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1.
Ars méd ; 47(2): 56-67, jun. 03, 2022.
Article in Spanish | LILACS-Express | LILACS | ID: biblio-1399836

ABSTRACT

El desarrollo de biomarcadores de la proteína tau para el diagnóstico temprano de la enfermedad de Alzheimer (EA) emerge como un desafío fundamental, pudiendo mejorar la efectividad de un tratamiento preventivo o que enlentezca la progresión de la enfermedad. Esta revisión analiza las evidencias que justificarían el uso de la proteína tau como biomarcador en Alzheimer preclínico. Para esto se seleccionaron artículos científicos (2011-2021) que incluyeran a la proteína tau en plasma y plaquetas como biomarcador. La presencia de la proteína tau fosforilada en el líquido cefalorraquídeo presenta limitaciones por su carácter invasivo mientras que las técnicas de imagen son costosas. La medición de tau en plaquetas se correlaciona con la severidad de la demencia, y sería útil en el seguimiento de la EA. Sin embargo, la pertinencia de su uso en la detección temprana de EA se mantiene en discusión. La presencia de proteína tau fosforilada en plasma correspondería al biomarcador con mayor nivel de desarrollo, respecto de beta amiloide. La proteína tau plas-mática detecta la EA con gran precisión en casos de demencia y ha sido validada por estudios neuropatológicos. p-tau217 plasmática medida por primera vez junto a técnicas de imagen, fue importante en la etapa preclínica de EA pudiendo predecir la formación de ovillos neurofibrilares. La correlación entre especies fosforiladas de tau en plasma y EA preclínica ha sido bien establecida, por lo que su uso como biomarcador podría ser de utilidad para la comprensión del proceso fisiopatológico de la neurodegeneración y la detección temprana de EA


The development of tau protein biomarkers for the early diagnosis of Alzheimer's disease (AD) emerges as a fundamental challenge, which may improve the effectiveness of preventive treatment or slow the progression of the disease. This review analyzes the evidence that would justify the use of tau protein as a biomarker in preclinical Alzheimer's disease. For this purpose, we selected scientific arti-cles (2011-2021) that included tau protein in plasma and platelets as a biomarker. Phosphorylated tau protein in cerebrospinal fluid has limitations due to its invasiveness, while imaging techniques are expensive. The tau measurement in platelets correlates with the severity of dementia and would be helpful in the follow-up of AD. However, the relevance of its use in the early detection of AD remains under discussion. Plasma phosphorylated tau protein would correspond to the biomarker with the highest level of development for beta-amyloid. Plasma tau protein detects AD with high accuracy in cases of dementia, and neuropathological studies validate its use. Plasma p-tau217 measured for the first time with imaging techniques was important in preclinical AD and could predict the formation of neurofibrillary tangles. The correlation between plasma phosphorylated tau species and preclinical AD is well-established, so its use as a biomarker would help understand the pathophysiological process of neurodegeneration and early AD detection.

2.
Acta Pharmaceutica Sinica ; (12): 1954-1961, 2022.
Article in Chinese | WPRIM | ID: wpr-936582

ABSTRACT

With the acceleration of the aging process of our country's population, the impact of aging-related diseases - Alzheimer's disease (AD) on society and families has become increasingly prominent. AD is caused by multiple mechanisms, and the pathogenesis has not been fully elucidated. Most of the clinical treatments are single therapy, which mainly focuses on improving symptoms and are difficult to reverse the disease process. Therefore, the development of drugs that can both improve symptoms and reverse the disease process is extremely urgent in clinical. Increasing number of studies has shown that traditional Chinese medicine plays an important role in the prevention and treatment of AD. The natural products have many advantages, such as novel structures, multiple targets and diverse activities, which can be used as an important source of leading compounds for the treatment of AD. The review summarizes the main clinical treatment methods and the research progress of natural ingredients in traditional Chinese medicine, and provides a reference for the follow-up clinical treatment of AD combined with the advantages of traditional Chinese medicine treatment.

3.
Acta Pharmaceutica Sinica ; (12): 1630-1640, 2022.
Article in Chinese | WPRIM | ID: wpr-929445

ABSTRACT

Mitochondrial oxidative stress has been recognized as a preliminary and critical factor that aggravates the pathological cascade of Alzheimer's disease, which induces the production of β-amyloid protein, upregulates the expression of phosphorylated tau protein and triggers oxidative damage to lipids, proteins and mitochondrial deoxyribonucleic acid. Central neurons are more vulnerable to oxidative stress than non-neuronal cells due to their high oxygen demand, abundant unsaturated fatty acids and antioxidant enzymes deficiency. On this account, this review introduces the causes of mitochondrial oxidative stress, and analyzes the important role of mitochondrial oxidative stress in the pathogenesis of Alzheimer's disease. Meanwhile, the review focuses on the design and intervention strategies of drug delivery systems targeting mitochondrial oxidative stress in neurons, aiming to provide new ideas for the prevention and treatment of Alzheimer's disease.

