Investigation of anti-Alzheimer's activity of aqueous extract of areca nuts (Areca catechu L): in vitro and in vivo studies / Investigación de la actividad anti-Alzheimer del extracto acuoso de nueces de areca (Areca catechu L): estudios in vitro e in vivo

Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Sever cognitive and memory impairments, huge increase in the prevalence of the disease, and lacking definite cure have absorbed worldwide efforts to develop therapeutic approaches. Since many drugs have failed in the clinical trials due to multifactorial nature of AD, symptomatic treatments are still in the center attention and now, nootropic medicinal plants have been found as versatile ameliorators to reverse memory disorders. In this work, anti-Alzheimer's activity of aqueous extract of areca nuts (Areca catechu L.) was investigated via in vitro and in vivo studies. It depicted good amyloid ß (Aß) aggregation inhibitory activity, 82% at 100 µg/mL. In addition, it inhibited beta-secretase 1 (BACE1) with IC50 value of 19.03 µg/mL. Evaluation of neuroprotectivity of the aqueous extract of the plant against H2O2-induced cell death in PC12 neurons revealed 84.5% protection at 1 µg/mL. It should be noted that according to our results obtained from Morris Water Maze (MWM) test, the extract reversed scopolamine-induced memory deficit in rats at concentrations of 1.5 and 3 mg/kg.

La enfermedad de Alzheimer (EA) es un trastorno neurodegenerativo relacionado con la edad. Los severos deterioros cognitivos y de la memoria, el enorme aumento de la prevalencia de la enfermedad y la falta de una cura definitiva han absorbido los esfuerzos mundiales para desarrollar enfoques terapéuticos. Dado que muchos fármacos han fallado en los ensayos clínicos debido a la naturaleza multifactorial de la EA, los tratamientos sintomáticos siguen siendo el centro de atención y ahora, las plantas medicinales nootrópicas se han encontrado como mejoradores versátiles para revertir los trastornos de la memoria. En este trabajo, se investigó la actividad anti-Alzheimer del extracto acuoso de nueces de areca (Areca catechu L.) mediante estudios in vitro e in vivo. Representaba una buena actividad inhibidora de la agregación de amiloide ß (Aß), 82% a 100 µg/mL. Además, inhibió la beta-secretasa 1 (BACE1) con un valor de CI50 de 19,03 µg/mL. La evaluación de la neuroprotección del extracto acuoso de la planta contra la muerte celular inducida por H2O2 en neuronas PC12 reveló una protección del 84,5% a 1 µg/mL. Cabe señalar que, de acuerdo con nuestros resultados obtenidos de la prueba Morris Water Maze (MWM), el extracto revirtió el déficit de memoria inducido por escopolamina en ratas a concentraciones de 1,5 y 3 mg/kg.

Evolution of blood-brain barrier in brain diseases and related systemic nanoscale brain-targeting drug delivery strategies

Blood-brain barrier (BBB) strictly controls matter exchange between blood and brain, and severely limits brain penetration of systemically administered drugs, resulting in ineffective drug therapy of brain diseases. However, during the onset and progression of brain diseases, BBB alterations evolve inevitably. In this review, we focus on nanoscale brain-targeting drug delivery strategies designed based on BBB evolutions and related applications in various brain diseases including Alzheimer's disease, Parkinson's disease, epilepsy, stroke, traumatic brain injury and brain tumor. The advances on optimization of small molecules for BBB crossing and non-systemic administration routes (

Physalin B reduces Aβ secretion through down-regulation of BACE1 expression by activating FoxO1 and inhibiting STAT3 phosphorylation / 中国天然药物

Physalin B (PB), one of the major active steroidal constituents of Solanaceae Physalis plants, has a wide variety of biological activities. We found that PB significantly down-regulated β-amyloid (Aβ) secretion in N2a/APPsw cells. However, the underlying mechanisms are not well understood. In the current study, we investigated the changes in key enzymes involved in β-amyloid precursor protein (APP) metabolism and other APP metabolites by treating N2a/APPsw cells with PB at different concentrations. The results indicated that PB reduced Aβ secretion, which was caused by down-regulation of β-secretase (BACE1) expression, as indicated at both the protein and mRNA levels. Further research revealed that PB regulated BACE1 expression by inducing the activation of forkhead box O1 (FoxO1) and inhibiting the phosphorylation of signal transducer and activator of transcription 3 (STAT3). In addition, the effect of PB on BACE1 expression and Aβ secretion was reversed by treatment with FoxO1 siRNA and STAT3 antagonist S3I-201. In conclusion, these data demonstrated that PB can effectively down-regulate the expression of BACE1 to reduce Aβsecretion by activating the expression of FoxO1 and inhibiting the phosphorylation of STAT3.

