Parkinson’s disease in China:a forty-year growing track of bedside work

The number and health burden of Parkinson’s disease increase rapidly in China.It is estimated that China will have nearly half of the Parkinson’s disease population in the world in 2030.In this review,we present an overview of epidemiology and health economics status of Parkinson’s disease across China and discuss the risk factors of Parkinson’s disease and related complications.From the view of clinical research,we also discuss the current status of clinical trials,diagnostic biomarkers,treatment of Parkinson’s disease,tertiary network and post-occupation education in Chinese Parkinson’s disease clinics.

Neuroinflammation in neurodegenerative disorders:the roles of microglia and astrocytes

Neuroinflammation is associated with neurodegenerative diseases,such as Alzheimer's disease,Parkinson's disease,ancamyotrophic lateral sclerosis.Microglia and astrocytes are key regulators of inflammatory responses in the central nervous system.The activation of microglia and astrocytes is heterogeneous and traditionally categorized as neurotoxi(M1-phenotype microglia and A1-phenotype astrocytes)or neuroprotective(M2-phenotype microglia and A2-phenotype astrocytes).However,this dichotomized classification may not reflect the various phenotypes of microgliaand astrocytes.The relationship between these activated glial cells is also very complicated,and the phenotypic distribution can change,based on the progression of neurodegenerative diseases.A better understanding of the rolesof microglia and astrocytes in neurodegenerative diseases is essential for developing effective therapies.In this review,we discuss the roles of inflammatory response in neurodegenerative diseases,focusing on the contributions of microglia and astrocytes and their relationship.In addition,we discuss biomarkers to measure neuroinflammation andstudies on therapeutic drugs that can modulate neuroinflammation.

Current understanding of the molecular mechanisms in Parkinson's disease:Targets for potential treatments

Gradual degeneration and loss of dopaminergic neurons in the substantia nigra,pars compacta and subsequent reduction of dopamine levels in striatum are associated with motor deficits that characterize Parkinson’s disease(PD).In addition,half of the PD patients also exhibit frontostriatal-mediated executive dysfunction,including deficits in attention,short-term working memory,speed of mental processing,and impulsivity.The most commonly used treatments for PD are only partially or transiently effective and are available or applicable to a minority of patients.Because,these therapies neither restore the lost or degenerated dopaminergic neurons,nor prevent or delay the disease progression,the need for more effective therapeutics is critical.In this review,we provide a comprehensive overview of the current understanding of the molecular signaling pathways involved in PD,particularly within the context of how genetic and environmental factors contribute to the initiation and progression of this disease.The involvement of molecular chaperones,autophagy-lysosomal pathways,and proteasome systems in PD are also highlighted.In addition,emerging therapies,including pharmacological manipulations,surgical procedures,stem cell transplantation,gene therapy,as well as complementary,supportive and rehabilitation therapies to prevent or delay the progression of this complex disease are reviewed.

Imaging biomarkers in Parkinson’s disease and Parkinsonian syndromes:current and emerging concepts

