Mechanism of axonal transport dysfuction of mitochondria in Alzheimer's disease / 中华神经医学杂志

Alzheimer's disease (AD) is a central neurodegenerative disease with still unclear pathogenesis. Recent studies have shown that axonal transport dysfuction of mitochondria may contribute to AD progression. Normal mitochondrial axonal transport mainly involves microtubules, molecular motors and connexins, while AD early pathological changes can damage mitochondrial axonal transport by interfering with these proteins: accumulated β-amyloid (Aβ) impairs the function of molecular motors; abnormally modified Tau protein reduces microtubule stability; mutant presenilin-1 (PS1) can induce phosphorylation of some related proteins by activating glycogen synthase kinase-3β (GSK-3β); all these processes can damage mitochondrial axonal transport, leading to synaptic dysfunction. This review aims to clarify the possible mechanisms of axonal transport dysfuction of mitochondria in AD and provides new ideas for AD treatment.

Recent advance in mechanism of abnormal β-amyloid deposition in Alzheimer's disease / 中华神经医学杂志

Recent studies have found that neuronal damage events precede abnormal deposition of β-amyloid (Aβ), and Aβ plaques may not be the direct cause of AD, but only the pathological manifestation of AD, but abnormal Aβ deposition is closely related to AD, so it is important to explore the mechanism of abnormal Aβ deposition in diagnosis and treatment of AD. The abnormal Aβ deposition has been linked to autophagy dysfunction, pyroptosis, ferroptosis and meningeal lymphatic vessels (Mlvs) reflux disorder, therefore, this paper reviews the roles of autophagy dysfunction, pyroptosis, ferroptosis and Mlvs reflux disorder in abnormal Aβ deposition during AD, aiming to find new targets for AD intervention.

Recent advance in clinical drug therapy for Alzheimer's disease / 中华神经医学杂志

Alzheimer's disease (AD) is the first degenerative disease of the nervous system, but no drugs have been found to reverse AD progression. Starting from 2 major pathogenesis of AD, namely amyloid beta (Aβ) cascade and Tau protein, this study systematically reviews anti-Aβ or Tau protein AD new drugs that have entered clinical research; this study also expounds their clinical trial findings and mechanisms, and analyzes the reasons for their success or failure to provide a theoretical basis for AD drug exploitation.

Proteína precursora del beta-amiloide (ß-App) y daño axonal difuso tras un traumatismo craneoencefálico: un punto de vista forense / Beta-amiloid precursos protein (ß-App) and diffuse axonal damage after head injuries: a forensic point of view

Resumen La proteína precursora del β- Amiloide (β-APP) es una glicoproteína de membrana y un componente habitual de las neuronas. Tiene funciones en el crecimiento y la adhesión celular tras un traumatismo. Es transportada mediante transporte rápido axonal anterógrado y se acumula dentro de las neuronas cuando se daña citoesqueleto. Este proceso es activo, es decir consume energía. El β-APP no es específico de los traumatismos. Se acumula en cualquier circunstancia en la que se dañen los axones, tal como la hipoxia, alteraciones metabólicas, y cualquier otra causa de edema cerebral y aumento de la presión intracraneal que puedan conducir a un daño axonal difuso (DAI) En el presente estudio estudiamos la expresión de esta proteína en casos de traumatismo cráneo-encefálico con diferente evolución cronológica El daño del citoesqueleto producido por la proteólisis, junto con la alteración de las quinasas y las fosfatasas, aumentan la permeabilidad de la membrana, lo que provoca la entrada de calcio en la célula que, a su vez, activa la calmodulina que hace que los neurofilamentos se compacten, los microtúbulos desaparezcan y se rompa la espectrina. Esta disrupción del citoesqueleto tiene como consecuencia que las sustancias que se transportan a su través, se acumulen, sobre todo en las zonas afectadas por el DAI. Al final de todo este proceso, los axones se rompen, lo que se conoce como axotomía secundaria. El estudio de la acumulación del β-APP es útil para valorar la extensión del DAI y para determinar el tiempo de supervivencia tras el traumatismo o cualquier otro daño cerebral.