Osthole suppresses BACE-1 expression by up-regulating miR-9 in Alzheimer's disease / 中国药理学通报

Aim: To explore the mechanism of osthole regulating the expression of miR-9 to delay the occurance of Alzheimer' s disease (AD). Methods: The miRNA which expressed differently with osthole treatment was selected by microarray; the target gene binding to miRNA-9 was verified by databases and Cytoscape; the SH-SY5Y cells with over expression of APP were established using Lipofectamine2000. The cell viability was determined by MTT assay. The miRNA-9 inhibitor was transfected into cells, and the expression of miRNA-9 and BACE-1 mRNA was determined by RT-PCR; the changes of BACE-1 protein were determined by Western blot. Results: The results of database showed that osthole-mediated miRNA-9 was combined with BACE-1 genes. Our lab had established SH-SY5Y cells with over expression of APP. The results of MTT assay showed that 50 p,mol · L-1 osthole had a protective effect on cells. Osthole could increase the expression of miRNA-9, and the expression of miR- 9 was lowest in inhibitor group determined by RT- PCR. Osthole decreased the expression of BACE-1 mRNA and protein compared with APP group, and the expression of BACE-1 was highest in inhibitor group. Conclusion: Osthole plays a protective role in AD partly through suppressing the expression of BACE-1 by up-regulating miRNA-9.

Small interfering RNA delivery to the neurons near the amyloid plaques for improved treatment of Alzheimer׳s disease

Gene therapy represents a promising treatment for the Alzheimer׳s disease (AD). However, gene delivery specific to brain lesions through systemic administration remains big challenge. In our previous work, we have developed an siRNA nanocomplex able to be specifically delivered to the amyloid plaques through surface modification with both CGN peptide for the blood-brain barrier (BBB) penetration and QSH peptide for -amyloid binding. But, whether the as-designed nanocomplex could indeed improve the gene accumulation in the impaired neuron cells and ameliorate AD-associated symptoms remains further study. Herein, we prepared the nanocomplexes with an siRNA against -site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme of A production, as the therapeutic siRNA of AD. The nanocomplexes exhibited high distribution in the A deposits-enriched hippocampus, especially in the neurons near the amyloid plaques after intravenous administration. In APP/PS1 transgenic mice, the nanocomplexes down-regulated BACE1 in both mRNA and protein levels, as well as A and amyloid plaques to the level of wild-type mice. Moreover, the nanocomplexes significantly increased the level of synaptophysin and rescued memory loss of the AD transgenic mice without hematological or histological toxicity. Taken together, this work presented direct evidences that the design of precise gene delivery to the AD lesions markedly improves the therapeutic outcome.

Isolation and Quantitative Analysis of BACE1 Inhibitory Compounds from Cirsium maackii Flower

The purpose of our study was to evaluate anti-AD potential of Cirsium maackii flowers. MeOH extract, CH2Cl2, EtOAc, and n-BuOH fraction of this flower notably inhibited BACE1 (IC₅₀ = 76.47 ± 1.66, 22.98 ± 1.45, 8.65 ± 0.63, and 72.47 ± 3.04 µg/mL, respectively). β-amyrenone (49.70 mg) (1), lupeol acetate (1.43 g) (2), lupeol (1.22 g) (3), lupenone (23.70 mg) (4), β-sitosterol (1.01 g) (6), and β-sitosterol glucoside (13.00 mg) (7) from CH₂Cl₂, apigenin (100.20 mg) (8), luteolin (19.00 mg) (9), apigenin 7-O-glucuronide methyl ester (21.30 mg) (14), and tracheloside (53.70 mg) (5) from EtOAc, apigenin 5-O-glucoside (11.00 mg) (10), luteolin 5-O-glucoside (11.00 mg) (11) and apigenin 7-O-glucuronide (91.00 mg) (12) from n-BuOH, and luteolin 7-O-glucuronide (22.00 mg) (13) from H₂O fraction were isolated. HPLC showed high levels of 8, 9 and 12 in MeOH extract (33.07 ± 0.07, 31. 44 ± 0.17 and 16.89 ± 0.33 mg/g, respectively), EtOAc (161.01 ± 1.78, 96.93 ± 0.34 and 73.38 ± 0.06 mg/g, respectively), and n-BuOH fraction (32.18 ± 0.33, 44.31 ± 0.32 and 105.94 ± 0.36 mg/g, respectively). Since, 3 and 9 are well-known BACE1 inhibitors, the anti-AD activity of C. maackii flower might be attributable to their presence.

