CONCLUSION</b>Three kinds extracts of QKR might play roles in anti-AD possibly by decreasing expression levels of Syt-1, IL-1β, GFAP, and βAPP in the cortex and hippocampus.</p>


Subject(s)
Alzheimer Disease , Amyloid beta-Protein Precursor , Animals , Disease Models, Animal , Drugs, Chinese Herbal , Pharmacology , Glial Fibrillary Acidic Protein , Hippocampus , Interleukin-1beta , Learning , Male , Memory , Rats , Rats, Sprague-Dawley , Saponins
18.
Medicina (B.Aires) ; 74(4): 282-286, ago. 2014. ilus, graf
Article in Spanish | LILACS | ID: lil-734386

ABSTRACT

Existen múltiples evidencias de alteraciones neuronales y gliales en etapas avanzadas de la enfemedad de Alzheimer con abundantes depósitos cerebrales de beta amiloide, aunque hay pocos datos de cambios tempranos que podrían contribuir al desarrollo de la enfermedad. Evaluamos alteraciones morfológicas neuronales y gliales, y cambios cognitivos y emocionales tempranos en ratones transgénicos PDAPP-J20 (Tg), portadores del gen humano de APP (amyloid precursor protein) mutado, a los 5 meses de edad, aún sin depósitos amiloides en el hipocampo y con niveles bajos de péptidos amiloides cerebrales. Mediante inmunohistoquímica para NeuN, los Tg presentaron menor número de neuronas piramidales y granulares en el hipocampo, junto con un menor volumen de la estructura, en comparación con los controles no transgénicos. La neurogénesis se encontró afectada, evidenciada por reducido número de neuronas DCX+ en el giro dentado. En la región CA3, hubo una menor densidad de sinaptofisina sugiriendo alteraciones sinápticas entre neuronas granulares y piramidales, sin cambios en la densidad de espinas dendríticas en CA1. Utilizando microscopía confocal, observamos una disminución del número de astrocitos GFAP+ con una reducción de la complejidad celular, sugiriendo atrofia glial. Se detectó un déficit cognitivo (reconocimiento de localización novedosa de un objeto) y un aumento de la ansiedad (campo abierto) en los Tg, con aumento en los núcleos c-Fos+ en amígdala, evidenciando el papel de la emocionalidad en los inicios de la enfermedad. El estudio de las alteraciones iniciales en la enfermedad amiloide podría contribuir al desarrollo de métodos de diagnóstico temprano y de terapéutica preventiva.


Although there is strong evidence about neuronal and glial disturbances at advanced stages of Alzheimer’s disease, less attention has been directed to early, pre-amyloid changes that could contribute to the progression of the disease. We evaluated neuronal and glial morphological changes and behavioral disturbances in PDAPP-J20 transgenic (Tg) mice, carrying mutated human APP gene (amyloid precursor protein), at 5 months of age, before brain amyloid deposition occurs. Using NeuN immunohistochemistry we found decreased numbers of pyramidal and granular neurons in the hippocampus associated with a reduction of hippocampal volume in Tg mice compared with controls. Neurogenesis was impaired, evidenced by means of DCX immunohistochemistry in the dentate gyrus. In the CA3 region we found a decreased density of synaptophysin, suggesting synaptic disturbance, but no changes were found in CA1 synaptic spine density. Using confocal microscopy we observed decreased number and cell complexity of GFAP+ astrocytes, indicating potential glial atrophy. Cognitive impairment (novel location recognition test) and increased anxiety (open field) were detected in Tg mice, associated with more c-Fos+ nuclei in the amygdala, possibly indicating a role for emotionality in early stages of the disease. The study of early alterations in the course of amyloid pathology could contribute to the development of diagnostic and preventive strategies.


Subject(s)
Animals , Humans , Alzheimer Disease/pathology , Amyloid beta-Protein Precursor/genetics , Disease Models, Animal , Hippocampus/pathology , Cognitive Dysfunction/pathology , Plaque, Amyloid/pathology , Amyloid beta-Protein Precursor/metabolism , Anxiety Disorders/pathology , Astrocytes/pathology , Disease Progression , Dentate Gyrus/metabolism , Mice, Transgenic , Cognitive Dysfunction/genetics , Cognitive Dysfunction/metabolism , Neurogenesis/physiology , Neurons/pathology , Synaptophysin/isolation & purification
19.
Acta Physiologica Sinica ; (6): 631-638, 2014.
Article in English | WPRIM | ID: wpr-255992