Abstract β-Amyloid Precursor Protein (β-APP) is a membrane glycoprotein and a common component of neurons. It is involved in adhesion and cell growth processes after traumatic events. It is carried by anterograde fast axonal transport, and it accumulates inside neurons when the cytoskeleton is damaged. This is a vital biochemical process that consumes energy. β-APP is not specific of traumatic events. It accumulates in any case of axonal damage, whatever its cause may be, like hypoxia, metabolic disorders, and any other circumstances that lead to brain swelling and intracranial pressure rising and in consequence to Diffuse Axonal Injury (DAI). In this study we review the expression of this protein in cases of traumatic brain injury with different chronological evolution. The damage of cytoskeleton due to proteolysis in addition to the disturbance of kinases and phosphatases increase the permeability of the membrane. Calcium gets into the cell and activates calmodulin, thus neurofilaments compact, microtubules disappear and spectrin breaks. This disruption of the cytoskeleton has as consequence that the transported substances accumulate in the most affected areas by DAI. At the end of this process axon breaks, which is known as secondary axotomy. The study of the accumulation of β-APP is useful to assess the extent of DAI and to determine the time elapsed after trauma or another insult to CNS.

BRAIN MALARIA: PRESENTATION OF A CASE AND REVIEW OF THE LITERATURE

Malaria is a zoonotic disease caused by protozoa of the genus Plasmodium, acquired through the bite of a female of the Anopheles mosquito genus. The initial symptoms of malaria are usually non-speci?c, presenting with fever, moderate to severe dehydration, tachycardia and tachypnea, with systolic blood pressure usually within normal ranges and in some cases with headache, nausea and vomiting. The clinical diagnosis can be con?rmed by the presence of malarial retinopathy or the presence of parasites in at least 20% of the capillaries in the histopathological study of the brain. The drugs of choice are those derived from artemisinin, artesunate and quinine. We present a case of severe malaria with brain involvement.

Time dependent expression profiling of PTK2B and its relationship with Aβ, Tau and LRP-1 in hippocampus and blood of APPswe/PS1dE9 double-transgenic mouse / 中国应用生理学杂志

Objective: To uncover the time-dependent expression pattern of ptk2b gene and ptk2b-encoded protein, protein tyrosine kinase 2 beta(PTK2B), in the brain tissues of transgenic animal models of Alzheimer's disease (AD) and its relationship with the levels of Aβ1-42, phosphorylation of Tau (p-Tau) and low density lipoprotein receptor-related protein-1(LRP-1) in blood and brain tissues. Methods: In this study, 5-, 10- and 15-month-old APPswe/PS1dE9 double-transgenic mice harboring the genotype of AD confirmed by the gene test were divided into the 5-, 10- and 15-month-old experiment groups, and simultaneously, age-matched C57BL/6J mice were placed into the corresponding control groups, with 8 mice in each group. All mice were subjected to the Morris Water Maze for test of cognitive and behavioral ability. Expression profiles of PTK2B, Aβ1-42, p-Tau/Tau and LRP-1 in the hippocampus or blood of mice were quantified by using the immunohistochemistry staining, Western blot or enzyme-linked immunosorbent assay (ELISA), while the mRNA expression of ptk2b in the hippocampus was quantified by using the real-time quantitative polymerase chain reaction (qRT-PCR). Results: Results of experiment groups demonstrated that as mice aged, the expression levels of PTK2B, ptk2b mRNA, Aβ1-42 and p-Tau/Tau in the hippocampus were increased, and the expression of LRP-1 was decreased gradually. While in the blood, the level of Aβ1-42 was decreased, and the cognitive and behavioral ability was decreased in an age-dependent manner (all P＜ 0.05). However, comparisons among the control groups, only the age-dependent downregulation of LRP-1 were observed in hippocampus(P＜0.05), but other indicators had no significant differences (P＞0.05). Conclusion: In the hippocampus of APP/PS1 double-transgenic mice, the expressions of PTK2B, Aβ1-42 and p-Tau/Tau are upregulated, LRP-1 is downregulated, while cognitive and behavioral ability is decreased, and such changes are presented in a time-dependent manner.