4.
Acta Pharmaceutica Sinica B ; (6): 483-495, 2022.
Article in English | WPRIM | ID: wpr-929310

ABSTRACT

Alzheimer's disease (AD), the most prominent form of dementia in the elderly, has no cure. Strategies focused on the reduction of amyloid beta or hyperphosphorylated Tau protein have largely failed in clinical trials. Novel therapeutic targets and strategies are urgently needed. Emerging data suggest that in response to environmental stress, mitochondria initiate an integrated stress response (ISR) shown to be beneficial for healthy aging and neuroprotection. Here, we review data that implicate mitochondrial electron transport complexes involved in oxidative phosphorylation as a hub for small molecule-targeted therapeutics that could induce beneficial mitochondrial ISR. Specifically, partial inhibition of mitochondrial complex I has been exploited as a novel strategy for multiple human conditions, including AD, with several small molecules being tested in clinical trials. We discuss current understanding of the molecular mechanisms involved in this counterintuitive approach. Since this strategy has also been shown to enhance health and life span, the development of safe and efficacious complex I inhibitors could promote healthy aging, delaying the onset of age-related neurodegenerative diseases.

5.
Rev. neuropsiquiatr ; 84(2): 113-127, abr.-jun. 2021. tab, graf
Article in Portuguese | LILACS-Express | LILACS | ID: biblio-1341577

ABSTRACT

RESUMO A doença neurodegenerativa mais comum no mundo é a doença de Alzheimer (DA), e 10% dos casos apresentam sintomas antes dos 65 anos, quase todos com associação genética, com hereditariedade autossômica dominante e penetrância entre 92 a 100% dos portadores. Na presente revisão, realizamos uma busca sobre as variantes genéticas associadas à doença de Alzheimer de início precoce (DAIP), enfatizando as características associadas mais importantes e as principais mutações já descritas. Os genes mais comumente relacionados com o surgimento da DAIP são APP, PSEN1, PSEN2 e MAPT, e mutações nestes afetam o metabolismo e a estrutura destas proteínas, resultando em acúmulos de peptídeo Aβ que causam inflamação e toxicidade no cérebro, levando à ativação da micróglia e promovendo a liberação de fatores neurotóxicos e pró-inflamatórios que aceleram a neurodegeneração. O gene PSEN1 é responsável por 70% das mutações conhecidas da DAIP, sendo a L166P associada à idade de ocorrência da doença abaixo dos 30 anos. Mutações em APP levam à agregação da proteína em placas neurodegenerativas. Todas as mutações descritas para MAPT estão associadas a um aumento dos emaranhados neurofibrilares. O polimorfismo E4 da Apolipoproteína E (APOE) influencia o aumento no risco de DAIP elevando as chances em três vezes para portadores heterozigotos e entre oito a dez vezes para os homozigotos. Apenas 5% das mutações associadas à DAIP são conhecidas, e novos estudos apresentam outros genes candidatos, bem como a importância de alterações epigenéticas na gênese desta doença.


SUMMARY The most common neurodegenerative disease in the world is Alzheimer's Disease (AD). Ten percent of Alzheimer patients experience symptoms before the age of 65, and almost all of them present genetic features of autosomal dominant inheritance nature, and penetrance of 92 to 100%. In the present review, we searched for genetic variants associated with early onset Alzheimer's disease (EOAD), emphasizing the most important characteristics and the main mutations. The genes most commonly related to the onset of EOAD are APP, PSEN1, PSEN2 and MAPT, whose mutations affect the metabolism and structure of these proteins. This process results in accumulations of Aβ peptide that leads to activation of the microglia and release of neurotoxic and pro-inflammatory factors that accelerate neurodegeneration. The PSEN1 gene is responsible for 70% of the known mutations in EOAD, while L166P is associated with below 30 years as the starting age of occurrence. APP mutations lead to protein aggregation in neurodegenerative plaques. All of the mutations described for MAPT are associated with an increase in neurofibrillary tangles. The E4 polymorphism of Apolipoprotein E (APOE) influences an increased risk of EOAD increasing up to three times the chances for heterozygous, and between eight and ten times for homozygotes carriers. Only 5% of the mutations associated with EOAD are known; new studies will show other candidate genes, as well as the importance of epigenetic factors changes in the etio-pathogenesis of this disease.