Synthesis and Development of BACE 1 Inhibitor for Alzheimer’s Diseases from Medicinal Plants

Medicinal plants have shown great promise in treating Alzheimer’s disease (AD), which significantly contributes to the production of pharmaceutical and cosmetic molecules with biologically efficient moieties. Plants derived bioactive compounds have been isolated from the medicinal plants and are used in brain diseases. Accountable for brain diseases. Plant extracts have undesirable effects such as acute or chronic toxicity; this could be involved in the delay or discouraging the adoption to the brain cells for proper and effective treatment. β-secretase is the primary protease in the process of producing Amyloid β (Aβ), which is an amyloid precursor protein in brain cells. This review is focused on the numerous different bioactive compounds present in medicinal plants such as Flavonoids, Phenyl propanoids, Prenylated flavones, Naphthoquinone, Resveratrol, Phlorotannins and Glycoside derivatives. Even though medicinal plants and their functional derivatives were reported to be good source of alternative medicines for long sought diseases like AD; but clinical trials on human are yet to be beyond the preliminary stages. The useful applications of these compounds, as bio-markers are also being explored, to further enrich control of Alzheimer’s.

Clinical Research on Alzheimer's Disease: Progress and Perspectives / 神经科学通报·英文版

Alzheimer's disease (AD), the most common type of dementia, is becoming a major challenge for global health and social care. However, the current understanding of AD pathogenesis is limited, and no early diagnosis and disease-modifying therapy are currently available. During the past year, significant progress has been made in clinical research on the diagnosis, prevention, and treatment of AD. In this review, we summarize the latest achievements, including diagnostic biomarkers, polygenic hazard score, amyloid and tau PET imaging, clinical trials targeting amyloid-beta (Aβ), tau, and neurotransmitters, early intervention, and primary prevention and systemic intervention approaches, and provide novel perspectives for further efforts to understand and cure the disease.

Effect of microenvironment on β-site amyloid precursor protein cleaving enzyme 1 expression in PC12 Cells / 上海交通大学学报（医学版）

Objective • To investigate the effect of microenvironment on the expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) in PC12 cells. Methods • The PC12 cells were respectively treated with thapsigargin (Tg), lipopolysaccharide (LPS), H2O2, hypoxia incubator and hypoglycemic medium to produce mild endoplasmic reticulum stress (ERS), inflammatory environment, mild oxidative stress, hypoxia and low glucose conditions. Western blotting and fluorescence quantitative PCR were used to detect the expression of BACE1 protein and BACE1 mRNA. Results • After PC12 cells were treated with Tg (0.13 μmol/L) for 12 h or LPS (0.01 mg/mL) for 36 h, BACE1 protein and mRNA levels were significantly up-regulated (P0.05). Conclusion • Mild ERS and inflammatory condition can up-regulate BACE1 mRNA and protein expression in PC12 cells.