Research status of molecular mechanisms of reactive astrocytes in progress and treatment of Alzheimer's disease / 中华神经医学杂志

In recent years, it has been found that reactive astrocytes (RAS) can affect the pathological process of AD through various mechanisms, such as increasing the production and deposition of β-amyloid (Aβ), aggravating the neurotoxicity of Aβ and disturbance of neurotransmitter release. Currently, the mechanism of drug treatment for AD is mainly targeted at clearance of Aβ, but the efficacy is still uncertain. Recent studies have shown that most AD-related genes are obviously expressed in RAS. Therefore, regulating the morphology and function of RAS through drug intervention may provide new ideas for treatment of AD. The authors review the research status in the molecular mechanism of RAS in the progress and treatment of AD, in order to provide more references for RAS as a target in the prevention and treatment of AD.

Recent advance in mechanism of ATP-binding cassette transporter in Alzheimer's disease / 中华神经医学杂志

ATP-binding cassette (ABC) transporters are the largest transporter families in human bodies; they are widely distributed and have complex functions. ABC transporters can mediate the translocation of various substrates on the cell membrane. This paper summarizes the structure, classification, function and action mechanism of ABC transporters and the research progress of ABC transporters in AD in recent years, and discusses the future research direction for preventing and treating AD in this field to provide new ideas and references for the prevention and treatment of AD.

Age-related episodic memory decline and the role of amyloid-ß: a systematic review / Declínio da memória episódica relacionado à idade e o papel da beta-amiloide: uma revisão sistemática

ABSTRACT Aging has been associated with the functional decline of episodic memory (EM). Unanswered questions are whether the decline of EM occurs even during healthy aging and whether this decline is related to amyloid-β (Aβ) deposition in the hippocampus. Objective: The main purpose of this study was to investigate data on the relationship between the age-related EM decline and Aβ deposition. Methods: We searched the Cochrane, MEDLINE, Scopus, and Web of Science databases and reference lists of retrieved articles that were published in the past 10 years. The initial literature search identified 517 studies. After screening the title, abstract, key words, and reference lists, 56 studies met the inclusion criteria. Results: The overall results revealed that increases in Aβ are related to lower hippocampal volume and worse performance on EM tests. The results of this systematic review revealed that high levels of Aβ may be related to EM deficits and the progression to Alzheimer's disease. Conclusions: We discussed the strengths and pitfalls of various tests and techniques used for investigating EM and Aβ deposition, methodological issues, and potential directions for future research.

RESUMO O envelhecimento tem sido associado a um declínio funcional da memória episódica (ME). Algo ainda sem resposta é se o declínio da ME ocorre mesmo no envelhecimento saudável e se esse declínio pode estar relacionado à deposição de Aβ no hipocampo. Objetivo: Nosso objetivo principal foi investigar os dados sobre a relação entre a memória episódica e a deposição de Aβ no envelhecimento saudável. Métodos: Nós buscamos nas bases de dados Cochrane, MEDLINE, Scopus, Web of Science e nas listas de referências dos estudos dos últimos 10 anos. A busca inicial nas bases de dados identificou 517 estudos. Após a triagem de título, resumos, palavras-chave e referências, 56 estudos atenderam aos critérios de inclusão. Resultados: O resultado geral revelou que o aumento de Aβ estava relacionado ao menor volume do hipocampo e pior desempenho em testes de ME. Em resumo, os resultados da presente revisão sistemática revelaram que altos níveis de Aβ podem estar relacionados ao declínio de ME e conversão progressiva para a Doença de Alzheimer. Conclusões: Aqui, discutimos os pontos fortes e as limitações dos testes e técnicas para investigar a deposição ME e Aβ, bem como questões metodológicas e direções futuras.

Operation technology and clinical application of 18F-AV45 PET imaging in Alzheimer's disease / 中华神经医学杂志

18F-florbetapir (AV45) positron emission tomography (PET) imaging, as a non-invasive method for early diagnosis of Alzheimer's disease, has been gradually recognized in China. Standard examination procedures, standard examination techniques, and standard image interpretation and reports will help us to obtain high-quality images and accurate quantitative analysis data. Therefore, in reference to the domestic and foreign guidelines, the standardization examinations and clinical researches of 18F-AV45 PET in China are introduced based on the the current status of our country and clinical practical experience to provide accurate diagnosis services to the patients.