6.
Article in Chinese | WPRIM | ID: wpr-912011

ABSTRACT

Objective:To observe the effect of electroacupuncture at the Baihui acupoint on learning and memory ability and on the calmodulin kinase (CaMK)Ⅱ-Tau protein signal pathway in rats exposed to infrasound, and to explore its mechanism.Methods:Forty-eight Sprague-Dawley rats were randomly divided into a blank group, an infrasound group, a Baihui group and a non-acupoint group, each of 12. The rats in the blank group were placed in an infrasound chamber without infrasound for 2 hours daily. Those in the other 3 groups were exposed to 8Hz, 130dB infrasound in the chamber for 2 hours daily for 7 consecutive days. The rats in the Baihui and non-acupoint groups were given electroacupuncture within 2 hours after the infrasound exposure at the Baihui acupoint or elsewhere respectively. The rats in the blank and infrasound groups were given the same grasping and fixation, but no electroacupuncture. On the 6th and 7th day of intervention, Morris water maze positioning and navigation experiments and spatial exploration experiments were used to quantify the rats′ spatial learning and memory ability. Nissl staining was used to observe any changes in the morphology of the neurons in the hippocampus of 6 rats in each group. The expression of phosphorylated calmodulin-dependent protein kinase II (P-CaMKⅡ) and phosphorylated Tau protein (P-Tau) in the hippocampus was also documented using western blotting.Results:After 6 or 7 days the average escape latency of the rats in the infrasound group was significantly longer than the blank group′s average. Platform quadrant time and distance ratios and the number of times crossing the platform area were also significantly lower. Compared with the infrasound group, the average escape latency of the Baihui group was significantly shorter, with the platform quadrant time and distance ratios and the number of times crossing the platform area significantly higher. After 7 days, the damage to hippocampal neurons among the rats in the infrasound group was significantly aggravated and the number of neurons was reduced significantly compared with the blank group. Compared with the infrasound group, significantly fewer neurons in the hippocampus were damaged in the Baihui group and the number of neurons had increased significantly. After the intervention the levels of P-CaMKⅡand P-Tau protein in the infrasound group had increased significantly compared with the blank group, but those levels in the Baihui group were significantly lower, on average.Conclusion:Electroacupuncture at the Baihui acupoint can improve the learning and memory ability of rats exposed to infrasound, and has some protective effect against infrasound brain damage. That may be due to its inhibiting Tau protein hyperphosphorylation in the hippocampus by reducing CaMKⅡ activity.

7.
Chinese Journal of Neurology ; (12): 635-639, 2021.
Article in Chinese | WPRIM | ID: wpr-911770

ABSTRACT

Alzheimer′s disease (AD), the most common neurodegenerative disease, is a major challenge in China and all the world. However, the pathogenesis of AD remains unclear, and no disease-modifying therapies are available to prevent or treat the disease. Amyloid-beta (Aβ) and hyperphosphorylated tau protein are key pathological molecules of AD. A series of clinical trials targeting Aβ, tau protein and neuroinflammation have been carried out in the past 20 years, but none of them have been successful in attenuating the cognitive decline so far. This paper discusses the challenges of the current clinical trials of AD and proposes future directions for the research of AD prevention and treatment.

8.
Article in Chinese | WPRIM | ID: wpr-910015

ABSTRACT

Objective:To explore the changes in the expression of Tau protein and phosphorylated Tau (p-Tau) protein in neurons after spinal cord ischemia-reperfusion injury (SCII).Methods:Ninety-six healthy adult SD rats were randomly divided into a sham operation group ( n=48) and a SCII group ( n=48). Based on the reperfusion time of 3 h, 6 h, 12 h, 24 h, 48 h and 72 h, the SCII group was divided into 6 subgroups ( n=8 per subgroup). Immunohistochemical staining was used to observe the apoptosis of spinal cord neurons in the L 4-L 5 segments and the expression of Tau protein and p-Tau protein. Results:In the sham operation group, the neuron cells were intact, mainly concentrated in the gray matter. Tau protein was seen in a small number of neuron cells, and a small amount of filamentous p-Tau protein in the pernucleus and cytoplasm. There was no significant difference between Tau protein and p-Tau protein expression in neurons at each time point ( P>0.05). In the SCII group, scattered Tau protein was seen in the apoptotic cells while there was a strong positive expression of Tau protein in the non-apoptotic cells. The expression of Tau protein in the SCII group gradually increased after injury, reaching a peak at 48h and plateauing at 72 h, and was significantly different between any 2 time points (except for 72 h) ( P<0.05). In the SCII group, the positive expression of p-Tau protein was observed in the cytoplasm of the apoptotic cells in strips and sheets. It increased rapidly within 6 h but did not change significantly after 6 h, showing no significant difference between any 2 time points afterwards ( P>0.05). There was a statistically significant difference in the expression of Tau protein and p-Tau protein between the SCII group and the sham operation group at each time point ( P<0.05). Conclusion:It is hopeful to reduce the severity of spinal cord injury by regulating the expression of Tau protein and p-Tau protein within 6 to 48 hours after SCII.

