In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation...In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation of P-glycoprotein.The amyloid cascade hypothesis describes amyloid-βas the central cause of Alzheimer’s disease neuropathology.Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-βand their potential association in the pathological process of Alzheimer’s disease is critical.Herein,we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age.The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age.Decreased sphingomyelin levels,increased ceramide levels,and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice.Similar results were observed in the Alzheimer’s disease mouse model induced by intracerebroventricular injection of amyloid-β1-42 and human cerebral microvascular endothelial cells treated with amyloid-β1-42.In human cerebral microvascular endothelial cells,neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-β1-42 treatment.Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide.Together,these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway.These studies may serve as new pursuits for the development of anti-Alzheimer’s disease drugs.展开更多
Previous studies have shown that fibroblast growth factor 13 is downregulated in the brain of both Alzheimer’s disease mouse models and patients,and that it plays a vital role in the learning and memory.However,the u...Previous studies have shown that fibroblast growth factor 13 is downregulated in the brain of both Alzheimer’s disease mouse models and patients,and that it plays a vital role in the learning and memory.However,the underlying mechanisms of fibroblast growth factor 13 in Alzheimer’s disease remain unclear.In this study,we established rat models of Alzheimer’s disease by stereotaxic injection of amyloid-β(Aβ_(1-42))-induced into bilateral hippocampus.We also injected lentivirus containing fibroblast growth factor 13 into bilateral hippocampus to overexpress fibroblast growth factor 13.The expression of fibroblast growth factor 13 was downregulated in the brain of the Alzheimer’s disease model rats.After overexpression of fibroblast growth factor 13,learning and memory abilities of the Alzheimer’s disease model rats were remarkably improved.Fibroblast growth factor 13 overexpression increased brain expression levels of oxidative stress-related markers glutathione,superoxide dismutase,phosphatidylinositol-3-kinase,AKT and glycogen synthase kinase 3β,and anti-apoptotic factor BCL.Furthermore,fibroblast growth factor 13 overexpression decreased the number of apoptotic cells,expression of pro-apoptotic factor BAX,cleaved-caspase 3 and amyloid-βexpression,and levels of tau phosphorylation,malondialdehyde,reactive oxygen species and acetylcholinesterase in the brain of Alzheimer’s disease model rats.The changes were reversed by the phosphatidylinositol-3-kinase inhibitor LY294002.These findings suggest that overexpression of fibroblast growth factor 13 improved neuronal damage in a rat model of Alzheimer’s disease through activation of the phosphatidylinositol-3-kinase/AKT/glycogen synthase kinase 3βsignaling pathway.展开更多
Cannabidiol (CBD), one of the most studied phytocannabinoids, is non-psychotropic and can induce protective effects on the central nervous system against acute and chronic brain injury. Interestingly, CBD inhibits pro...Cannabidiol (CBD), one of the most studied phytocannabinoids, is non-psychotropic and can induce protective effects on the central nervous system against acute and chronic brain injury. Interestingly, CBD inhibits processes relating to amyloid beta (Aβ)-induced neurotoxicity in mouse models of Alzheimer’s disease, though the detailed molecular mechanism underlying the CBD neurotoxicity modulation is not fully understood. In this study, using atomic force microscopy, we find that CBD promotes the aggregation of Aβ peptides, enhancing the formation of Aβ oligomers, also known as Aβ-derived diffusible ligands (ADDLs). The CBD-mediated sequestration of Aβ monomers in soluble ADDLs could reduce neurotoxicity. This study highlights a possible role of CBD in modulating the formation of ADDL aggregates and provides insight into potentially neuroprotective properties of CBD in Alzheimer’s disease.展开更多
Lycium barbarum(LB)is a traditional Chinese medicine that has been demonstrated to exhibit a wide variety of biological functions,such as antioxidation,neuroprotection,and immune modulation.One of the main mechanisms ...Lycium barbarum(LB)is a traditional Chinese medicine that has been demonstrated to exhibit a wide variety of biological functions,such as antioxidation,neuroprotection,and immune modulation.One of the main mechanisms of Alzheimer’s disease is that microglia activated by amyloid beta(Aβ)transform from the resting state to an M1 state and release pro-inflammatory cytokines to the surrounding environment.In the present study,immortalized microglial cells were pretreated with L.barbarum extract for 1 hour and then treated with oligomeric Aβfor 23 hours.The results showed that LB extract significantly increased the survival of oligomeric Aβ-induced microglial cells,downregulated the expression of M1 pro-inflammatory markers(inducible nitric oxide synthase,tumor necrosis factorα,interleukin-6,and interleukin-1β),and upregulated the expression of M2 anti-inflammatory markers(arginase-1,chitinase-like protein 3,and interleukin-4).LB extract also inhibited the oligomeric Aβ-induced secretion of tumor necrosis factorα,interleukin-6,and interleukin-1βin microglial cells.The results of in vitro cytological experiments suggest that,in microglial cells,LB extract can inhibit oligomeric Aβ-induced M1 polarization and concomitant inflammatory reactions,and promote M2 polarization.展开更多