Two centuries ago in 1817,James Parkinson provided the first medical description of Parkinson’s disease,later refined by Jean-Martin Charcot in the mid-to-late 19th century to include the atypical parkinsonian variants(also termed,Parkinson-plus syndromes).Today,Parkinson’s disease represents the second most common neurodegenerative disorder with an estimated global prevalence of over 10 million.Conversely,atypical parkinsonian syndromes encompass a group of relatively heterogeneous disorders that may share some clinical features with Parkinson’s disease,but are uncommon distinct clinicopathological diseases.Decades of scientific advancements have vastly improved our understanding of these disorders,including improvements in in vivo imaging for biomarker identification.Multimodal imaging for the visualization of structural and functional brain changes is especially important,as it allows a‘window’into the underlying pathophysiological abnormalities.In this article,we first present an overview of the cardinal clinical and neuropathological features of,1)synucleinopathies:Parkinson’s disease and other Lewy body spectrum disorders,as well as multiple system atrophy,and 2)tauopathies:progressive supranuclear palsy,and corticobasal degeneration.A comprehensive presentation of wellestablished and emerging imaging biomarkers for each disorder are then discussed.Biomarkers for the following imaging modalities are reviewed:1)structural magnetic resonance imaging(MRI)using T1,T2,and susceptibilityweighted sequences for volumetric and voxel-based morphometric analyses,as well as MRI derived visual signatures,2)diffusion tensor MRI for the assessment of white matter tract injury and microstructural integrity,3)proton magnetic resonance spectroscopy for quantifying proton-containing brain metabolites,4)single photon emission computed tomography for the evaluation of nigrostriatal integrity(as assessed by presynaptic dopamine transporters and postsynaptic dopamine D2 receptors),and cerebral perfusion,5)positron emission tomography for gauging nigrostriatal functions,glucose metabolism,amyloid and tau molecular imaging,as well as neuroinflammation,6)myocardial scintigraphy for dysautonomia,and 7)transcranial sonography for measuring substantia nigra and lentiform nucleus echogenicity.Imaging biomarkers,using the‘multimodal approach’,may aid in making early,accurate and objective diagnostic decisions,highlight neuroanatomical and pathophysiological mechanisms,as well as assist in evaluating disease progression and therapeutic responses to drugs in clinical trials.

Blocking meningeal lymphatic drainage aggravates Parkinson’s disease-like pathology in mice overexpressing mutated α-synuclein

Background:Abnormal aggregation of brainα-synuclein is a central step in the pathogenesis of Parkinson’s disease(PD),thus,it is reliable to promote the clearance ofα-synuclein to prevent and treat PD.Recent studies have revealed an essential role of glymphatic system and meningeal lymphatic vessels in the clearance of brain macromolecules,however,their pathophysiological aspects remain elusive.Method:Meningeal lymphatic drainage of 18-week-old A53T mice was blocked via ligating the deep cervical lymph nodes.Six weeks later,glymphatic functions and PD-like phenotypes were systemically analyzed.Results:Glymphatic influx of cerebrospinal fluid tracer was reduced in A53T mice,accompanied with perivascular aggregation ofα-synuclein and impaired polarization of aquaporin 4 expression in substantia nigra.Cervical lymphatic ligation aggravated glymphatic dysfunction of A53T mice,causing more severe accumulation ofα-synuclein,glial activation,inflammation,dopaminergic neuronal loss and motor deficits.Conclusion:The results suggest that brain lymphatic clearance dysfunction may be an aggravating factor in PD pathology.

Meta-analyses on prevalence of selected Parkinson’s nonmotor symptoms before and after diagnosis

Background:Nonmotor symptoms are common among patients with Parkinson’s disease(PD)and some may precede disease diagnosis.Methods:We conducted a meta-analysis on the prevalence of selected nonmotor symptoms before and after PD diagnosis,using random-effect models.We searched PubMed(1965 through October/November 2012)for the following symptoms:hyposmia,constipation,rapid eye movement sleep behavior disorder,excessive daytime sleepiness,depression,and anxiety.Eligible studies were publications in English with original data on one or more of these symptoms.Results:The search generated 2,373 non-duplicated publications and 332 met the inclusion criteria,mostly(n=320)on symptoms after PD diagnosis.For all symptoms,the prevalence was substantially higher in PD cases than in controls,each affecting over a third of the patients.Hyposmia was the most prevalent(75.5%in cases vs.19.1%in controls),followed by constipation(50%vs.17.7%),anxiety(39.9%vs.19.1%),rapid eye movement sleep behavior disorder(37.0%vs.7.0%),depression(36.6%vs.14.9%),and excessive daytime sleepiness(33.9%vs.10.5%).We observed substantial heterogeneities across studies and meta-regression analyses suggested that several factors might have contributed to this.However,the prevalence estimates were fairly robust in several sensitivity analyses.Only 20 studies had data on any symptoms prior to PD diagnosis,but still the analyses revealed higher prevalence in future PD cases than in controls.Conclusion:These symptoms are common among PD patients both before and after diagnosis.Further studies are needed to understand the natural history of nonmotor symptoms in PD and their etiological and clinical implications.