9.
Article in Chinese | WPRIM | ID: wpr-905066

ABSTRACT

Objective:To investigate the effect of Huangjingwan (HW) on the activities of glycogen synthase kinase-3β (GSK-3β), protein phosphatase 2A (PP2A) and the mechanism in inhibiting tau protein hyperphosphorylation in the hippocampal neurons of mice with Alzheimer's disease. Method:After subcutaneous injection with 1.0% D-galactose (0.14 g·kg-1·d-1) into the back and neck of mice for 4 weeks, the right ventricle of mice was injected with 2 μL (75 ng) of okadaic acid for one time to make AD model, and the successfully modeled AD mice were selected by Morris water maze. Then, the selected AD mice were randomly divided into AD model group, memantine group (1.3×10-3 g·kg-1·d-1) and HW group (2.5 g·kg-1·d-1). In addition, the sham model control group and the normal control group were set up. At the same time, 2 μL normal saline was injected into the right ventricle of mouse in the sham model control group for modeling control. Two weeks after modeling, the mice in the two experimental drug groups were given the corresponding dose of the experimental drug by gavage for 4 weeks. In addition, after 2 weeks of AD modeling, mice in control group and AD model group were intragastrically administrated with the same amount of normal saline daily for 4 weeks. The mice in normal control group were only given daily feed. At the end of gavage, all the mice were tested by the open field experiment and jumping platform experiment to evaluate the differences in exploratory activity ability, anxiety level and learning and memory ability. The number of neurons in CA1 and CA3 areas of hippocampus in all the mice was detected by Nissl staining. Quantitative real-time polymerase chain reaction (Real-time PCR) was used to detect mRNA expressions of GSK-3β and PP2A in hippocampus of mice in each group. Protein expressions of GSK-3β, PP2A, phosphorylated tau (p-tau) and total tau protein (t-tau) in hippocampus of mice in each group were detected by Western blot. Result:Compared with the normal control group, mice in AD model group showed an obvious dementia state, which was characterized by a lower spontaneous activity, lower exploration behavior ability, higher anxiety level, less movement and easier to stay and hide, longer learning response time, significantly increased number of learning and memory errors, and decreased numbers of hippocampal neuron in CA1 and CA3 areas, and reduced mRNA and protein expressions of PP2A, mRNA and protein expressions of GSK-3β, p-tau protein and the ratio of p-tau/t-tau were all increased significantly (P<0.01), while expression of t-tau protein was decreased, with no significant difference. Compared with the AD model group, mice in the HW group showed a higher spontaneous activity, higher exploration ability, lower anxiety level, higher learning and memory performance, and the numbers of hippocampal neuron in CA1 and CA3 areas increased, while mRNA and protein expressions of PP2A increased, and the mRNA and protein expressions of GSK-3β, the expression of p-tau protein and the ratio of p-tau/t-tau were all decreased significantly (P<0.01), but with no significant difference in the protein expression of t-tau. Conclusion:HW can inhibit tau hyperphosphorylation in hippocampal neurons of AD mice, restore tau protein function, protect hippocampal neurons, and exert an anti-AD effect, which may be related to the regulatory mechanism in the activity balance between GSK-3β and PP2A in hippocampal neurons.

10.
Article in Chinese | WPRIM | ID: wpr-904753

ABSTRACT

Objective To optimize the synthesis method of 18F-T807 and study preliminary biodistribution. Methods 18F-T807 was synthesized using an optimized method in TRACERlab FXFN synthesizer with a t-BOC(t-Butyloxy carbonyl)-protected 18F-T807 precursor NPPI-9 as starting material, improving experimental conditions for synthesis, then QC and biodistribution study in Wistar rats conducted. Results The improved synthesis conditions increased the synthesis yield from 20.5%±6.1% to 25.7%±5.8%. QC met the standard. Wistar rats had higher intake in kidney, liver, blood and lowest intake in brain, heart, lung. Conclusion The optimized synthesis method to synthesize 18F-T807 is simple and easy, and high yield, which can meet the needs of scientific research and clinical practice.

11.
China Pharmacy ; (12): 1485-1491, 2021.
Article in Chinese | WPRIM | ID: wpr-881286

ABSTRACT

OBJECTIVE:To study the effects and mechanism of panaxadiol (PD) on Tau protein phosphorylation in the SH-SY5Y cells transfected with APP gene(APP-SH-SY5Y). METHODS :The target of PD and non-receptor tyrosine kinases Fyn was verified by molecular docking. SH-SY 5Y cells were cultured in vitro ,and the APP-SH-SY 5Y cell models and green fluorescent (GFP)-SH-SY5Y cell model (control cell )was constructed. The expression of Aβ1-42 was detected so as to verify the success of APP-SH-SY5Y cell model. Taking GFP-SH-SY 5Y cells as control ,the effects of 5,10,20,30,40 μmol/L PD and 125,250, 500,1 000,2 000 nmol/L PP 2(Fyn inhibitor ,positive control )on the survival rate of APP-SH-SY 5Y cells were detected by CCK-8 assay after treated for 24 h,so as to confirm the optimal concentration. The concentration of Ca 2 + ,the ratio fophosphorylated Tau protein (p-Tau)/Tau,phosphorylatedn Src(p-Src)/Fyn and phosphorylated glutamate receptor 2B(p-GluN2B)/ GluN2B were detected in APP-SH-SY 5Y cells after trated with the optimal concentration of PD and PP 2 for 24 h. RESULTS :The results of molecular simulation docking showed that PD could target Fyn protein. Compared with GFP-SH-SY 5Y cells ,the protein expression of Aβ1-42 in APP-SH-SY 5Y cell were increased significantly (P<0.01). The optimal concentration of PD and PP 2 were 20 μmol/L and 500 nmol/L. The 20 μmol/L PD and 500 nmol/L PP 2 could increase the survival rate of the cells and reduced the concentration of Ca 2+,the ratio of p-Tau/Tau ,p-Src/Fyn,and p-GluN 2B/GluN2B. CONCLUSIONS:PD can reduce the the phosphorylation of Tau protein through inhibiting Fyn/GluN 2B signaling pathway.