Although amyloid-β peptide is considered neurotoxic, it may mediate several physiological processes during embryonic development and in the adult brain. The pathological function of amyloid-β peptide has been extens...Although amyloid-β peptide is considered neurotoxic, it may mediate several physiological processes during embryonic development and in the adult brain. The pathological function of amyloid-β peptide has been extensively studied due to its implication in Alzheimer’s disease, but its physiological function remains poorly understood. Amyloid-β peptide can be detected in non-aggregated (monomeric) and aggregated (oligomeric and fibrillary) forms. Each form has different cytotoxic and/or physiological properties, so amyloid-β peptide and its role in Alzheimer’s disease need to be studied further. Neural stem cells and neural precursor cells are good tools for the study on neurodegenerative diseases and can provide future therapeutic applications in diseases such as Alzheimer’s disease. In this review, we provide an outline of the effects of amyloid-β peptide, in monomeric and aggregated forms, on the biology of neural stem cells/neural precursor cells, and discuss the controversies. We also describe the possible molecular targets that could be implicated in these effects, especially GSK3β. A better understanding of amyloid-β peptide (both physiological and pathological), and the signaling pathways involved are essential to advance the field of Alzheimer’s disease.展开更多
Background:Amyloid-β(Aβ)metabolic imbalance is the pivotal pathogenesis leading to Alzheimer’s disease(AD).In sporadic AD,decreased clearance of Aβimportantly contributes to the onset and progression.Astrocytes,th...Background:Amyloid-β(Aβ)metabolic imbalance is the pivotal pathogenesis leading to Alzheimer’s disease(AD).In sporadic AD,decreased clearance of Aβimportantly contributes to the onset and progression.Astrocytes,the most abundant cell type in the brain,are mainly responsible for maintaining neuronal homeostasis.Most recently,it has been demonstrated that astrocytes play an important role in regulating Aβmetabolism.Icariin(ICA),a flavonoid glucoside extracted from the traditional Chinese herb Epimedium brevicornu,has been shown to produce protective effects against AD by decreasing Aβproduction.However,it remains unclear whether ICA regulates cellular Aβclearance in the astrocytes.Objective:To examine the regulatory effects of ICA on Aβremoval by astrocytes and explore the mechanisms of its actions.Methods:Uptake and subsequent degradation of Aβby astrocytes were evaluated using a combination of enzyme-linked immunosorbent assay(ELISA)and laser confocal microscopy.The effects of oligomer Aβ(oAβ1-42)and/or ICA on the expressions of sirt6 in the primary astrocytes were examined using western blotting and q-PCR assays.The expression of autophagy markers including P62 and LC3-Ⅱ,and phosphorylated-mTOR were measured by western blotting.In order to determine whether sirt6 is involved in the intracellular Aβmetabolism,sirt6 was knocked down using lentiviral vectors containing sirt6-shRNAs and autophagy levels were assessed by western blotting.Results:①In primary astrocytes,ICA not only significantly increased Aβinternalization but also obviously accelerated its degradation in a concentration-dependent manner.②Treatment of astrocytes with Aβ1-42 at 1μmol·L-1 significantly down-regulated the expression of sirt6,which was rescued by ICA.In addition,ICA at 20μmol·L-1 significantly increased the expression of LC3-Ⅱand markedly decreased the expression of P62 and phosphorylated-mTOR in primary astrocytes.③Sirt6 knockdown in primary astrocytes resulted in decreased cellular Aβuptake and degradation.Simultaneously,silencing of sirt6 in astrocytes increased P62 levels and reduced LC3-Ⅱand phosphorylated-mTOR levels.Conclusion:Taken together,our results demonstrate that sirt6 plays an important role in Aβmetabolism in astrocytes via induction of autophagy.ICA is a potential drug for treatment of AD as it upregulates cellular sirt6.展开更多
Amyloid-β<sub>42</sub> (Aβ<sub>42</sub>) accumulates within senileplaque, a pathological hall mark of Alzheimer’s disease (AD). Our previous reports showed that the monoclonal antibodies 37-...Amyloid-β<sub>42</sub> (Aβ<sub>42</sub>) accumulates within senileplaque, a pathological hall mark of Alzheimer’s disease (AD). Our previous reports showed that the monoclonal antibodies 37-11 and 77-3 react with conformational epitopes on the surface of the soluble aggregates of Aβ<sub>42</sub> and that sandwich ELISA using these two monoclonal antibodies yields high reactivity to detect soluble aggregates of Aβ<sub>42</sub>. Here, the reactivity of the sandwich ELISA was shown to increase in the presence of 50 μM Cu<sup>2+</sup>. However, the addition of Cu<sup>2+</sup> had only a small effect on the reactivity of a direct ELISA using antibody 37-11 or 77-3, suggesting that Cu<sup>2+</sup> has a small effect on the number of epitopes on the surface of the aggregates. Atomic force microscopy images showed that larger aggregates were formed in the presence of Cu<sup>2+</sup>, as shown in the other reports. Cu<sup>2+</sup> may gather the aggregates with distinct epitopes recognized by antibodies 37-11 and 77-3, leading to increased signal intensity of the sandwich ELISA.展开更多