The study of plasma biomarker for early diagnosis of Alzheimer disease / 中华老年医学杂志

Objective To extract,detect and validate the BACE1 expression-regulating lncRNA BACE1-AS containing in the plasma of patients with AD in Chinese Han people,so as to provide a research basis for plasma BACE1-AS in AD to be a plasma molecular markers and a new target for treatment.Methods The study included 27 AD patients and 28 normal individuals whose age,sex,education,etc.were matched between AD and controi group.Total RNA extraction of plasma was performed using guanidine isothiocyanate-phenol chloroform method.Target gene amplification was executed by RT-PCR Kit.Gel electrophoresis and its imaging analysis were performed on the RT-PCR amplified products.Target gene amplified products were sequenced,its sequence consistency with gene bank-reported sequence were compared,and differences in target gene transcription between the two groups were statistically analyzed.Results The positive expression rates of BACE1-AS were 18.5％(5/27 cases)in ADgroup and 0.0％ in control group,respectively(P=0.023).In comparison between two groups,there was a significant difference (P =0.023).Gene sequencing confirmed the consistent between BACE1-AS gene sequence of 3 patients with AD and Gene Bank's BACE1-AS sequence.But the two other AD cases showed individual base replacement.Conclusions Compared with the healthy control group,patients with AD show specific BACE1 expression-regulating lncRNA BACE1-AS in plasma of AD patients,which provides theoretical basis for BACE1 AS as a biomarker of AD diagnosis and a new target in therapy of AD.

Influence of aluminum on microRNA29 and β-site amyloid precursor protein cleaving enzyme 1 in the brain of rats / 中华劳动卫生职业病杂志

Objective@#To investigate the influence of aluminum on microRNA29 (miR29) subtypes miR29a, miR29a*, miR29b1, miR29b2, miR29c1, and miR29c2 and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) in the brain of rats.@*Methods@#A total of 40 Sprague-Dawley rats were randomly divided into control group and 15, 30, and 45 μmol/kg groups according to the body weight, with 10 rats in each group. The rats were exposed to aluminum (at a dose of 0.1 ml/100 g body weight) by intraperitoneal injection for 8 weeks. The rats in control group were given 0.9% normal saline, and those in exposure groups were given aluminum-maltolate (equivalent volumesof maltolate and aluminum solution were mixed before exposure) . The cerebral cortex and hippocampus were isolated after exposure ended; Western blotting was used to measure the change in BACE1 expression, and real-time reverse transcription polymerase chain reaction was used to measure the mRNA expression of miR29 subtypes in the cerebral cortex and hippocampus.@*Results@#Compared with the control group, the 45 μmol/kg group had a significant increase in BACE1 expression in the cerebral cortex, and the 30 and 45 μmol/kg groups had significant increases in BACE1 expression in the hippocampus (all P<0.05) . Compared with the control group, the 15, 30, and 45 μmol/kg groups had significant reductions in the mRNA expression of miR29a*, miR29b2, miR29c1, and miR29c2 in the cerebral cortex and hippocampus (all P<0.01) , and the 45 μmol/kg group had significant reductions in the mRNA expression of miR29a and miR29b1 in the cerebral cortex and hippocampus (all P<0.05) . The results of correlation analysis showed that there was no correlation between the mRNA expression of miR29a*, miR29b2, miR29c1, and miR29c2 and BACE1 expression in the cerebral cortex and hippocampus (all P>0.05) , while the mRNA expression of miR29a and miR29b1 was negatively correlated with BACE1 expression (cerebral cortex: r=-0.987 and -0.981, P<0.05; hippocampus: r=-0.992 and -0.991, P<0.05) .@*Conclusion@#Aluminum can reduce the expression of miR29 subtypes and increase BACE1 expression in the brain, and the expression of miR29a and miR29b1 is negatively correlated with BACE1 expression.

Comparative molecular docking studies of lupeol and lupenone isolated from Pueraria lobata that inhibits BACE1: Probable remedies for Alzheimer's disease

Objective To discover lead lupane triterpenoid's potential isolated from Pueraria lobata roots against β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which serve as a rate limiting step in amyloid beta (Aβ) production altering the course of Alzheimer's disease. In addition, enzyme kinetics study and molecular docking were conducted to establish the inhibition type and structure activity relationship. Methods A systematic study of 70% ethanolic P. lobata root extract was employed to identify its BACE1 inhibitory potential. Further, BACE1 inhibitory potential of two lupane terpenoids, yielded from ethanolic extract, was assessed. In order to determine their inhibition mode, Lineweaver–Burk plots and Michaelis–Menten model for BACE1 was performed. AutoDock 4.2 program in addition determined the molecular interaction of BACE1 with isolated terpenoids. Results Considering the inhibitory potential of 70% ethanolic extract of P. lobata against BACE1 (IC