12.
Int. j. morphol ; 38(1): 230-234, Feb. 2020. graf
Article in English | LILACS | ID: biblio-1056427

ABSTRACT

The hypotheses currently considered the most likely causes of Alzheimer's disease (AD) are amyloid beta peptide deposition in the cerebral cortex and hyperphosphorylation of the Tau protein, with the consequent formation of neurofibrillary tangles. In clinical practice, although not accurate, AD diagnosis is based on the exclusion of other diseases, behavioural assessments and complementary examinations, such as imaging and blood tests. Advances in the field of biotechnology have created exciting prospects for the early detection of AD via biomarker assessment, which is considered a safer and more efficient procedure. Molecules recognised as biomarkers can be expressed in some body fluids, including cerebrospinal fluid, saliva and blood. The presence of amyloid beta peptide and Tau can be confirmed in saliva, which is also an easily and non-invasively collectable material with an accessible cost. The objective was evaluate the concentrations of the t-Tau protein and Ab42 peptide in the saliva of elderly individuals with and without dementia of the AD type Method: The objective of this case-control study, involving a total of 120 individuals, was to analyse whether a correlation exists between variations in the concentrations of the t-Tau and Ab42 biomarkers in the saliva of patients with confirmed AD and individuals in the inclusion group but without AD . We found that t-Tau expression in AD patients is significantly lower than that in individuals without AD, whereas the salivary concentration of Ab42 is higher in patients with AD but not significantly different from that of the group without AD. Conclusion: Thus, we demonstrate the feasibility of using salivary biomarkers as predictive markers for diagnosis of Alzheimer's disease.


Las hipótesis consideradas actualmente como las causas más probables de la enfermedad de Alzheimer (EA) son la deposición de péptido beta amiloide en la corteza cerebral y la hiperfosforilación de la proteína Tau, con la consiguiente formación de ovillos neurofibrilares. En la práctica clínica, aunque no es precisa, el diagnóstico de la EA se basa en la exclusión de otras enfermedades, evaluaciones de comportamiento y exámenes complementarios, como imágenes y análisis de sangre. Los avances en el campo de la biotecnología han creado interesantes perspectivas para la detección temprana de la EA a través de la evaluación de biomarcadores, que se considera un procedimiento más seguro y más eficiente. Las moléculas reconocidas como biomarcadores se pueden expresar en algunos fluidos corporales, incluidos el líquido cerebroespinal, la saliva y la sangre. La presencia del péptido beta amiloide (AB) y la proteína Tau (t-Tau) se puede confirmar en la saliva, que también es un material fácil y no invasivo de recolección con un costo accesible. El objetivo fue evaluar las concentraciones de la proteína t-Tau y el péptido Ab42 en la saliva de las personas de edad avanzada con y sin demencia del tipo de tipo EA. El estudio de casos y controles, se realizó en un total de 120 personas, para analizar si existe una correlación entre las variaciones en las concentraciones de los biomarcadores t-Tau y Ab42 en la saliva de pacientes con EA confirmada e individuos en el grupo de inclusión pero sin AD. Encontramos que la expresión de t-Tau en pacientes con EA es significativamente menor que en individuos sin EA, mientras que la concentración salival de Ab42 es mayor en pacientes con EA pero no significativamente diferente de la del grupo sin la enfermedad . Por lo tanto, se demuestra la viabilidad del uso de biomarcadores salivales como marcadores predictivos para el diagnóstico de la enfermedad de Alzheimer.