Neuroinflammation in Parkinson’s disease and its potential as therapeutic target

Parkinson’s disease(PD),the second most common age-associated neurodegenerative disorder,is characterized by the loss of dopaminergic(DA)neurons and the presence ofα-synuclein-containing aggregates in the substantia nigra pars compacta(SNpc).Chronic neuroinflammation is one of the hallmarks of PD pathophysiology.Postmortem analyses of human PD patients and experimental animal studies indicate that activation of glial cells and increases in pro-inflammatory factor levels are common features of the PD brain.Chronic release of proinflammatory cytokines by activated astrocytes and microglia leads to the exacerbation of DA neuron degeneration in the SNpc.Besides,peripheral immune system is also implicated in the pathogenesis of PD.Infiltration and accumulation of immune cells from the periphery are detected in and around the affected brain regions of PD patients.Moreover,inflammatory processes have been suggested as promising interventional targets for PD and even other neurodegenerative diseases.A better understanding of the role of inflammation in PD will provide new insights into the pathological processes and help to establish effective therapeutic strategies.In this review,we will summarize recent progresses in the neuroimmune aspects of PD and highlight the potential therapeutic interventions targeting neuroinflammation.

Peripheral clearance of brain-derived Aβ in Alzheimer's disease: pathophysiology and therapeutic perspectives

Alzheimer’s disease(AD)is the most common type of dementia,and no disease-modifying treatments are available to halt or slow its progression.Amyloid-beta(Aβ)is suggested to play a pivotal role in the pathogenesis of AD,and clearance of Aβfrom the brain becomes a main therapeutic strategy for AD.Recent studies found that Aβclearance in the periphery contributes substantially to reducing Aβaccumulation in the brain.Therefore,understanding the mechanism of how Aβis cleared in the periphery is important for the development of effective therapies for AD.In this review,we summarized recent findings on the mechanisms of Aβefflux from the brain to the periphery and discuss where and how the brain-derived Aβis cleared in the periphery.Based on these findings,we propose future strategies to enhance peripheral Aβclearance for the prevention and treatment of AD.This review provides a novel perspective to understand the pathogenesis of AD and develop interventions for this disease from a systemic approach.

miRNA expression profiles in cerebrospinal fluid and blood of patients with Alzheimer’s disease and other types of dementia-an exploratory study

Background:MicroRNAs(miRNAs)are small non-coding RNA molecules that function as posttranscriptional regulators of gene expression.Measurements of miRNAs in cerebrospinal fluid(CSF)and blood have just started gaining attention as a novel diagnostic tool for various neurological conditions.The purpose of this exploratory investigation was to analyze the expression of miRNAs in CSF and blood of patients with Alzheimer’s disease(AD)and other neurodegenerative disorders in order to identify potential miRNA biomarker candidates able to separate AD from other types of dementia.Methods:CSF was collected by lumbar puncture performed on 10 patients diagnosed with AD and 10 patients diagnosed with either vascular dementia,frontotemporal dementia or dementia with Lewy bodies.Blood samples were taken immediately after.Total RNA was extracted from cell free fractions of CSF and plasma,and a screening for 372 known miRNA sequences was carried out by real time quantitative polymerase chain reactions(miRCURY LNA™Universal RT miRNA PCR,Polyadenylation and cDNA synthesis kit,Exiqon).Results:Fifty-two miRNAs were detected in CSF in at least nine out of ten patients in both groups.Among these,two miRNAs(let-7i-5p and miR-15a-5p)were found significantly up-regulated and one miRNA(miR-29c-3p)was found significantly down-regulated in patients with AD compared to controls.One hundred and sixty-eight miRNAs were frequently detected in the blood,among which miR-590-5p and miR-142-5p were significantly up-regulated and miR-194-5p was significantly down-regulated in AD patients compared to controls.Conclusions:Detection of miRNA expression profiles in blood and in particular CSF of patients diagnosed with different types of dementia is feasible and it seems that several expressional differences between AD and other dementia types do exist when measured in a clinically relevant setup.In this explorative pilot study,the deregulated miRNAs in CSF of AD patients may be associated with relevant target genes related to AD pathology,including APP and BACE1,which suggests that miRNAs are interesting candidates for AD biomarkers in the future.