Comparative molecular docking studies of lupeol and lupenone isolated from Pueraria lobata that inhibits BACE1: Probable remedies for Alzheimer's disease

OBJECTIVE@#To discover lead lupane triterpenoid's potential isolated from Pueraria lobata roots against β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which serve as a rate limiting step in amyloid beta (Aβ) production altering the course of Alzheimer's disease. In addition, enzyme kinetics study and molecular docking were conducted to establish the inhibition type and structure activity relationship.@*METHODS@#A systematic study of 70% ethanolic P. lobata root extract was employed to identify its BACE1 inhibitory potential. Further, BACE1 inhibitory potential of two lupane terpenoids, yielded from ethanolic extract, was assessed. In order to determine their inhibition mode, Lineweaver-Burk plots and Michaelis-Menten model for BACE1 was performed. AutoDock 4.2 program in addition determined the molecular interaction of BACE1 with isolated terpenoids.@*RESULTS@#Considering the inhibitory potential of 70% ethanolic extract of P. lobata against BACE1 (IC = 80.35 μg/mL), lupeol and lupenone were subsequently isolated and exhibited notable or moderate BACE1 inhibitory activity with IC values of 5.12 and 62.98 μmol/L, respectively, as compared to the positive control quercetin (IC = 21.28 μmol/L). The enzyme kinetics study enabled us to identify both compounds as competitive inhibitors, where lupeol displayed a very potent inhibition against BACE1 with low inhibition constant (K) value of 1.43 μmol/L, signifying greater binding affinity. In order to understand the binding mechanism and structure-activity relationship of two triterpene-based BACE1 inhibitors, we employed computer aided docking studies which evidently revealed that hydroxyl group of lupeol formed two hydrogen bonds with the ASP32 (catalytic aspartic residue) and SER35 residues of BACE1 with the binding energy of (-8.2 kcal/mol), while the ketone group of lupenone did not form any hydrogen bonds with BACE1 giving evidence for less binding affinity. These results in turn have predicted the dependence of the inhibitory activity in the presence of hydroxyl group which has provided a new basis for BACE1 blockade.@*CONCLUSIONS@#Our results have successfully explored the molecular mechanism of lupane triterpenoids via BACE1 inhibition, suggesting that lupeol in particular could be utilized as a useful therapeutic and preventive agent to mitigate Alzheimer's disease.

Anti-Alzheimer's disease potential of coumarins from Angelica decursiva and Artemisia capillaris and structure-activity analysis

Objective: To use structure-activity analysis to study the anti-Alzheimer's disease (anti-AD) activity of natural coumarins isolated from Angelica decursiva and Artemisia capillaris, along with one purchased coumarin (daphnetin). Methods: Umbelliferone, umbelliferone 6-carboxylic acid, scopoletin, isoscopoletin, 7-methoxy coumarin, scoparone, scopolin, and esculetin have been previously isolated; however 2'-isopropyl psoralene was isolated from Angelica decursiva for the first time to evaluate their inhibitory effects against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) enzyme activity. We scrutinized the potentials of coumarins as cholinesterase and BACE1 inhibitors via enzyme kinetics and molecular docking simulation. Results: Among the test compounds, umbelliferone 6-carboxylic acid, esculetin and daphnetin exhibited potent inhibitory activity against AChE, BChE and BACE1. Both esculetin and daphnetin have a catechol group and exhibit significant anti-AD activity against AChE and BChE. In contrast, presence of a sugar moiety and methoxylation markedly reduced the anti-AD activity of the coumarins investigated in this study. With respect to BACE1 inhibition, umbelliferone 6-carboxylic acid, esculetin and daphnetin contained carboxyl or catechol groups, which significantly contributed to their anti-AD activities. To further investigate these results, we generated a 3D structure of BACE1 using Autodock 4.2 and simulated binding of umbelliferone 6-carboxylic acid, esculetin and daphnetin. Docking simulations showed that different residues of BACE1 interacted with hydroxyl and carboxylic groups, and the binding energies of umbelliferone 6-carboxylic acid, esculetin and daphnetin were negative (-4.58, -6.25 and -6.37 kcal/mol respectively). Conclusions: Taken together, our results suggest that umbelliferone 6-carboxylic acid, esculetin and daphnetin have anti-AD effects by inhibiting AChE, BChE and BACE1, which might be useful against AD.