Subject(s)
Humans , Male , Female , Middle Aged , Aged , Amyloid beta-Peptides/metabolism , tau Proteins/metabolism , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Saliva/metabolism , Saliva/chemistry , Biomarkers/analysis , Biomarkers/metabolism , Amyloid beta-Peptides/analysis , tau Proteins/analysis
13.
Article in Chinese | WPRIM | ID: wpr-781767

ABSTRACT

OBJECTIVE@#To explore the effect of early intervention electroacupuncture (EA) at "Baihui" (GV 20), "Dazhui" (GV 14) and "Shenshu" (BL 23) on the learning-memory ability and the expression of phosphorylated Tau protein in the hippocampus of SAMP8 mice, so as to provide reference for the intervening period of EA for Alzheimer's disease (AD).@*METHODS@#A total of 36 3-month old SAMP8 mice were randomly divided into a model group, a 3-month-old EA group and a 9-month-old EA group, 12 mice in each group. Twelve normal SAMR1 mice with the same age were taken as the control group. The mice in the 3-month-old EA group and 9-month-old EA group were treated with EA at "Baihui" (GV 20), "Dazhui" (GV 14) and "Shenshu" (BL 23) separately 3 months old and 9 months old (continuous wave, 2 Hz, 1.5-2 mA), 20 min each time, once a day, 8 days as a course of treatment, with an interval of 2 days between courses, totally 3 courses of treatment were given. The mice sample in each group was collected at the age of 10 months after the learning-memory ability tested by Morris water maze. The expression of phosphorylated Tau protein in the hippocampus was detected by immunohistochemistry and Western blot, and the expression of Tau mRNA was detected by real-time PCR.@*RESULTS@#Compared with the control group, in the model group, the escape latency was significantly increased (<0.01), the time of stay in the original platform quadrant and the number of crossing the platform quadrant were reduced (<0.01), and the expressions of phosphorylated Tau protein and Tau mRNA in hippocampus were increased (<0.01). Compared with the model group, in the 3-month-old EA group and 9-month-old EA group, the escape latency was significantly reduced (<0.05), the time of stay in the original platform quadrant and the number of crossing the platform quadrant were increased (<0.05), and the expressions of phosphorylated Tau protein and Tau mRNA in hippocampus were reduced (<0.05). Compared with the 9-month-old EA group, in the 3-month-old EA group, the escape latency was significantly reduced (<0.05), the time of stay in the original platform quadrant and the number of crossing the platform quadrant were increased (<0.05), and the expressions of phosphorylated Tau protein and Tau mRNA were reduced (<0.01).@*CONCLUSION@#The early EA intervention could more effectively improve the learning-memory ability and inhibit phosphorylation of Tau protein in the hippocampus of SAMP8 mice.


Subject(s)
Animals , Disease Models, Animal , Electroacupuncture , Hippocampus , Learning , Memory , Mice , tau Proteins
14.
Acupuncture Research ; (6): 529-534, 2020.
Article in Chinese | WPRIM | ID: wpr-844138

ABSTRACT

OBJECTIVE: To observe the effect of electroacupuncture (EA) and manual acupuncture (MA) on learning-memory ability, changes of ultrastructure of neurons and expression of CDK5 and Tau proteins in hippocampus of SAMP8 mice,so as to explore its mechanisms underlying improvement of Alzheimer's disease (AD).. METHODS: A total of 45 male SAMP8 mice were randomly divided into model, EA and MA groups, with 15 mice in each group. The other 15 SAMR1 mice were used as the normal group. In the EA group, EA (2 Hz, 1 mA) was applied to bilateral "Shenshu"(BL23) and manual acupuncture was applied to "Baihui"(GV20) for 20 min. In the MA group, MA was applied to GV20 and bilateral BL23 for 20 min. Both group were treated once a day for 31 days, and with an interval of one day between every two 7 days. Morris water maze was performed to assess the animals' learning-memory ability. The morphological changes of hippocampal neurons were observed under transmission electron microscopy. The expression levels of CDK5, p25 and Tau-5 proteins in the hippocampus were detected by immunohistochemistry and Western blot, separately. RESULTS: ①Compared with the normal group, the average escape latency of Morris water maze test was prolonged in the model group(P<0.05, P<0.01), duration of swimming in the original platform quadrant and the number of original platform crossing were significantly shorter and less respectively (P<0.01). Compared with the model group, the average escape latency in the EA group was shortened (P<0.05, P <0.01), the duration of swimming in the original platform quadrant and the number of original platform crossing were significantly prolonged and increased (P<0.01); The average escape latency in the MA group was shortened (P<0.05, P <0.01),and the duration of swimming in the original platform quadrant was prolonged (P<0.05). Compared with the EA group, the average escape latency of the MA group was prolonged (P<0.05), the duration of swimming in the original platform quadrant was shortened(P<0.05). ②Transmission electron microscopy revealed that the neurons in the hippocampal CA1 area had irregular shape and vague structure, reduction in size and number of mitochondria accompanied with swelling, and malformed changes of mitochondrial crest in the model group, which was relatively milder in both EA and MA groups. ③The expression levels of hippocampal Tau-5, p25 and CDK5 proteins were significantly up-regulated in the model group in contrast to the normal group (P<0.01, P<0.05), and obviously down-regulated in both EA and MA groups relevant to the model group (P<0.05, P<0.01). Compared with the EA group, the expression levels of p25 and CDK5 proteins were significantly increased in the MA group (P<0.05). CONCLUSION: EA of BL23 can improve the learning-memory ability in SAMP8 mice, which is associated with its effect in down-regulating the expression of hippocampal CDK5, p25 and Tau-5 proteins.

