Pro-resolving lipid mediator reduces amyloid-β42–induced gene expression in human monocyte–derived microglia

Specialized pro-resolving lipid mediators including maresin 1 mediate resolution but the levels of these are reduced in Alzheimer's disease brain, suggesting that they constitute a novel target for the treatment of Alzheimer's disease to prevent/stop inflammation and combat disease pathology. Therefore, it is important to clarify whether they counteract the expression of genes and proteins induced by amyloid-β. With this objective, we analyzed the relevance of human monocyte–derived microglia for in vitro modeling of neuroinflammation and its resolution in the context of Alzheimer's disease and investigated the pro-resolving bioactivity of maresin 1 on amyloid-β42–induced Alzheimer's disease–like inflammation. Analysis of RNA-sequencing data and secreted proteins in supernatants from the monocyte-derived microglia showed that the monocyte-derived microglia resembled Alzheimer's disease–like neuroinflammation in human brain microglia after incubation with amyloid-β42. Maresin 1 restored homeostasis by down-regulating inflammatory pathway related gene expression induced by amyloid-β42 in monocyte-derived microglia, protection of maresin 1 against the effects of amyloid-β42 is mediated by a re-balancing of inflammatory transcriptional networks in which modulation of gene transcription in the nuclear factor-kappa B pathway plays a major part. We pinpointed molecular targets that are associated with both neuroinflammation in Alzheimer's disease and therapeutic targets by maresin 1. In conclusion, monocyte-derived microglia represent a relevant in vitro microglial model for studies on Alzheimer's disease-like inflammation and drug response for individual patients. Maresin 1 ameliorates amyloid-β42–induced changes in several genes of importance in Alzheimer's disease, highlighting its potential as a therapeutic target for Alzheimer's disease.

FUBP3 mediates the amyloid-β-induced neuronal NLRP3 expression

Alzheimer's disease is characterized by deposition of amyloid-β,which forms extracellular neuritic plaques,and accumulation of hyperphosphorylated tau,which aggregates to form intraneuronal neurofibrillary tangles,in the brain.The NLRP3 inflammasome may play a role in the transition from amyloid-βdeposition to tau phosphorylation and aggregation.Because NLRP3 is primarily found in brain microglia,and tau is predominantly located in neurons,it has been suggested that NLRP3 expressed by microglia indirectly triggers tau phosphorylation by upregulating the expression of pro-inflammatory cytokines.Here,we found that neurons also express NLRP3 in vitro and in vivo,and that neuronal NLRP3 regulates tau phosphorylation.Using biochemical methods,we mapped the minimal NLRP3 promoter and identified FUBP3 as a transcription factor regulating NLRP3 expression in neurons.In primary neurons and the neuroblastoma cell line Neuro2A,FUBP3 is required for endogenous NLRP3 expression and tau phosphorylation only when amyloid-βis present.In the brains of aged wild-type mice and a mouse model of Alzheimer's disease,FUBP3 expression was markedly increased in cortical neurons.Transcriptome analysis suggested that FUBP3 plays a role in neuron-mediated immune responses.We also found that FUBP3 trimmed the 5′end of DNA fragments that it bound,implying that FUBP3 functions in stress-induced responses.These findings suggest that neuronal NLRP3 may be more directly involved in the amyloid-β-to–phospho-tau transition than microglial NLRP3,and that amyloid-βfundamentally alters the regulatory mechanism of NLRP3 expression in neurons.Given that FUBP3 was only expressed at low levels in young wild-type mice and was strongly upregulated in the brains of aged mice and Alzheimer's disease mice,FUBP3 could be a safe therapeutic target for preventing Alzheimer's disease progression.