BACE1 inhibitors: From peptide mimics to small molecules / 国际药学研究杂志

Alzheimer’s disease(AD)is a chronic neurodegenerative disorder. According to the amyloid cascade hypothesis, abnormal accumulation of amyloid peptides(Aβ)in the brain resulting in neuronal toxicity is the main cause of AD. β-secretase1 (BACE1)is a rate-limiting enzyme that hydrolyzes β-amyloid precursor protein(β-APP)to produce amyloid peptides(Aβ). Therefore, BACE1 has been considered to be an attractive therapeutic target for the treatment of AD. Different structural classes of BACE1 inhibitors have been designed and developed since BACE1 was cloned and identificated. This review highlights the core scaffold to summarize the evolution of structure-based design of BACE1 inhibitors.

BACE1 inhibitors:from peptide mimics to small molecules / 国际药学研究杂志

Alzheimer′s disease(AD)is a chronic neurodegenerative disorder. According to the amyloid cascade hypothesis, abnormal accumulation of amyloid peptides(Aβ)in the brain resulting in neuronal toxicity is the main cause of AD. β-secretase1 (BACE1)is a rate-limiting enzyme that hydrolyzesβ-amyloid precursor protein(β-APP)to produce amyloid peptides(Aβ). There?fore,BACE1 has been considered to be an attractive therapeutic target for the treatment of AD. Different structural classes of BACE 1 inhibitors have been designed and developed since BACE1 was cloned and identificated. This review highlights the core scaffold to summarize the evolution of structure-based design of BACE1 inhibitors.

Anti-Alzheimer's disease potential of coumarins from Angelica decursiva and Artemisia capillaris and structure-activity analysis

OBJECTIVE@#To use structure-activity analysis to study the anti-Alzheimer's disease (anti-AD) activity of natural coumarins isolated from Angelica decursiva and Artemisia capillaris, along with one purchased coumarin (daphnetin).@*METHODS@#Umbelliferone, umbelliferone 6-carboxylic acid, scopoletin, isoscopoletin, 7-methoxy coumarin, scoparone, scopolin, and esculetin have been previously isolated; however 2'-isopropyl psoralene was isolated from Angelica decursiva for the first time to evaluate their inhibitory effects against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and β-site amyloid precursor protein cleaving enzyme 1 (BACE1) enzyme activity. We scrutinized the potentials of coumarins as cholinesterase and BACE1 inhibitors via enzyme kinetics and molecular docking simulation.@*RESULTS@#Among the test compounds, umbelliferone 6-carboxylic acid, esculetin and daphnetin exhibited potent inhibitory activity against AChE, BChE and BACE1. Both esculetin and daphnetin have a catechol group and exhibit significant anti-AD activity against AChE and BChE. In contrast, presence of a sugar moiety and methoxylation markedly reduced the anti-AD activity of the coumarins investigated in this study. With respect to BACE1 inhibition, umbelliferone 6-carboxylic acid, esculetin and daphnetin contained carboxyl or catechol groups, which significantly contributed to their anti-AD activities. To further investigate these results, we generated a 3D structure of BACE1 using Autodock 4.2 and simulated binding of umbelliferone 6-carboxylic acid, esculetin and daphnetin. Docking simulations showed that different residues of BACE1 interacted with hydroxyl and carboxylic groups, and the binding energies of umbelliferone 6-carboxylic acid, esculetin and daphnetin were negative (-4.58, -6.25 and -6.37 kcal/mol respectively).@*CONCLUSIONS@#Taken together, our results suggest that umbelliferone 6-carboxylic acid, esculetin and daphnetin have anti-AD effects by inhibiting AChE, BChE and BACE1, which might be useful against AD.