15.
China Pharmacy ; (12): 2847-2852, 2020.
Article in Chinese | WPRIM | ID: wpr-837537

ABSTRACT

OBJECTIVE:To study the e ffects of stilbene glycoside c(TSG)on phosphorylation of Thr 205,Ser404 sites of Tau protein in Aizheimer ’s disease (AD)model mice ,and to investigate the potential anti-AD mechanism of TSG. METHODS :APP/ PS1/Tau three transgenes (3×Tg-AD)mice were randomly divided into model group ,positive control group (huperzine,0.15 mg/kg),TSG low-dose ,medium-dose and high-dose groups (0.033,0.1,0.3 g/kg),with 6 mice in each group. In addition ,6 C57BL/6J mice were chosen as normal control group. Administration groups were given relevant medicine intragastrically. Model group and normal control group were given equal volume of normal saline intragastrically ,once a day ,for consecutive 60 days. After last medication ,immunofluorescence staining was used to detect Tau protein and phosphorylated Tau protein (Thr205, Ser404 sites) distribution and expression in brain tissue of mice in each group. Western blotting assay was used to detect phosphorylated Tau protein (Thr205,Ser404 sites)expression level in brain tissue of mice in each group. RESULTS :Compared with normal control group ,the expression of Tau protein,phosphorylated Tau protein (Thr205,Ser404 sites)in 729011126@qq.com the brain tissue of mice were increased in model group ,which were easy to aggregate and distributed more widely ;theirrelative expression were increased significantly (P<0.01). Results of Western blotting assay showed that the expression levels of phosphorylat ed Tau protein (Thr205,Ser404 sites)were increased significantly (P<0.01). Compared with model group ,the expression of Tau protein ,phosphorylated Tau protein (Thr205,Ser404 sites) in the brain tissue of mice were decreased in positive control group and TSG groups ;aggregation decreased,distribution narrowed and their relative expression were decreased significantly (P<0.01). Results of Western blotting assay showed that the expression levels of phosphorylated Tau protein (Thr205,Ser404 sites)were decreased significantly (P< 0.01). Compared with positive control group ,There was no significant difference in the distribution of Tau protein ,phosphorylated Tau protein (Thr205,Ser404 sites)in the brain tissue of mice in TSG groups ;the relative expression were not statistically significant(P>0.05);but Western blotting assay showed the expression levels of phosphorylated Tau protein (Thr205 site)in TSG medium-dose and high-dose groups as well as the expression levels of phosphorylated Tau protein (Ser404 site)in TSG groups were decreased significantly (P<0.05 or P<0.01). CONCLUSIONS :TSG can play an anti-AD effect on AD model mice by down-regulating the expression of phosphorylated Tau protein (Thr205,Ser404 sites)in brain tissue.

16.
Article in Chinese | WPRIM | ID: wpr-905350

ABSTRACT

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, which is characterized by cognitive and memory dysfunction. Calpain is widely activated in cells. Disturbance of calpain is currently thought to a main cause of hyperphosphorylation and abnormal cleavage of tau protein in AD pathology. Calpain affects the activities of glycogen synthase kinase 3 and protein phosphatase 2A, which causes abnormal hyperphosphorylation of multiple sites of tau protein, and mediates truncation of tau protein monomers, and induces neurodegeneration. Calpain is expected to be a potential target for drug therapy of AD.