A Polypeptide Specifically Binds to RAGE can Alleviate the Destroy of Blood Brain-Barrier caused by Amyloid beta

Background The interaction of the receptor for advanced glycation end product (RAGE) on blood-brain-barrier(BBB) with amyloid β (Aβ) plays an important role in the occurrence and development of AD. RP1 is a RAGEspecific binding peptide, which was discovered in our previous experiments, and it has been proved to beeffective on AD cell model, however, its effects on BBB tight junctions (TJs) and on Aβ transport into the brain isunclear.Methods Immunofluorescence experiment was used to identify whether RP1 bound with RAGE specifically.BEnd3-immortalized mouse brain microvascular endothelial cells were used to construct a BBB model. TEER andFD40 tests were used to confirm the stability of the BBB model, and the colocalization of the RP1 and RAGE onthe surface bEnd3 cells was observed with confocal microscopy.Results We confirmed that RP1 can bind to RAGE specifically in vitro. Functional analyses indicated that RP1 caneffectively alleviate the destroy of TJs of BBB and the decrease of permeability of BBB caused by Aβ. Furthermore,RP1 can competitively inhibit the interaction of Aβ with the RAGE in vitro, and effectively inhibit Aβ transport intothe brain.Conclusion RP1 can inhibit BBB damage induced by Aβ and block RAGE-Aβ interaction effectively, and RP1 canbe a candidate of RAGE inhibitors contributing to AD treatment

Neuroprotective role and mechanism of S14G-humanin in amyloid precursor protein/presenolin-1 double transgenic mice / 中华神经医学杂志

Objective:To investigate the effect of S14G-humanin (HNG) on spatial learning and memory abilities and hippocampal neuron autophagy in amyloid precursor protein (APP)/presenolin-1 (PS1) double-transgenic mice.Methods:The APP/PSl transgenic mice were randomly divided into model group and HNG treatment group ( n=8). Another 8 C57BL/6J mice were chosen as controls; 0.5 mL double-steamed water was intraperitoneally injected into mice in the control group and model group every day, and 0.5 mL of HNG (50 μg/kg) was intraperitoneally injected into mice in the HNG treatment group every day; after 4 weeks of continuous injection, Morris water maze test was used to test the spatial learning and memory abilities of mice in each group. Western blotting and reverse transcription-PCR were used to detect the protein and mRNA expressions of ubiquitin like kinase1 (ULK1), P62, anti-microtubule associated protein 1 light chain 3 (LC3) II/LC3 I and cathepsin D in the hippocampus. Immunohistochemical staining was used to detect the deposition of amyloid β protein (Aβ) in the hippocampus of mice in each group. Results:Morris water maze test showed that the escape latency of mice in the control group, HNG treatment group and model group was statistically prolonged in turn, and the number of times traversing through the quadrant of the original platform was significantly smaller in turn ( P<0.05). Western blotting and reverse transcription-PCR showed that the ULK1 protein and mRNA expressions in the hippocampus decreased successively, P62 protein and mRNA expressions increased successively, LC3 II protein/LC3 I protein and LC3 II mRNA/ LC3 I mRNA ratio increased successively, and cathepsin D protein and mRNA expressions decreased successively in the control group, HNG treatment group and model group, with significant differences ( P<0.05). Immunohistochemical staining showed that the Aβ positive expressions in the hippocampal neurons of the control group, HNG treatment group and model group increased successively, with statistical differences ( P<0.05). Conclusion:HNG treatment can improve the spatial learning and memory abilities, which may be attributed to ameliorate autophagic network dysfunction and reduce Aβ plaques in the hippocampi of APP/PSl transgenic mice.

Study on the toxic effects of Aβ1-42 oligomers in SHSY5Y with human A53T mutant α-synuclein over-expression / 中国神经精神疾病杂志