Objective:Alzheimer’s disease( AD) is the most common neurodegenerative disorder which is characterized by amyloid-β( Aβ) aggradation in the brain and impairment of cognitive function. Thioredoxin-1( Trx-1) is a re...Objective:Alzheimer’s disease( AD) is the most common neurodegenerative disorder which is characterized by amyloid-β( Aβ) aggradation in the brain and impairment of cognitive function. Thioredoxin-1( Trx-1) is a redox regulating protein,and plays roles in resisting the oxidative stress and protecting neurons. Our previous study found that Trx-1 improved the cognitive function of Parkinson’s Disease( PD) mice. Geranylgeranylacetone( GGA) is an antiulcer drug and induces the expression of Trx-1 in vivo and in vitro. However,whether Trx-1 improves cognitive functions in mice of APP/PS1 or GGA protects SH-SY5 Y cells from cytotoxicity induced by Aβ is still unknown. The objective of present is to investigate the roles of Trx-1 and GGA in inhibiting neurotoxicity of Aβ. Methods:We used MTT assay to test the cell viability induced by Aβ(25-35) and western blot to detect the expression of Trx-1 in SH-SY5 Y cells. Trx-1 overexpression transgenic mice were hybridized with APP/PS1 transgenic mice to get control,Trx-1,Tx-1/APP/PS1 and APP/PS1 mice. Then we used Morris water maze,high plus maze and object recognition test to detect the cognitive function of different kinds of mice. We also used RT-PCR and western blot to test the mRNA level and expression of Trx-1,APP,PS1 and Aβ. Results:In our present study,we demonstrated that Aβ(25-35) decreased the cell viability and the expression of Trx-1 in SH-SY5 Y cells. The cell viability and the expression of Trx-1 were reversed by GGA. Our results showed that the escape latency in APP/PS1 mice was longer when compared with the Trx-1/APP/PS1 mice in Morris water maze and high plus maze. Whereas navigational experiments in Morris water maze result showed that the total number of crossings and the percentage of time spent in the target quadrant were significantly decreased in APP/PS1 mice when compared to Trx-1/APP/PS1 mice. Object recognition test the discrimination index was significantly decreased in APP/PS1 mice when compared with Trx-1/APP/PS1 mice. The mRNA levels and the expression of APP,PS1 and Aβ were decreased in Trx-1/APP/PS1 mice when compared to APP/PS1 mice. Conclusion:These results suggest that GGA protects SH-SY5 Y cells from cytotoxicity induced by Aβ(25-35) and restored the expression of Trx-1. Trx-1 overexpression improves cognitive function of APP/PS1 mice. Trx-1 may be a potential therapeutic target for the clinical management of AD.展开更多
Amyloid-β (AP) peptide, the primary constituent of senile plaques in Alzheimer's disease (AD), is generated byβ-secretase- and γ-secretase-mediated sequential proteolysis of the amyloid precursor protein (APP)....Amyloid-β (AP) peptide, the primary constituent of senile plaques in Alzheimer's disease (AD), is generated byβ-secretase- and γ-secretase-mediated sequential proteolysis of the amyloid precursor protein (APP). The aspartic pro-tease, β -site APP cleavage enzyme (BACE), has been identified as the main P-secretase in brain but the regulation of itsactivity is largely unclear. Here, we demonstrate that both BACE activity and subsequent Aβ production are enhancedafter stimulation of receptor tyrosine kinases (RTKs), such as the receptors for epidermal growth factor (EGF) and nervegrowth factor (NGF), in cultured cells as well as in mouse hippocampus. Furthermore, stimulation of RTKs also inducesBACE internalization into endosomes and Golgi apparatus. This enhancement of BACE activity and Aβ production uponRTK activation could be specifically inhibited by Src family kinase inhibitors and by depletion of endogenous c-Src withRNAi, and could be mimicked by over-expressed c-Src. Moreover, blockage of BACE internalization by a dominantnegative form of Rab5 also abolished the enhancement of BACE activity and Aβ production, indicating the requirementof BACE internalization for the enhanced activity. Taken together, our study presents evidence that BACE activity andAβ production are under the regulation of RTKs and this is achieved via RTK-stimulated BACE internalization, andsuggests that an aberration of such regulation might contribute to pathogenic Aβ production.展开更多
Astrocytes' roles in late-onset Alzheimer's disease(LOAD) promotion are important, since they survive soluble or fibrillar amyloid-β peptides(Aβs) neurotoxic effects, undergo alterations of intracellular and...Astrocytes' roles in late-onset Alzheimer's disease(LOAD) promotion are important, since they survive soluble or fibrillar amyloid-β peptides(Aβs) neurotoxic effects, undergo alterations of intracellular and intercellular Ca2+ signaling and gliotransmitters release via the Aβ/α7-n ACh R(α7-nicotinic acetylcholine receptor) signaling, and overproduce/oversecrete newly synthesized Aβ42 oligomers, NO, and VEGF-A via the Aβ/Ca SR(calcium-sensing receptor) signaling. Recently, it was suggested that the NMDAR(N-methyl-D-aspartate receptor) inhibitor nitromemantine would block the synapse-destroying effects of Aβ/α7-n ACh R signaling. Yet, this and the progressive extracellular accrual and spreading of Aβ42 oligomers would be stopped well upstream by NPS 2143, an allosteric Ca SR antagonist(calcilytic).展开更多