17.
Article in Chinese | WPRIM | ID: wpr-849729

ABSTRACT

Objective To explore the effect and potential mechanism of tenuigenin (TEN) treatment on ameliorating cognitive impairment of Alzheimer's disease (AD) model mice. Methods 6-month-old APP/PS1 transgenic mice (n=18) were randomly divided into the saline group and TEN group (9 each), 9 wild-type mice of the same age were selected as control group. Mice in TEN group were intraperitoneally injected with TEN at a dose of 8 mg/(kg.d) for 8 weeks, those in both saline group and control group were intraperitoneally injected with same dose of saline for 8 weeks. The Morris water maze test was carried out with all the mice of the three groups to assess the spatial memory level, and immunohistochemistry was performed to detect the distribution and expression of postsynaptic density protein 95 (PSD-95) in hippocampal area of brain, and thioflavin staining was performed to check the senile plaque in hippocampus. ELISA was used to assess the Aβ42 level. Western blotting was used to detect the levels of PSD-95 and p-tau protein (Ser231, Ser214, Ser396) in brain. Results In the Morris water maze test, mice in saline group exhibited greater escape latency compared with that of mice in control group after the second day, the difference was statistically significant (P0.05); mice in TEN group exhibited longer escape latency compared with that of control group at the 5th day. Space search trial found that mice in saline group spent obviously longer time to find the original position of the platforms than those in control group [(40.428±3.408) s vs. (14.142±7.289) s, P0.05). It was found that mice in saline group exhibited fewer times of crossing platform than those in control group (0.428±0.035 vs. 2.285±1.380, P0.05). The relative amount of PSD-95 was lower in mice of saline group than that in control group (0.570±0.700 vs. 0.740±0.054), the difference was statistically significant (P0.05). The number of plaques and Aβ42 level in hippocampus decreased significantly in TEN group than those in saline group [(8.889±1.692 vs. 18.000±2.000) and (2.859±0.864) ng/mg vs. (5.154±0.735) ng/mg, P<0.05]. As to the expression level of protein p-tau Ser231, Ser214 and Ser396 in mice hippocampus, they were higher significantly in saline group than those in control group (0.947±0.131 vs. 0.540±0.076, 0.832±0.161 vs. 0.305±0.088 and 0.819±0.053 vs. 0.338±0.052, P<0.05), while they were obviously lower in TEN group than in saline group (0.568±0.051 vs. 0.947±0.131, 0.472±0.094 vs. 0.832±0.161 and 0.452±0.071 vs. 0.819±0.053, P<0.05). The expression levels of protein p-tau Se214 and Ser396 in mice hippocampus of TEN group were higher than those in control group with statistical significance (0.472±0.094 vs. 0.305±0.088 and 0.452±0.071 vs. 0.338±0.052, P<0.05), but the expression level of p-tau Ser231 showed no significant difference between TEN group and control group (0.568±0.051 vs. 0.540±0.076). Conclusion Tenuigenin may attenuate cognitive deficits by up-regulating the PSD-95 level in APP/PS1 mice, decrease Aβ deposition and excessive phosphorylation of protein p-tau, and might be a potential therapeutic agent for Alzheimer's disease.

18.
Article in Chinese | WPRIM | ID: wpr-847558

ABSTRACT

BACKGROUND: Deposition of neurofibrillary tangles is closely related to cognitive decline in Alzheimer’s disease, and tau protein is an important component. OBJECTIVE: To investigate the possible pathogenesis of Alzheimer’s disease and the role of tau protein hyperphosphorylation in the progression of Alzheimer’s disease. METHODS: The first author searched for relevant articles published from January 2001 to January 2019 in WanFang, CNKI, Vip, PubMed, and Embase with the key words of “Alzheimer’s disease; tau protein; β-amyloid cascade.” RESULTS AND CONCLUSION: Hyperphosphorylation of tau protein and formation of paired helix filaments are considered to be the basis of neuronal degradation in Alzheimer’s disease. tau protein may not depend on the cascade response triggered by β-amyloid deposition in the pathogenesis of Alzheimer’s disease, and tau protein-associated vaccine immunity has been verified to produce a curative effect in clinical trials. Further exploration on the relationship between tau protein, β-amyloid protein and Alzheimer’s disease is necessary to better understand the pathogenesis of Alzheimer’s disease, and provide a theoretical basis for the development of therapeutic drugs for Alzheimer’s disease.

19.
Article in Chinese | WPRIM | ID: wpr-821076

ABSTRACT

@#Alzheimer′s disease(AD)is a chronic neurodegenerative diseasecommonly seen in the elderlys. Several therapeutic drugs have failed in phase III clinical trials in recent years and there have been no efficient treatment for AD currently. Thus, there has been an urgent need for the effective methods of AD diagnosis at early stage. Developingnear-infrared fluorescentprobes for AD hallmarks detection has been a promising research field. In this review, we summarized a variety of near-infrared fluorescence(NIRF)probes reported in the past decade, which capable of detecting β-amyloid, Tau protein and reactive oxygen species, including their chemical strucutres、optical properties, in vitro and in vivo studies. Furthermore, we alsoraised some new directions for AD diagnosing. We believe that these new directions raised herein will benefit the future development of NIRF probes in the field of AD research.

20.
Med. interna Méx ; 35(5): 795-801, sep.-oct. 2019. tab, graf
Article in Spanish | LILACS-Express | LILACS | ID: biblio-1250273

ABSTRACT

Resumen: La enfermedad de Creutzfeldt-Jakob es una afección neuroselectiva y neurodegenerativa, de curso fatal, poco frecuente, que representa un desafío para el diagnóstico clínico. Se comunica el caso de un paciente de 52 años de edad con antecedente de ingesta de mamíferos silvestres durante su vida, con cuadro de disminución de la agudeza visual, demencia rápidamente progresiva, mioclonías, movimientos anormales y disfunción motora; con estudios auxiliares de diagnóstico diferencial dentro de parámetros normales y la determinación de la proteína TAU reactiva.


Abstract: Creutzfeldt-Jakob disease is a neuroselective and neurodegenerative illness, with fatal course, which is rare and represents a challenge for clinical diagnosis. This paper reports the case of a 52-year-old male with a history of ingestion of wild mam- mals during his life, with a picture of diminished visual acuity, rapidly progressive dementia, myoclonus, abnormal movements and motor dysfunction; with auxiliary studies of differential diagnosis within normal parameters and the determination of reactive TAU protein.

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