Objective To establish an in vitro cell model of Parkinson disease with SHSY5Y cells over-expressing human A53T mutant alpha-synuclein and to examine the effects of Aβ1-42 oligomer on cell survival and autophagy function in the cell model Method The recombinant lentivirus containing the A53T mutant alpha-synuclein gene or empty vector were transfected to SHSY5Y cells. The expression of α-synuclein mRNA in SHSY5Y cells was detected by RT-qPCR. The effect of Aβ1-42 oligomer on cell proliferation was detected with CCK-8 after incubation with Aβ1-42 oligomer for 24 hours. The autophagy-related proteins were evaluated with Western Blot. Result The mRNA and protein levels of alpha-synuclein were significantly increased in SHSY5Y cells expressing alpha-synuclein. There were no significant difference in the cell proliferation between alpha-synuclein group and control group (P<0.001) . Incubation with Aβ1-42 oligomer significantly decreased the proliferation rate in alpha-synuclein group in a dose-dependent manner compared with the control group. The levels of autophagy related proteins including LC3-Ⅱ and Beclin-1 were significantly lower in alpha-synuclein group than in control group (P<0.05). Conclusion This work has constructed an in vitro cell model of Parkinson′s disease. The over-expression of A53T mutant alpha-synuclein do not affect the cell survival whereas the Aβ1-42 oligomer exhibits toxic effects on cells expressing alpha-synuclein possible through suppression of the autophagy activation.

Mechanisms of low density lipoprotein receptor related protein 1 regulating β-amyloid metabolism and its implications for prevention and treatment of Alzheimer's disease in the future / 中华神经医学杂志

Almost all active immunotherapy attempts which targeted at clearing or reducing β-amyloid (Aβ) plaques in brains of patients with Alzheimer'disease (AD) were fallen into unprecedented difficulties,because of unsatisfactory curative effects.Recently,more and more evidences support that low density lipoprotein receptor related protein 1 (LRP1) is involved in Aβ production and clearance through multiple non-immune pathways,which has showed the potential as a whole-new interference target different with classical Aβ immunotherapies.So,we try to summarize the research developments of roles of LRP1 in Aβ metabolic process in physiological and AD conditions,and look forward to its possible applications in the prevention and treatment of AD.

Acupuncture and Moxibustion Improves Learning-memory Ability of Alzheimer's Disease Rats Possibly by Up-regulating Serum Aβ Internalization Enzyme Contents / 针刺研究

OBJECTIVE: To observe the effect of acupuncture and moxibustion (AM) on learning-memory ability and expression of amyloid beta (Aβ) in the hippocampal dentate gyrus (DG) of Alzheimer's disease (AD) rats, so as to explore its mechanism underlying improvement of AD. METHODS: Forty male Wistar rats were randomly divided into normal, sham operation, model and AM groups (n＝10 in each). The AD model was established by bilateral hippocampal injection of Aβ1-42(5 µL). The AM was applied at "Baihui" (GV 20) and "Shenshu" (BL 23) for 15 min, once daily for 12 times. Morris water maze tests were used to assess the rats' learning-memory ability. The levels of serum Aβ1-42 and Aβ internalizing enzymes including transthyretin (TTR), lipoprotein lipase (LPL), alpha 2 macroglobulin (α 2M) and apolipoprotein E (ApoE) were detected by ELISA. The expression of Aβ1-42 in the hippocampal DG was detected by immunohistochemistry. RESULTS: Compared with the sham operation group, the average escape latency of location navigation test was significantly prolonged in the first 5 days and the last 3 days (P0.05). CONCLUSION: AM can improve the learning-memory ability of AD rats, which may be related to its effects in up-regulating the contents of serum Aβ internalizing enzymes and promoting the clearance of hippocampal Aβ. It suggests a protective role of AM on hippocampal neurons.

Research Progress in the Pathogenesis of Alzheimer's Disease / 中华医学杂志(英文版)

<p><b>Objective</b>Alzheimer's disease (AD) is a kind of chronic degenerative disease of the central nervous system, characteristics of cognitive dysfunction, and behavioral disability. The pathological changes include the formation of senile plaques-containing beta-amyloid (Aβ), neurofibrillary tangles (NFTs), loss of neurons, and synapses. So far, the pathogenesis of AD is still unclear. This study was aimed to review the major pathogenesis of AD-related to the published AD studies in recent 20 years.</p><p><b>Data Sources</b>The author retrieved information from the PubMed database up to January 2018, using various search terms and their combinations, including AD, Aβ, NFTs, pathogenesis, and genetic mutation.</p><p><b>Study Selection</b>The author included data from peer-reviewed journals printed in English and Chinese on pathophysiological factors in AD. He organized these informations to explain the possible pathogenesis in AD.</p><p><b>Results</b>There are many amounts of data supporting the view that AD pathogenesis so far there mainly are Aβ toxicity, tau protein, gene mutation, synaptic damages, intermediate neurons and network abnormalities, changes in mitochondrial function, chemokines, etc., Its nosogenesis may be involved in multiple theories and involved in multiple molecular signaling pathways, including Aβ, tau protein, and synaptic anomaly; mutual relationship between the mechanisms urge jointly neuronal degeneration.</p><p><b>Conclusions</b>This review highlights the research advances in the pathogenesis of AD. Future research has needed to fully disclose the association between multiple pathogenesis at the same time to interdict multiple signaling pathways, etc.</p>