Soluble peptides or proteins can self-aggregate into insoluble, ordered amyloid fibrils under appropriate conditions.These amyloid aggregates are the hallmarks of several human diseases ranging from neurodegenerative ...Soluble peptides or proteins can self-aggregate into insoluble, ordered amyloid fibrils under appropriate conditions.These amyloid aggregates are the hallmarks of several human diseases ranging from neurodegenerative disorders to systemic amyloidoses. In this review, we first introduce the common structural features of amyloid fibrils and the amyloid fibrillation kinetics determined from experimental studies. Then, we discuss the structural models of Alzheimer's amyloid-β(Aβ) fibrils derived from solid-state nuclear magnetic resonance spectroscopy. On the computational side, molecular dynamics simulations can provide atomic details of structures and the underlying oligomerization mechanisms. We finally summarize recent progress in atomistic simulation studies on the oligomerization of Aβ(including full-length Aβ and its fragments) and the influence of carbon nanoparticles.展开更多
Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheime...Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer’s disease.Hence,promoting neuroplasticity may represent an effective strategy with which Alzheimer’s disease can be alleviated.Due to their significant ability to self-renew,differentiate,and migrate,neural stem cells play an essential role in reversing synaptic and neuronal damage,reducing the pathology of Alzheimer’s disease,including amyloid-β,tau protein,and neuroinflammation,and secreting neurotrophic factors and growth factors that are related to plasticity.These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain.Consequently,neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer’s disease and other neurodegenerative diseases.In this review,we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer’s disease in the clinic.展开更多
Kai Xin San is a Chinese herbal formula composed of Radix Ginseng, Poria, Radix Polygalae and Acorus Tatarinowii Rhizome. It has been used in China for many years for treating amnesia. Kai Xin San ameliorates amyloid-...Kai Xin San is a Chinese herbal formula composed of Radix Ginseng, Poria, Radix Polygalae and Acorus Tatarinowii Rhizome. It has been used in China for many years for treating amnesia. Kai Xin San ameliorates amyloid-β(Aβ)-induced cognitive dysfunction and is neuroprotective in vivo, but its precise mechanism remains unclear. Expression of insulin-degrading enzyme(IDE), which degrades Aβ, is strongly correlated with cognitive function. Here, we injected rats with exogenous Aβ42(200 μM, 5 μL) into the hippocampus and subsequently administered Kai Xin San(0.54 or 1.08 g/kg/d) intragastrically for 21 consecutive days. Hematoxylin-eosin and Nissl staining revealed that Kai Xin San protected neurons against Aβ-induced damage. Furthermore, enzyme-linked immunosorbent assay, western blot and polymerase chain reaction results showed that Kai Xin San decreased Aβ42 protein levels and increased expression of IDE protein, but not m RNA, in the hippocampus. Our findings reveal that Kai Xin San facilitates hippocampal Aβ degradation and increases IDE expression, which leads, at least in part, to the alleviation of hippocampal neuron injury in rats.展开更多
Although humans have spent exactly 100 years combating Alzheimer’s disease (AD), the molecular mechanisms of AD remain unclear. Owing to the rapid growth of the oldest age groups of the popula-tion and the continuous...Although humans have spent exactly 100 years combating Alzheimer’s disease (AD), the molecular mechanisms of AD remain unclear. Owing to the rapid growth of the oldest age groups of the popula-tion and the continuous increase of the incidence of AD, it has become one of the crucial problems to modern sciences. It would be impossible to prevent or reverse AD at the root without elucidating its molecular mechanisms. From the point of view of metal-amyloid-β peptide (Aβ) interactions, we review the molecular mechanisms of AD, mainly including Cu2+ and Zn2+ inducing the aggregation of Aβ, cata-lysing the production of active oxygen species from Aβ, as well as interacting with the ion-channel-like structures of Aβ. Moreover, the development of therapeutic drugs on the basis of metal-Aβ interactions is also briefly introduced. With the increasingly rapid progress of the molecular mechanisms of AD, we are now entering a new dawn that promises the delivery of revolutionary developments for the control of dementias.展开更多
Senile plaques(SPs)are one of the pathological features of Alzheimer’s disease(AD)and they are formed by the overproduction and aggregation of amyloid-beta(Aβ)peptides derived from the abnormal cleavage of amyloid p...Senile plaques(SPs)are one of the pathological features of Alzheimer’s disease(AD)and they are formed by the overproduction and aggregation of amyloid-beta(Aβ)peptides derived from the abnormal cleavage of amyloid precursor protein(APP).Thus,understanding the regulatory mechanisms during Aβ metabolism is of great importance to elucidate AD pathogenesis.Recent studies have shown that epigenetic modulation-including DNA methylation,non-coding RNA alterations,and histone modifications-is of great significance in regulating Aβ metabolism.In this article,we review the aberrant epigenetic regulation of Aβ metabolism.展开更多
基金supported by the National Key Research and Development Program of ChinaNos.2021YFC2 701800 and 2021YFC2 701805 (to QY)+2 种基金Open Research Fund of State Key Laboratory of Genetic EngineeringFudan UniversityNo.SKLGE-21 19 (to TXH and QY)