The recommendations of Chinese Parkinson’s disease and movement disorder society consensus on therapeutic management of Parkinson’s disease

Background:Parkinson’s disease(PD)is a chronic,progressive and debilitating disease,which affects over 2.5 million people in China.PD is characterized clinically by resting tremor,muscular rigidity,bradykinesia and postural instability.As the disease progresses,additional complications can arise such as non-motor and neurobehavioral symptoms.Pharmacological treatment and surgical intervention for PD have been implemented in China.Until 10 years ago,there was lack of standardization for the management of PD in different regions and among different physicians,leading to different treatment levels in different regions and different physicians.Since then,the Chinese Parkinson’s Disease and Movement Disorder Society have published three versions of guidelines for the management of PD in China,in 2006,2009 and 2014,respectively.Correspondingly,the overall level of treatment for PD in China improved.Objectives:To update the treatment guidelines based on current foreign and domestic practice guidelines and clinical evidence,and to improve the treatment options available to physicians in the management of PD.Summary:A variety of treatment recommendations in the treatment guidelines have been proposed,including physical activity and disease-modifying medication,which should be initiated at the early-stage of the disease.The principles of dosage titration should be followed to avoid acute adverse reactions to the drugs,to achieve a satisfactory clinical effect with a low dose and to reduce the incidence of long-term motor complications.Moreover,different treatment strategies should be considered at different stages of the disease.Importantly,treatment guidelines and personalized treatments should be valued equally.A set of treatment recommendations has been developed to assist physicians to improve and optimize clinical outcomes for patients with PD in China.

Advances in the Pathogenesis of Alzheimer’s Disease:Focusing on Tau-Mediated Neurodegeneration

In addition to senile plaques and cerebral amyloid angiopathy,the hyperphosphorylation of tau protein and formation of intraneuronal neurofibrillary tangles(NFTs)represents another neuropathological hallmark in AD brain.Tau is a microtubule-associated protein and localizes predominantly in the axons of neurons with the primary function in maintaining microtubules stability.When the balance between tau phosphorylation and dephosphorylation is changed in favor of the former,tau is hyperphosphorylated and the level of the free tau fractions elevated.The hyperphosphorylation of tau protein and formation of NFTs represent a characteristic neuropathological feature in AD brain.We have discussed the role of Aβin AD in our previous review,this review focused on the recent advances in tau-mediated AD pathology,mainly including tau hyperphosphorylation,propagation of tau pathology and the relationship between tau and Aβ.

Advances in the pathogenesis of Alzheimer’s disease:a re-evaluation of amyloid cascade hypothesis

Alzheimer’s disease(AD)is a common neurodegenerative disease characterized clinically by progressive deterioration of memory,and pathologically by histopathological changes including extracellular deposits of amyloid-beta(A-beta)peptides forming senile plaques(SP)and the intracellular neurofibrillary tangles(NFT)of hyperphosphorylated tau in the brain.This review focused on the new developments of amyloid cascade hypothesis with details on the production,metabolism and clearance of A-beta,and the key roles of some important A-beta-related genes in the pathological processes of AD.The most recent research advances in genetics,neuropathology and pathogenesis of the disease were also discussed.