Enhanced autophagic clearance of amyloid-βvia histone deacetylase 6-mediated V-ATPase assembly and lysosomal acidification protects against Alzheimer's disease in vitro and in vivo

Recent studies have suggested that abnormal acidification of lysosomes induces autophagic accumulation of amyloid-βin neurons,which is a key step in senile plaque formation.Therefore,resto ring normal lysosomal function and rebalancing lysosomal acidification in neurons in the brain may be a new treatment strategy for Alzheimer's disease.Microtubule acetylation/deacetylation plays a central role in lysosomal acidification.Here,we show that inhibiting the classic microtubule deacetylase histone deacetylase 6 with an histone deacetylase 6 shRNA or thehistone deacetylase 6 inhibitor valproic acid promoted lysosomal reacidification by modulating V-ATPase assembly in Alzheimer's disease.Fu rthermore,we found that treatment with valproic acid markedly enhanced autophagy.promoted clearance of amyloid-βaggregates,and ameliorated cognitive deficits in a mouse model of Alzheimer's disease.Our findings demonstrate a previously unknown neuroprotective mechanism in Alzheimer's disease,in which histone deacetylase 6 inhibition by valproic acid increases V-ATPase assembly and lysosomal acidification.

Jiaohong pills attenuate neuroinflammation and amyloid-βprotein-induced cognitive deficits by modulating the mitogen-activated protein kinase/nuclear factor kappa-B pathway

Background:Jiaohong pills(JHP)consist of Pericarpium Zanthoxyli(PZ)and Radix Rehmanniae,two herbs that have been extensively investigated over many years due to their potential protective effects against cognitive decline and memory impairment.However,the precise mechanisms underlying the beneficial effects remain elusive.Here,research studies were conducted to investigate and validate the therapeutic effects of JHP on Alzheimer's disease.Methods:BV-2 cell inflammation was induced by lipopolysaccharide.AD mice were administered amyloid-β(Aβ).Behavioral experiments were used to evaluate learning and memory ability.The levels of nitric oxide(NO),tumor necrosis factor-alpha(TNF-α),interleukin-1β(IL-1β),and interleukin-10(IL-10)were detected using enzymelinked immunosorbent assay(ELISA).The protein expressions of inducible nitric oxide synthase(iNOS)and the phosphorylation level of mitogen-activated protein kinase(MAPK)and nuclear factor kappa-B(NF-κB)were detected using Western blot.Nissl staining was used to detect neuronal degeneration.Results:The results demonstrated that an alcoholic extract of PZ significantly decreased the levels of NO,IL-1β,TNF-α,and iNOS;increased the expression level of IL-10;and significantly decreased the phosphorylation levels of MAPK and NF-κB.These inhibitory effects were further confirmed in the AD mouse model.Meanwhile,JHP improved learning and memory function in AD mice,reduced neuronal damage,and enriched the Nissl bodies in the hippocampus.Moreover,IL-1βand TNF-αin the cortex were significantly downregulated after JHP administration,whereas IL-10showed increased expression.Conclusions:It was found that JHP reduced neuroinflammatory response in AD mice by targeting the MAPK/NF-κB signaling pathway.

The relationship among amyloid-βdeposition,sphingomyelin level,and the expression and function of P-glycoprotein in Alzheimer’s disease pathological process

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.

Overexpression of fibroblast growth factor 13 ameliorates amyloid-β-induced neuronal damage

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.

Cannabidiol-Mediated Sequestration of Alzheimer’s Amyloid-β Peptides in ADDL Oligomers

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.