文摘In Alzheimer’s disease,the transporter P-glycoprotein is responsible for the clearance of amyloid-βin the brain.Amyloid-βcorrelates with the sphingomyelin metabolism,and sphingomyelin participates in the regulation of P-glycoprotein.The amyloid cascade hypothesis describes amyloid-βas the central cause of Alzheimer’s disease neuropathology.Better understanding of the change of P-glycoprotein and sphingomyelin along with amyloid-βand their potential association in the pathological process of Alzheimer’s disease is critical.Herein,we found that the expression of P-glycoprotein in APP/PS1 mice tended to increase with age and was significantly higher at 9 and 12 months of age than that in wild-type mice at comparable age.The functionality of P-glycoprotein of APP/PS1 mice did not change with age but was significantly lower than that of wild-type mice at 12 months of age.Decreased sphingomyelin levels,increased ceramide levels,and the increased expression and activity of neutral sphingomyelinase 1 were observed in APP/PS1 mice at 9 and 12 months of age compared with the levels in wild-type mice.Similar results were observed in the Alzheimer’s disease mouse model induced by intracerebroventricular injection of amyloid-β1-42 and human cerebral microvascular endothelial cells treated with amyloid-β1-42.In human cerebral microvascular endothelial cells,neutral sphingomyelinase 1 inhibitor interfered with the changes of sphingomyelin metabolism and P-glycoprotein expression and functionality caused by amyloid-β1-42 treatment.Neutral sphingomyelinase 1 regulated the expression and functionality of P-glycoprotein and the levels of sphingomyelin and ceramide.Together,these findings indicate that neutral sphingomyelinase 1 regulates the expression and function of P-glycoprotein via the sphingomyelin/ceramide pathway.These studies may serve as new pursuits for the development of anti-Alzheimer’s disease drugs.
文摘Previous studies have shown that fibroblast growth factor 13 is downregulated in the brain of both Alzheimer’s disease mouse models and patients,and that it plays a vital role in the learning and memory.However,the underlying mechanisms of fibroblast growth factor 13 in Alzheimer’s disease remain unclear.In this study,we established rat models of Alzheimer’s disease by stereotaxic injection of amyloid-β(Aβ_(1-42))-induced into bilateral hippocampus.We also injected lentivirus containing fibroblast growth factor 13 into bilateral hippocampus to overexpress fibroblast growth factor 13.The expression of fibroblast growth factor 13 was downregulated in the brain of the Alzheimer’s disease model rats.After overexpression of fibroblast growth factor 13,learning and memory abilities of the Alzheimer’s disease model rats were remarkably improved.Fibroblast growth factor 13 overexpression increased brain expression levels of oxidative stress-related markers glutathione,superoxide dismutase,phosphatidylinositol-3-kinase,AKT and glycogen synthase kinase 3β,and anti-apoptotic factor BCL.Furthermore,fibroblast growth factor 13 overexpression decreased the number of apoptotic cells,expression of pro-apoptotic factor BAX,cleaved-caspase 3 and amyloid-βexpression,and levels of tau phosphorylation,malondialdehyde,reactive oxygen species and acetylcholinesterase in the brain of Alzheimer’s disease model rats.The changes were reversed by the phosphatidylinositol-3-kinase inhibitor LY294002.These findings suggest that overexpression of fibroblast growth factor 13 improved neuronal damage in a rat model of Alzheimer’s disease through activation of the phosphatidylinositol-3-kinase/AKT/glycogen synthase kinase 3βsignaling pathway.
文摘Cannabidiol (CBD), one of the most studied phytocannabinoids, is non-psychotropic and can induce protective effects on the central nervous system against acute and chronic brain injury. Interestingly, CBD inhibits processes relating to amyloid beta (Aβ)-induced neurotoxicity in mouse models of Alzheimer’s disease, though the detailed molecular mechanism underlying the CBD neurotoxicity modulation is not fully understood. In this study, using atomic force microscopy, we find that CBD promotes the aggregation of Aβ peptides, enhancing the formation of Aβ oligomers, also known as Aβ-derived diffusible ligands (ADDLs). The CBD-mediated sequestration of Aβ monomers in soluble ADDLs could reduce neurotoxicity. This study highlights a possible role of CBD in modulating the formation of ADDL aggregates and provides insight into potentially neuroprotective properties of CBD in Alzheimer’s disease.
基金supported by Midstream Research Program for UniversitiesHong Kong Special Administrative Region,China,No.MRP-092-17X。
文摘Lycium barbarum(LB)is a traditional Chinese medicine that has been demonstrated to exhibit a wide variety of biological functions,such as antioxidation,neuroprotection,and immune modulation.One of the main mechanisms of Alzheimer’s disease is that microglia activated by amyloid beta(Aβ)transform from the resting state to an M1 state and release pro-inflammatory cytokines to the surrounding environment.In the present study,immortalized microglial cells were pretreated with L.barbarum extract for 1 hour and then treated with oligomeric Aβfor 23 hours.The results showed that LB extract significantly increased the survival of oligomeric Aβ-induced microglial cells,downregulated the expression of M1 pro-inflammatory markers(inducible nitric oxide synthase,tumor necrosis factorα,interleukin-6,and interleukin-1β),and upregulated the expression of M2 anti-inflammatory markers(arginase-1,chitinase-like protein 3,and interleukin-4).LB extract also inhibited the oligomeric Aβ-induced secretion of tumor necrosis factorα,interleukin-6,and interleukin-1βin microglial cells.The results of in vitro cytological experiments suggest that,in microglial cells,LB extract can inhibit oligomeric Aβ-induced M1 polarization and concomitant inflammatory reactions,and promote M2 polarization.