Salidroside reduces tau hyperphosphorylation via up-regulating GSK-3β phosphorylation in a tau transgenic Drosophila model of Alzheimer’s disease

Background:Alzheimer’s disease(AD)is an age-related and progressive neurodegenerative disease that causes substantial public health care burdens.Intensive efforts have been made to find effective and safe treatment against AD.Salidroside(Sal)is the main effective component of Rhodiola rosea L.,which has several pharmacological activities.The objective of this study was to investigate the efficacy of Sal in the treatment of AD transgenic Drosophila and the associated mechanisms.Methods:We used tau transgenic Drosophila line(TAU)in which tau protein is expressed in the central nervous system and eyes by the Gal4/UAS system.After feeding flies with Sal,the lifespan and locomotor activity were recorded.We further examined the appearance of vacuoles in the mushroom body using immunohistochemistry,and detected the levels of total glycogen synthase kinase 3β(t-GSK-3β),phosphorylated GSK-3β(p-GSK-3β),t-tau and p-tau in the brain by western blot analysis.Results:Our results showed that the longevity was improved in salidroside-fed Drosophila groups as well as the locomotor activity.We also observed less vacuoles in the mushroom body,upregulated level of p-GSK-3βand downregulated p-tau following Sal treatment.Conclusion:Our data presented the evidence that Sal was capable of reducing the neurodegeneration in tau transgenic Drosophila and inhibiting neuronal loss.The neuroprotective effects of Sal were associated with its up-regulation of the p-GSK-3βand down-regulation of the p-tau.

Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration

Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system,acting to mediate excitatory neurotransmission.However,high levels of glutamatergic input elicit excitotoxicity,contribut-ing to neuronal cell death following acute brain injuries such as stroke and trauma.While excitotoxic cell death has also been implicated in some neurodegenerative disease models,the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration.Nevertheless,it is clear that excitatory synaptic dysregula-tion contributes to neurodegeneration,as evidenced by protective effects of partial N-methyl-D-aspartate receptor antagonists.Here,we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson’s disease,Alzheimer’s disease,amyotrophic lateral sclerosis and Huntington’s disease.In contrast to classic excitotoxicity,emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration.We discuss mechanisms that regulate mitochondrial calcium uptake and release,the impact of LRRK2,PINK1,Parkin,beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters,and the role of autophagic mitochondrial loss in axodendritic shrinkage.Finally,we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix,thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss.While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems,a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.

Dihydromyricetin and Salvianolic acid B inhibit alpha-synuclein aggregation and enhance chaperone-mediated autophagy

Background:Progressive accumulation ofα-synuclein is a key step in the pathological development of Parkinson’s disease.Impaired protein degradation and increased levels ofα-synuclein may trigger a pathological aggregation in vitro and in vivo.The chaperone-mediated autophagy(CMA)pathway is involved in the intracellular degradation processes ofα-synuclein.Dysfunction of the CMA pathway impairsα-synuclein degradation and causes cytotoxicity.Results:In the present study,we investigated the effects on the CMA pathway andα-synuclein aggregation using bioactive ingredients(Dihydromyricetin(DHM)and Salvianolic acid B(Sal B))extracted from natural medicinal plants.In both cell-free and cellular models ofα-synuclein aggregation,after administration of DHM and Sal B,we observed significant inhibition ofα-synuclein accumulation and aggregation.Cells were co-transfected with a Cterminal modifiedα-synuclein(SynT)and synphilin-1,and then treated with DHM(10μM)and Sal B(50μM)16 hours after transfection;levels ofα-synuclein aggregation decreased significantly(68%for DHM and 75%for Sal B).Concomitantly,we detected increased levels of LAMP-1(a marker of lysosomal homeostasis)and LAMP-2A(a key marker of CMA).Immunofluorescence analyses showed increased colocalization between LAMP-1 and LAMP-2A withα-synuclein inclusions after treatment with DHM and Sal B.We also found increased levels of LAMP-1 and LAMP-2A both in vitro and in vivo,along with decreased levels ofα-synuclein.Moreover,DHM and Sal B treatments exhibited anti-inflammatory activities,preventing astroglia-and microglia-mediated neuroinflammation in BAC-α-syn-GFP transgenic mice.Conclusions:Our data indicate that DHM and Sal B are effective in modulatingα-synuclein accumulation and aggregate formation and augmenting activation of CMA,holding potential for the treatment of Parkinson’s disease.