Effect of hyperforin on learning and memory abilities and Aβ₁₋₄₂, βAPP and BACE1 protein expressions in hippocampus of Alzheimer's disease model mice / 中国中药杂志

To investigate the effect of the hyperforin (HF) on learning and memory function and Aβ₁₋₄₂, βAPP and BACE1 protein expressions in hippocampus of five-month-old APP/PS1 double transgenic mice, and discuss the underlying mechanism of HF. The five-month-old APP/PS1 double transgenic mice were randomly divided into the model group, rosiglitazone group (12 mg•kg⁻¹•d⁻¹) and HF high dose, middle dose and low dose groups (600, 300 and 150 mg•kg⁻¹•d⁻¹) in each group; in addition, 15C57BL/6J mice with the same months and background were selected as normal group. Drugs were diluted in the same volume before using, and then administrated by ig for 7 months, 1 time a day; the mice in normal group and model group received the same volume of distilled water. The learning and memory ability was tested by Morris water maze; Aβ₁₋₄₂, βAPP and BACE1proteinexpressionlevelswere tested by immunohistochemistry and Western blot. The Morris water maze results showed that as compared with the normal group, the learning and memory ability was significantly impaired in mice of model group (P<0.01); as compared with the model group, the learning and memory ability was improved in mice of rosiglitazone group and HF high, middle and low dose groups(P<0.01 or P<0.05). Immunohistochemistry and western blot results showed thatas compared with the normal group, the Aβ₁₋₄₂, βAPP and BACE1 protein expression levels in hippocampus were significantly increased in mice of model group (P<0.01);as compared with the model group, Aβ₁₋₄₂, βAPP and BACE1 protein expression levels in hippocampus were decreased in mice of rosiglitazone group and HF high, middle and low dose groups (P<0.01 or P<0.05). HF may improve the learning and memory ability of AD model mice via inhibition of βAPP and BACE1 protein expressions, thus reduced the generation of Aβ₁₋₄₂ proteins and amyloid plaque deposits in the brain.

Rosiglitazone attenuates cognitive function via altering hippocampal IRS-1/Akt signaling pathways in ob/ob mouse / 中国药理学通报

Aim To identify alteration in key molecular components related to memory formation and insulin signaling in the hippocampus after rosiglitazone was in-jected into the ob/ob mice to test whether cognitive dysfunction was pharmacologically reversed by regula-tion of rosiglitazone. Methods The age-matched mice were divided into three groups ( n=18 ): Saline-trea-ted WT mice ( WT-Saline);Saline-treated ob/ob mice ( ob/ob-Saline) and RSG-treated ob/ob mice ( ob/ob-RSG) through intraperitoneal injection of rosiglitazone ( RSG) . The random glucose levels were measured for 10 days during the intraperitoneal injection period. No-vel object recognition was performed before mice were sacrificed. Western blot was implemented to evaluate the following proteins: BACE1, p-Tau, p-IRS1,IRS1, p-Akt and Akt in hippocampal tissues. The Aβ1-40 levels were detected by ELISA Kit. Results The random blood glucose levels were significantly re-duced in ob/ob-RSG compared with ob/ob-saline. RSG treatment led to an increase in hippocampus-de-pendent cognition of ob/ob mice according to the novel object recognition. The proteins levels of BACE1, p-Tau and Aβ were lowered in RSG-treated ob/ob mice. Furthermore, RSG treatment up-regulated hippocampal p-IRS1/IRS1 and p-Akt/Akt ratio. Conclusion Ros-iglitazone ameliorates cognitive deficits in ob/ob mice through up-regulating insulin signaling pathways in the hippocampus.

The inhibitory effects of different curcuminiods onβ-site amyloid precursor protein cleaving enzyme 1 ac- tivity / 中国神经精神疾病杂志

Objective The anti-amyloidogenic effects of Curcumin had been clearly certified, Whether the anti-amyliodogenic effects were mediated through the modulation of BACE1 activity was addressed. Methods SwAPP-HEK293 cells were incubated for 24h without or with 5μM curcumin mix, Cur, DMC and BDMC respectively, then the cells were collected for the cell viability evaluation by using MTT analysis and for the BACE1 activity evaluation by theβ-Secretase Activity Fluorometric Assay Kit. Results The cell viability of swAPPHEK293 cells was unchanged after cur-cuminoids incubation; All of Curcumin mix, Cur, DMC and BDMC could decreased the BACE1 activity, Cur was the most active in suppressing BACE1 activity, and the inhibition strength of others in order was DMC>COM>BDMC. Con-clusion This paper indicate that the anti-amyloidogenic effects of curcumin mix,Cur ,DMC,BDMC may be through the in-hibition of BACE1 activity.