基金supported by grants from the MICINN-ISCⅢ(PI-10/00291 and MPY1412/09)MINECO(SAF2015-71140-R)+1 种基金Comunidad de Madrid(NEUROSTEMCM consortium S2010/BMD-2336)(all to IL)
文摘Although amyloid-β peptide is considered neurotoxic, it may mediate several physiological processes during embryonic development and in the adult brain. The pathological function of amyloid-β peptide has been extensively studied due to its implication in Alzheimer’s disease, but its physiological function remains poorly understood. Amyloid-β peptide can be detected in non-aggregated (monomeric) and aggregated (oligomeric and fibrillary) forms. Each form has different cytotoxic and/or physiological properties, so amyloid-β peptide and its role in Alzheimer’s disease need to be studied further. Neural stem cells and neural precursor cells are good tools for the study on neurodegenerative diseases and can provide future therapeutic applications in diseases such as Alzheimer’s disease. In this review, we provide an outline of the effects of amyloid-β peptide, in monomeric and aggregated forms, on the biology of neural stem cells/neural precursor cells, and discuss the controversies. We also describe the possible molecular targets that could be implicated in these effects, especially GSK3β. A better understanding of amyloid-β peptide (both physiological and pathological), and the signaling pathways involved are essential to advance the field of Alzheimer’s disease.
文摘Background:Amyloid-β(Aβ)metabolic imbalance is the pivotal pathogenesis leading to Alzheimer’s disease(AD).In sporadic AD,decreased clearance of Aβimportantly contributes to the onset and progression.Astrocytes,the most abundant cell type in the brain,are mainly responsible for maintaining neuronal homeostasis.Most recently,it has been demonstrated that astrocytes play an important role in regulating Aβmetabolism.Icariin(ICA),a flavonoid glucoside extracted from the traditional Chinese herb Epimedium brevicornu,has been shown to produce protective effects against AD by decreasing Aβproduction.However,it remains unclear whether ICA regulates cellular Aβclearance in the astrocytes.Objective:To examine the regulatory effects of ICA on Aβremoval by astrocytes and explore the mechanisms of its actions.Methods:Uptake and subsequent degradation of Aβby astrocytes were evaluated using a combination of enzyme-linked immunosorbent assay(ELISA)and laser confocal microscopy.The effects of oligomer Aβ(oAβ1-42)and/or ICA on the expressions of sirt6 in the primary astrocytes were examined using western blotting and q-PCR assays.The expression of autophagy markers including P62 and LC3-Ⅱ,and phosphorylated-mTOR were measured by western blotting.In order to determine whether sirt6 is involved in the intracellular Aβmetabolism,sirt6 was knocked down using lentiviral vectors containing sirt6-shRNAs and autophagy levels were assessed by western blotting.Results:①In primary astrocytes,ICA not only significantly increased Aβinternalization but also obviously accelerated its degradation in a concentration-dependent manner.②Treatment of astrocytes with Aβ1-42 at 1μmol·L-1 significantly down-regulated the expression of sirt6,which was rescued by ICA.In addition,ICA at 20μmol·L-1 significantly increased the expression of LC3-Ⅱand markedly decreased the expression of P62 and phosphorylated-mTOR in primary astrocytes.③Sirt6 knockdown in primary astrocytes resulted in decreased cellular Aβuptake and degradation.Simultaneously,silencing of sirt6 in astrocytes increased P62 levels and reduced LC3-Ⅱand phosphorylated-mTOR levels.Conclusion:Taken together,our results demonstrate that sirt6 plays an important role in Aβmetabolism in astrocytes via induction of autophagy.ICA is a potential drug for treatment of AD as it upregulates cellular sirt6.
文摘Amyloid-β<sub>42</sub> (Aβ<sub>42</sub>) accumulates within senileplaque, a pathological hall mark of Alzheimer’s disease (AD). Our previous reports showed that the monoclonal antibodies 37-11 and 77-3 react with conformational epitopes on the surface of the soluble aggregates of Aβ<sub>42</sub> and that sandwich ELISA using these two monoclonal antibodies yields high reactivity to detect soluble aggregates of Aβ<sub>42</sub>. Here, the reactivity of the sandwich ELISA was shown to increase in the presence of 50 μM Cu<sup>2+</sup>. However, the addition of Cu<sup>2+</sup> had only a small effect on the reactivity of a direct ELISA using antibody 37-11 or 77-3, suggesting that Cu<sup>2+</sup> has a small effect on the number of epitopes on the surface of the aggregates. Atomic force microscopy images showed that larger aggregates were formed in the presence of Cu<sup>2+</sup>, as shown in the other reports. Cu<sup>2+</sup> may gather the aggregates with distinct epitopes recognized by antibodies 37-11 and 77-3, leading to increased signal intensity of the sandwich ELISA.