Angelica tenuissima Nakai Ameliorates Cognitive Impairment and Promotes Neurogenesis in Mouse Model of Alzheimer's Disease / 中国结合医学杂志

<p><b>OBJECTIVE</b>To research Angelica tenuissima Nakai (ATN) for use in novel Alzheimer's disease (AD) therapeutics.</p><p><b>METHODS</b>The effect of a 30% ethanol extract of ATN (KH032) on AD-like cognitive impairment and neuropathological and neuroinflammatory changes induced by bilateral intracerebroventricular injections of β-amyloid (Aβ) peptide (Aβ) was investigated. Male C57Bl/6 mice were randomly divided into 4 groups, 10 in each group. KH032-treated groups were administrated with a low or high dose of KH032 (50 and 200 mg/kg, respectively), intragastrically for 16 days; distilled water was applied in the sham and negative groups. Open fifield test, Y maze and Morris water maze test were used for behavior test and cognitive ability. In addition, the neuroprotective effects of KH032 in Aβ-infused mice on the histopathological markers [neuronspecific nuclear protein (NeuN), Aβ] of neurodegeneration were examined. The levels of glial fibrillary acidic protein (GFAP), NeuN, phosphorylation extracellular signal-regulated kinase (ERK)/ERK, brain-derived neurotrophic factor (BDNF), phosphorylation cAMP response element-binding (CREB)/CREB protein expression were measured by Western blot.</p><p><b>RESULTS</b>KH032 treatment ameliorated cognitive impairments, reduced the overexpression of Aβ, and inhibited neuronal loss and neuroinflammatory response in the Aβ-infused mice. Moreover, KH032 treatment enhanced BDNF expression levels in the hippocampus. Finally, KH032 treatment increased phosphorylation of ERK1/2 and CREB, vital for ERK-CREB signaling.</p><p><b>CONCLUSIONS</b>KH032 attenuated cognitive defificits in the Aβ-infused mice by increasing BDNF expression and ERK1/2 and CREB phosphorylation and inhibiting neuronal loss and neuroinflflammatory response, suggesting that KH032 has therapeutic potential in neurodegenerative disorders such as AD.</p>

Study of the neuroprotective effects and mechanisms of Tianma Gouteng Decoction on retinal ganglion cells in rat optic nerve crush model / 国际眼科杂志(Guoji Yanke Zazhi)

AIM:To observe the mechanism of Tianma Gouteng Decoction on the protein molecular level in the optic nerve crush model rats.METHODS:Totally 36 participants 36 male Wistar rats were divided randomly into six groups(6 in every group):normal control group,negative control group,Tianma Gouteng Decoction treatment groups (con-centrations were 0.6g/mL,1.2g/mL,2.4g/mL respictively) and ginkgo biloba tablets positive control group (concentrations was 1.2mg/mL).Nothing was done in the normal control group.The optic nerve of right eye in the other groups was done with the optic nerve crush model.Normal control group and negative control group was treated only with water.The average grey scale values of the N-methyl-D-aspartic acid receptor 2B (NMDA2B) receptor protein,beta-amyloid protein (Aβ) in the average grey scale values were detected.RESULTS:The average grey scale value of Tianma Gouteng Decoction in low,medium and high dose groups about NMDA2B receptor protein was significantly less than that of the negative control group (all P＜0.001),and there was no significant difference with the positive control group (P=0.092,0.411,0.676),the difference between normal control group and negative control group was significant (P＜0.001).The high dose group of betaamyloid's average grey scale value reduced significantly than the negative control group (P=0.030,0.001).The low dose group than the negative control group was not obviously (P=0.614).The high dose group was not significantly different from the positive control group (P=0.927),the difference between normal control group and negative control group was significant (P＜0.001).CONCLUSION:Tianma Gouteng Decoction can go through the decrease of the NMDA2B receptor protein expression and the control of beta-amyloid deposition to reduce the retinal ganglion cell injury and apoptosis.