壳寡糖对Amyloid-β_(1-42)致痴呆大鼠的学习记忆及血清抗氧化功能的影响

目的:探讨壳寡糖(chitosan oligosaccharide,COS)对Aβ_(1-42)致痴呆大鼠学习记忆及血清抗氧化功能的影响及其作用机制。方法:采用海马区微注射Aβ_(1-42)建立阿尔茨海默病大鼠痴呆模型,并使用COS干预,通过Morris水迷宫实验观察COS对阿尔茨海默病大鼠学习记忆能力的影响,同时通过测定血清中谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-Px)和超氧化物歧化酶(superoxide dismutase,SOD)等抗氧化酶的活力以及蛋白质羰基和丙二醛(malondialdehyde,MDA)含量变化观察COS的抗氧化能力。结果:经行为学测试,与假手术对照组相比,模型组大鼠的学习记忆能力明显下降;COS干预后,其学习记忆功能力有所改善。同时,模型组大鼠血清中的SOD和GSH-Px活力相比较假手术组显著降低,MDA和蛋白质羰基含量显著增加;经COS干预后,与模型组相比,大鼠血清中SOD和GSH-Px活力显著上升,MDA和蛋白质羰基含量均显著减少。结论:COS对海马区微注射Aβ_(1-42)致痴呆大鼠有一定的改善和保护作用,具体的作用机制可能与COS的抗氧化作用有关。

Antagonizing amyloid-β/calcium-sensing receptor signaling in human astrocytes and neurons: a key to halt Alzheimer's disease progression?

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/a7-nAChR （αT-nicotinic acetylcholine receptor） signaling, and overproduce/oversecrete newly synthesized Aβ42 oligomers, NO, and VEGF-A via the Aβ/CaSR （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-nAChR signaling. Yet, this and the progressive extracellular accrual and spreading of Aβ42 oligomers would be stopped well upstream by NPS 2143, an allosteric CaSR antagonist （calcilytic）.

Receptor tyrosine kinases positively regulate BACE activity and Amyloid-β production through enhancing BACE internalization

Amyloid-β （Aβ） peptide, the primary constituent of senile plaques in Alzheimer＇s disease （AD）, is generated by β-secretase- and y-secretase-mediated sequential proteolysis of the amyloid precursor protein （APP）. The aspartic protease, β -site APP cleavage enzyme （BACE）, has been identified as the main β-secretase in brain but the regulation of its activity is largely unclear. Here, we demonstrate that both BACE activity and subsequent Aβ production are enhanced after stimulation of receptor tyrosine kinases （RTKs）, such as the receptors for epidermal growth factor （EGF） and nerve growth factor （NGF）, in cultured cells as well as in mouse hippocampus. Furthermore, stimulation of RTKs also induces BACE internalization into endosomes and Golgi apparatus. This enhancement of BACE activity and A β production upon RTK activation could be specifically inhibited by Src family kinase inhibitors and by depletion of endogenous c-Src with RNAi, and could be mimicked by over-expressed c-Src. Moreover, blockage of BACE internalization by a dominant negative form of Rab5 also abolished the enhancement of BACE activity and Aβ production, indicating the requirement of BACE internalization for the enhanced activity. Taken together, our study presents evidence that BACE activity and Aβ production are under the regulation of RTKs and this is achieved via RTK-stimulated BACE internalization, and suggests that an aberration of such regulation might contribute to pathogenic Aβ production.

Lycium barbarum extract promotes M2 polarization and reduces oligomeric amyloid-β-induced inflammatory reactions in microglial cells

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.

Amyloid-β peptide aggregation and the influence of carbon nanoparticles

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 sys- temic 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 β （including full-length Af and its fragments） and the influence of carbon nanoparticles.

Physiological and pathological effects of amyloid-β species in neural stem cell biology

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.

NP-17 Icariin Facilitates Amyloid-βRemoval in Astrocytes via increased Autophagy by Up-Regulating Sirt6 Expression

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.

Copper Ions Enhance Signal Intensity of Sandwich ELISA for Amorphous Aggregates of Amyloid-β42

Amyloid-β42 (Aβ42) 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 Aβ42 and that sandwich ELISA using these two monoclonal antibodies yields high reactivity to detect soluble aggregates of Aβ42. Here, the reactivity of the sandwich ELISA was shown to increase in the presence of 50 μM Cu2+. However, the addition of Cu2+ had only a small effect on the reactivity of a direct ELISA using antibody 37-11 or 77-3, suggesting that Cu2+ 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 Cu2+, as shown in the other reports. Cu2+ may gather the aggregates with distinct epitopes recognized by antibodies 37-11 and 77-3, leading to increased signal intensity of the sandwich ELISA.