文摘Objective:Alzheimer’s disease( AD) is the most common neurodegenerative disorder which is characterized by amyloid-β( Aβ) aggradation in the brain and impairment of cognitive function. Thioredoxin-1( Trx-1) is a redox regulating protein,and plays roles in resisting the oxidative stress and protecting neurons. Our previous study found that Trx-1 improved the cognitive function of Parkinson’s Disease( PD) mice. Geranylgeranylacetone( GGA) is an antiulcer drug and induces the expression of Trx-1 in vivo and in vitro. However,whether Trx-1 improves cognitive functions in mice of APP/PS1 or GGA protects SH-SY5 Y cells from cytotoxicity induced by Aβ is still unknown. The objective of present is to investigate the roles of Trx-1 and GGA in inhibiting neurotoxicity of Aβ. Methods:We used MTT assay to test the cell viability induced by Aβ(25-35) and western blot to detect the expression of Trx-1 in SH-SY5 Y cells. Trx-1 overexpression transgenic mice were hybridized with APP/PS1 transgenic mice to get control,Trx-1,Tx-1/APP/PS1 and APP/PS1 mice. Then we used Morris water maze,high plus maze and object recognition test to detect the cognitive function of different kinds of mice. We also used RT-PCR and western blot to test the mRNA level and expression of Trx-1,APP,PS1 and Aβ. Results:In our present study,we demonstrated that Aβ(25-35) decreased the cell viability and the expression of Trx-1 in SH-SY5 Y cells. The cell viability and the expression of Trx-1 were reversed by GGA. Our results showed that the escape latency in APP/PS1 mice was longer when compared with the Trx-1/APP/PS1 mice in Morris water maze and high plus maze. Whereas navigational experiments in Morris water maze result showed that the total number of crossings and the percentage of time spent in the target quadrant were significantly decreased in APP/PS1 mice when compared to Trx-1/APP/PS1 mice. Object recognition test the discrimination index was significantly decreased in APP/PS1 mice when compared with Trx-1/APP/PS1 mice. The mRNA levels and the expression of APP,PS1 and Aβ were decreased in Trx-1/APP/PS1 mice when compared to APP/PS1 mice. Conclusion:These results suggest that GGA protects SH-SY5 Y cells from cytotoxicity induced by Aβ(25-35) and restored the expression of Trx-1. Trx-1 overexpression improves cognitive function of APP/PS1 mice. Trx-1 may be a potential therapeutic target for the clinical management of AD.
基金grants from the Ministry of Science and Technology （2003CB515405, 2005CB522406） the National Natural Science Foundation of China （30021003, 30400230, 30625014）+2 种基金 the Chinese Academy of Sciences （KSCX1- SW, KSCX2-SW） the Ministry of Education, Shanghai Municipal Commission for Science and Technology （06ZR14098） China Post Doctoral Science Foundation, and Shanghai Postdoctoral Science Foundation.
文摘Amyloid-β (AP) peptide, the primary constituent of senile plaques in Alzheimer's disease (AD), is generated byβ-secretase- and γ-secretase-mediated sequential proteolysis of the amyloid precursor protein (APP). The aspartic pro-tease, β -site APP cleavage enzyme (BACE), has been identified as the main P-secretase in brain but the regulation of itsactivity is largely unclear. Here, we demonstrate that both BACE activity and subsequent Aβ production are enhancedafter stimulation of receptor tyrosine kinases (RTKs), such as the receptors for epidermal growth factor (EGF) and nervegrowth factor (NGF), in cultured cells as well as in mouse hippocampus. Furthermore, stimulation of RTKs also inducesBACE internalization into endosomes and Golgi apparatus. This enhancement of BACE activity and Aβ production uponRTK activation could be specifically inhibited by Src family kinase inhibitors and by depletion of endogenous c-Src withRNAi, and could be mimicked by over-expressed c-Src. Moreover, blockage of BACE internalization by a dominantnegative form of Rab5 also abolished the enhancement of BACE activity and Aβ production, indicating the requirementof BACE internalization for the enhanced activity. Taken together, our study presents evidence that BACE activity andAβ production are under the regulation of RTKs and this is achieved via RTK-stimulated BACE internalization, andsuggests that an aberration of such regulation might contribute to pathogenic Aβ production.
文摘Astrocytes' roles in late-onset Alzheimer's disease(LOAD) promotion are important, since they survive soluble or fibrillar amyloid-β peptides(Aβs) neurotoxic effects, undergo alterations of intracellular and intercellular Ca2+ signaling and gliotransmitters release via the Aβ/α7-n ACh R(α7-nicotinic acetylcholine receptor) signaling, and overproduce/oversecrete newly synthesized Aβ42 oligomers, NO, and VEGF-A via the Aβ/Ca SR(calcium-sensing receptor) signaling. Recently, it was suggested that the NMDAR(N-methyl-D-aspartate receptor) inhibitor nitromemantine would block the synapse-destroying effects of Aβ/α7-n ACh R signaling. Yet, this and the progressive extracellular accrual and spreading of Aβ42 oligomers would be stopped well upstream by NPS 2143, an allosteric Ca SR antagonist(calcilytic).