ABSTRACT

To investigate the role and possible molecular mechanism of astrocytes in inflammation and amyloid β-protein (Aβ) formation, in this research, by using LPS to stimulate cultured rat astrocytes in vitro with or without anti-Toll-like receptor 4 (TLR4) antibody pretreatment, we first detected the TLR4, TNF-α, IL-1β, β-amyloid precursor protein (β-APP) and β-site APP clearing enzyme 1 (BACE1) mRNA with real-time PCR, and TLR4, NF-κB/P65 protein in cultured astrocytes by Western blot, and then further probed the translocation of NF-κB/P65 using immunofluorescence and the contents of TNF-α, IL-1β and Aβ in culture supernatant through ELISA. We found that all of these indexes increased at different degrees after LPS-stimulation. However, if pretreatment with anti- TLR4 antibody, such stimulating effects of LPS on the nuclear translocation of NF-κB/P65 and TNF-α, IL-1β, Aβ contents in astrocytic culture supernatant were reduced significantly or disappeared in comparison with the group with only LPS-administration. Our results suggest that TLR4 in astrocytes might play an important role in the inflammation and Aβ formation through the TLR4/NF-κB signaling pathway, thus providing new knowledge and understanding of the inflammatory hypothesis of AD pathogenesis.


Subject(s)
Amyloid Precursor Protein Secretases , Metabolism , Amyloid beta-Protein Precursor , Metabolism , Animals , Aspartic Acid Endopeptidases , Metabolism , Astrocytes , Metabolism , Cells, Cultured , Cerebral Cortex , Cell Biology , Inflammation , Metabolism , Interleukin-1beta , Metabolism , RNA, Messenger , Rats , Real-Time Polymerase Chain Reaction , Signal Transduction , Toll-Like Receptor 4 , Metabolism , Transcription Factor RelA , Metabolism , Tumor Necrosis Factor-alpha , Metabolism
20.
Chinese Medical Journal ; (24): 718-723, 2014.
Article in English | WPRIM | ID: wpr-317911

ABSTRACT

<p><b>BACKGROUND</b>We showed in our previous study that the N-terminal 17-mer peptide of amyloid precursor protein (APP17-mer peptide), an active peptide segment with trophic and antioxidative effects, protects skin fibroblasts against ultraviolet (UV) damage and downregulates matrix metalloproteinase 1 (MMP-1) expression. The aim of the current study was to explore the protective effects of P165, the N-terminal 5-mer peptide analog of amyloid precursor protein that is resistant to enzymolysis, on UVA-induced damage in human dermal fibroblasts (HDFs).</p><p><b>METHODS</b>HDFs were cultured in Dulbecco's modified Eagle's medium without and with P165 (concentrations were 1, 10, and 100 µmol/L). Then, 15 J/cm(2) UVA irradiation was used to obtain the UV-irradiated model. Cell proliferation was analyzed using MTT kit. The collagen type I and MMP-1 contents in cell lysate were determined by enzyme-linked immunosorbent assay (ELISA). Fluorometric assays were performed to detect the formation of intracellular reactive oxygen species (ROS) in the cells.</p><p><b>RESULTS</b>P165 significantly protected the HDFs against UVA-induced cytotoxicity. Compared with the UVA-irradiated control, 1, 10, and 100 µmol/L P165 elevated cell proliferation by 14.98% (P < 0.05), 17.52% (P < 0.01) and 28.34% (P < 0.001), respectively. Simultaneously, 10 and 100 µmol/L P165 increased collagen type I content (both P < 0.05). Moreover, P165 treatment (all concentrations) also markedly suppressed the UVA-induced MMP-1 expression (all P < 0.001). P165 at 1, 10, and 100 µmol/L also reduced UVA-induced ROS generation by 11.27%, 13.69% (both P < 0.05), and 25.48% (P < 0.001), respectively.</p><p><b>CONCLUSIONS</b>P165 could protect the HDFs against UVA-induced photodamage, including cytotoxicity, and MMP-1 generation. Furthermore, it also increased the collagen type I content in the cells. The inhibitory effect on intracellular ROS generation might be involved in these photoprotective effects. Thus, P165 may be a useful candidate in the prevention and treatment of skin photoaging.</p>


Subject(s)
Amyloid beta-Protein Precursor , Pharmacology , Cells, Cultured , Fibroblasts , Radiation Effects , Humans , Skin , Cell Biology , Ultraviolet Rays
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