Effects of 2,3,5,4'-tetrahydroxy-stilbene-2-O-β-D-glycoside on Senile Plaques Formation and Inflammatory Response in APP/PS1 Mice / 中国康复理论与实践

@#Objective To observe the effects of 2,3,5,4'-tetrahydroxy-stilbene-2-O-β-D-glycoside (TSG) on formation of senile plaques and beta amyloid (Aβ), as well as activation of microglia and astrocytes, in cortex and hippocampus of APP/PS1 double transgenic mice. Methods A total of 64 five-month-old APP/PS1 mice were randomly divided into model group (n=16), low-dose TSG (0.05 g/kg) group (n=16), high-dose TSG (0.1 g/kg) group (n=16), and donepezil group (n=16); other 32 same age wild type (WT) mice were randomly divided into normal control group (n=16) and high-dose TSG (0.1 g/kg) WT group (n=16). The normal control group and model group were given distilled water, and the other groups were given the corresponding drugs intragastrically. The mice were tested with object recognition test, the deposi-tion of plaques in brain was detected with Congo red staining, and the expression of Aβ40/42, ionized calcium bind-ing adapter molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP) with immunohistochemistry after seven months of treatment (twelve-month-old). Results Compared with the model group, the discrimination index significantly increased (P<0.01), the deposition of plaques decreased in brain (P<0.05), and the expression of Aβ40/42, Iba1 and GFAP all significantly decreased in each treatment group (P<0.05). Conclusion TSG can improve learning and memory of APP/PS1 transgenic mice, reduce Aβ deposition and senile plaques, and reduce the inflammatory response, even in low-dose, which is similar to that of donepezil.

The protective effect of rapamycin on beta-amyloid protein 25-35-induced PC12 cells death / 医学研究生学报

Objective Rapamycin can improve characteristic pathology of AD by improving the level of autophagy.But, its internal mechanism still needs further study.This study was aimed to observe the protective effect of Rapamycin (RAPA) on the injury of rat pheochromocytoma (PC12) cells induced by β-amyloid protein25-35 (Aβ25-35).Methods PC12 cells in the logarithmic phase were randomly divided into 5 groups: control group(similar free-serum DMEM), model group, 10μmol/L RAPA treated group, 40μmol/L RAPA treated group and 160μmol/L RAPA treated group(add 10μmol/L, 40μmol/L RAPA, 160μmol/L respectively).Except the control group, each group was cultured with 20μmol/L Aβ25-35 to established the cell injury model.Results ①Compared with the survival rate of cells[(51.47±2.59)%] and the apoptosis rate of cells[(52.22±2.33)%] of the model group,the survival rate of cells in 10、40、160μmol/L RAPA treated groups and control group[(54.64±2.42)%, (64.79±2.91)% ,(56.50±2.55)% and (99.98±0.73)%] significantly increased, but the apoptosis rate of cells [(45.33±2.83)%, (36.89±2.85)%, (48.00±2.83)% and (3.33±2.45)%] significantly decreased(All P<0.05).②In model group,the expressions of p-PKB is 0.33±0.01, p-mTOR is 1.97±0.05, p-tau is 2.09±0.19.Compared with model group, in 10、40、160μmol/L RAPA treated groups and control group,these expressions of p-PKB (0.37±0.01, 0.42±0.01, 0.40±0.01 and 0.44±0.02) were significantly increased, however p-mTOR (1.64±0.05, 0.66±0.04, 0.35±0.01 and 0.62±0.01) and p-tau (2.02±0.15, 1.79±0.05, 1.86±0.06 and1.53±0.04) were decreased(All, P<0.05).ConclusionRAPA can increase Aβ25-35-induced PC12 cells viability, decrease cells apoptosis rates, and have a protective effect on Aβ25-35-induced PC12 cells death.The mechanism of its protective effect may be related to the inhibition of mTOR regulating PI3K/PKB/mTOR signal transduction pathway by negative feedback and the reduction of tau protein hyperphosphorylation.