基金supported by the National Natural Science Foundation of China(Grant Nos.11274075 and 91227102)
文摘Soluble peptides or proteins can self-aggregate into insoluble, ordered amyloid fibrils under appropriate conditions.These amyloid aggregates are the hallmarks of several human diseases ranging from neurodegenerative disorders to systemic amyloidoses. In this review, we first introduce the common structural features of amyloid fibrils and the amyloid fibrillation kinetics determined from experimental studies. Then, we discuss the structural models of Alzheimer's amyloid-β(Aβ) fibrils derived from solid-state nuclear magnetic resonance spectroscopy. On the computational side, molecular dynamics simulations can provide atomic details of structures and the underlying oligomerization mechanisms. We finally summarize recent progress in atomistic simulation studies on the oligomerization of Aβ(including full-length Aβ and its fragments) and the influence of carbon nanoparticles.
基金supported by the National Natural Science Foundation of China,No.82074533(to LZ).
文摘Recent studies have demonstrated that neuroplasticity,such as synaptic plasticity and neurogenesis,exists throughout the normal lifespan but declines with age and is significantly impaired in individuals with Alzheimer’s disease.Hence,promoting neuroplasticity may represent an effective strategy with which Alzheimer’s disease can be alleviated.Due to their significant ability to self-renew,differentiate,and migrate,neural stem cells play an essential role in reversing synaptic and neuronal damage,reducing the pathology of Alzheimer’s disease,including amyloid-β,tau protein,and neuroinflammation,and secreting neurotrophic factors and growth factors that are related to plasticity.These events can promote synaptic plasticity and neurogenesis to repair the microenvironment of the mammalian brain.Consequently,neural stem cells are considered to represent a potential regenerative therapy with which to improve Alzheimer’s disease and other neurodegenerative diseases.In this review,we discuss how neural stem cells regulate neuroplasticity and optimize their effects to enhance their potential for treating Alzheimer’s disease in the clinic.
基金supported by the National Natural Science Foundation of China,No.81303248,81603321the Natural Science Foundation of Heilongjiang Province of China,No.H2015028+1 种基金a grant from the Nursing Program for Young Scholars of Heilongjiang Province of China,No.UNPYSCT-2016116the Scientific Research Fund for Doctors of Qiqihar Medical University in China,No.QY2016B-09
文摘Kai Xin San is a Chinese herbal formula composed of Radix Ginseng, Poria, Radix Polygalae and Acorus Tatarinowii Rhizome. It has been used in China for many years for treating amnesia. Kai Xin San ameliorates amyloid-β(Aβ)-induced cognitive dysfunction and is neuroprotective in vivo, but its precise mechanism remains unclear. Expression of insulin-degrading enzyme(IDE), which degrades Aβ, is strongly correlated with cognitive function. Here, we injected rats with exogenous Aβ42(200 μM, 5 μL) into the hippocampus and subsequently administered Kai Xin San(0.54 or 1.08 g/kg/d) intragastrically for 21 consecutive days. Hematoxylin-eosin and Nissl staining revealed that Kai Xin San protected neurons against Aβ-induced damage. Furthermore, enzyme-linked immunosorbent assay, western blot and polymerase chain reaction results showed that Kai Xin San decreased Aβ42 protein levels and increased expression of IDE protein, but not m RNA, in the hippocampus. Our findings reveal that Kai Xin San facilitates hippocampal Aβ degradation and increases IDE expression, which leads, at least in part, to the alleviation of hippocampal neuron injury in rats.
基金Supported by the National Natural Science Foundation of China (Grant Nos. 30470408 and 20637010)the Youth Foundation of Science and Technology of Shanxi Province (Grant No. 2006021009)
文摘Although humans have spent exactly 100 years combating Alzheimer’s disease (AD), the molecular mechanisms of AD remain unclear. Owing to the rapid growth of the oldest age groups of the popula-tion and the continuous increase of the incidence of AD, it has become one of the crucial problems to modern sciences. It would be impossible to prevent or reverse AD at the root without elucidating its molecular mechanisms. From the point of view of metal-amyloid-β peptide (Aβ) interactions, we review the molecular mechanisms of AD, mainly including Cu2+ and Zn2+ inducing the aggregation of Aβ, cata-lysing the production of active oxygen species from Aβ, as well as interacting with the ion-channel-like structures of Aβ. Moreover, the development of therapeutic drugs on the basis of metal-Aβ interactions is also briefly introduced. With the increasingly rapid progress of the molecular mechanisms of AD, we are now entering a new dawn that promises the delivery of revolutionary developments for the control of dementias.
基金This work was supported by the National Natural Science Foundation of China(No.81373741,No.81473786,No.81873380)“Acupuncture for Learning and Memory Disorders Related Diseases”-Preponderant Discipline Team Project funded by Hubei University of Chinese Medicine,and Hubei Provincial Health and Family Planning Commission Project of Integrated Traditional Chinese and Western Medicine of Traditional Chinese Medicine(No.2013Z-Y49).
文摘Senile plaques(SPs)are one of the pathological features of Alzheimer’s disease(AD)and they are formed by the overproduction and aggregation of amyloid-beta(Aβ)peptides derived from the abnormal cleavage of amyloid precursor protein(APP).Thus,understanding the regulatory mechanisms during Aβ metabolism is of great importance to elucidate AD pathogenesis.Recent studies have shown that epigenetic modulation-including DNA methylation,non-coding RNA alterations,and histone modifications-is of great significance in regulating Aβ metabolism.In this article,we review the aberrant epigenetic regulation of Aβ metabolism.