纳米粒子对amyloid-β聚集的影响的研究进展

阐述金属复合物和纳米粒子对β-类淀粉蛋白(amyloid-β,Aβ)聚集影响的最新研究进展.指出Aβ蛋白聚集过程始于寡聚体内核的组装,最终形成具有β-片层结构的螺旋状纤维.纳米粒子对纤维形成中的每一阶段都可能产生抑制或促进作用,从而影响Aβ的纤维化聚集.认为揭示Aβ聚集的影响因素及其作用机理,将有助于控制Aβ的纤维化聚集,减少其神经毒性,以此可寻找治疗阿尔茨海默症(Alzheimer's disease,AD)的途径.

Thioredoxin-1 and Geranylgeranylacetone Resist Neurotoxicity of Amyloid-β

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.

Rational design of hydroxytricyanopyrrole-based probes with high affinity and rapid visualization for amyloid-β aggregates in vitro and in vivo

As key biomarkers,amyloid-β(Aβ)plaques are frequently used to diagnose Alzheimer’s disease(AD).Although fluorescence imaging has proven to be effective in detecting these plaques,the gold standard probe thioflavin T(ThT),used for Aβaggregates,cannot be applied in vivo owing to its invasive nature.Therefore,the development of novel fluorescent probes capable of identifying Aβplaques in situ is necessary.Based on the ThT structure,twoπ-conjugated heterocyclic D-π-A probes were designed bearing the hydroxytricyanopyrrole acceptor and N,N-dimethylaminophenyl donor.These probes exhibited red to near-infrared fluorescence emission(λ_(max)=732 nm),large Stokes shifts(>100 nm),exceptional signal-to-noise ratio,rapid response(<30 s),and high binding affinity(NT-HTCP=33.32 nmol/L;NF-HTCP=53.35 nmol/L)for Aβaggregates.As the best candidate,NT-HTCP was used for in situ imaging of Aβplaques in AD mouse models.Furthermore,in vivo research demonstrated that NT-HTCP could cross the blood-brain barrier and continue imaging the Aβplaques with a good signal-to-noise ratio.Additionally,the outcomes of the docking computations helped guide the development of the Aβprobes.This study expands the family of N,N-dimethylaminophenyl-based Aβ-sensitive fluorophores,with NTHTCP emerging as a highly promising imaging agent.

H_(2)O_(2)-responsive multifunctional nanocomposite for the inhibition of amyloid-βand Tau aggregation in Alzheimer's disease

Amyloid-β(Aβ)and Tau proteins are the main components of Aβplaques and neurofibrillary tangles in Alzheimer's disease(AD),and their abnormal ag-gregation is closely related to the pathogenesis of AD.The production of reactive oxygen species(ROS)and the aggregation of Aβand Tau form a vi-cious circle,which leads to the aggravation of AD.However,inhibiting the aggregation of Aβand Tau or scavenging ROS is not able to effectively reverse the progression of AD.Herein,we prepared a H_(2)O_(2) responsive multifunctional nanocomposite UCNPs@mSiO_(2)-MB@AuNPs(abbreviated as USMA)to inhibit the aggregation of Aβand Tau.In this system,USMA could respond to H_(2)O_(2) to detach gold nanoparticles(AuNPs)and lead to the release of meth-ylene blue(MB)from mesoporous silica(mSiO_(2)),where AuNPs and MB can inhibit Aβand Tau aggregation,respectively.Furthermore,USMA could consume H_(2)O_(2) by reacting with them.Meanwhile,upconversion lumines-cence of UCNPs can be used to track USMA and monitor MB release,which could provide information on the content of MB in the lesion area.Impor-tantly,the USMA can effectively reduce the cytotoxicity induced by Aβand Tau aggregation.This work opens up a possibility to improve therapeutic ef-ficacy for the treatment of AD.

Neural stem cells promote neuroplasticity: a promising therapeutic strategy for the treatment of Alzheimer’s disease

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.