Freezing of gait in Parkinson’s disease: pathophysiology, risk factors and treatments

Background Freezing of gait(FOG)is a common,disabling symptom of Parkinson’s disease(PD),but the mechanisms and treatments of FOG remain great challenges for clinicians and researchers.The main focus of this review is to summarize the possible mechanisms underlying FOG,the risk factors for screening and predicting the onset of FOG,and the clinical trials involving various therapeutic strategies.In addition,the limitations and recommendations for future research design are also discussed.Main body In the mechanism section,we briefly introduced the physiological process of gait control and hypotheses about the mechanism of FOG.In the risk factor section,gait disorders,PIGD phenotype,lower striatal DAT uptake were found to be independent risk factors of FOG with consistent evidence.In the treatment section,we summarized the clinical trials of pharmacological and non-pharmacological treatments.Despite the limited effectiveness of current medications for FOG,especially levodopa resistant FOG,there were some drugs that showed promise such as istradefylline and rasagiline.Non-pharmacological treatments encompass invasive brain and spinal cord stimulation,noninvasive repetitive transcranial magnetic stimulation(rTMS)or transcranial direct current stimulation(tDCS)and vagus nerve stimulation(VNS),and physiotherapeutic approaches including cues and other training strategies.Several novel therapeutic strategies seem to be effective,such as rTMS over supplementary motor area(SMA),dual-site DBS,spinal cord stimulation(SCS)and VNS.Of physiotherapy,wearable cueing devices seem to be generally effective and promising.Conclusion FOG model hypotheses are helpful for better understanding and characterizing FOG and they provide clues for further research exploration.Several risk factors of FOG have been identified,but need combinatorial optimization for predicting FOG more precisely.Although firm conclusions cannot be drawn on therapeutic efficacy,the literature suggested that some therapeutic strategies showed promise.

Stepping closer to treating Alzheimer’s disease patients with BACE1 inhibitor drugs

Alzheimer’s disease(AD)is the most common age-dependent neurodegenerative disease which impairs cognitive function and gradually causes patients to be unable to lead normal daily lives.While the etiology of AD remains an enigma,excessive accumulation ofβ-amyloid peptide(Aβ)is widely believed to induce pathological changes and cause dementia in brains of AD patients.BACE1 was discovered to initiate the cleavage of amyloid precursor protein(APP)at theβ-secretase site.Only after this cleavage doesγ-secretase further cleave the BACE1-cleaved C-terminal APP fragment to release Aβ.Hence,blocking BACE1 proteolytic activity will suppress Aβgeneration.Due to the linkage of Aβto the potential cause of AD,extensive discovery and development efforts have been directed towards potent BACE1 inhibitors for AD therapy.With the recent breakthrough in developing brain-penetrable BACE1 inhibitors,targeting amyloid deposition-mediated pathology for AD therapy has now become more practical.This review will summarize various strategies that have successfully led to the discovery of BACE1 drugs,such as MK8931,AZD-3293,JNJ-54861911,E2609 and CNP520.These drugs are currently in clinical trials and their updated states will be discussed.With the promise of reducing Aβgeneration and deposition with no alarming safety concerns,the amyloid cascade hypothesis in AD therapy may finally become validated.

Prevalence of wearing-off and dyskinesia among the patients with Parkinson’s disease on levodopa therapy: a multi-center registry survey in China's Mainland

Objective:Chronic levodopa(L-dopa)treatment in Parkinson’s disease(PD)is often associated with the development of motor complications,but the corresponding epidemiological data is rare in Chinese PD patients.The present survey was to investigate the prevalence rate of wearing-off(WO)and dyskinesia among the patients with PD in China.Methods:From May 2012 to October 2012,a 3-step registry survey for wearing off(WO)and dyskinesia patients with PD receiving levodopa therapy was performed simultaneously at 28 movement disorders clinics in China.Results:There were 1,558 PD patients fulfilling the inclusion criteria.Among them,1,051 had at least one positive response of 9-item wearing off questionnaire(WOQ-9),724 and 160 patients were finally diagnosed with WO and dyskinesia by movement disorders specialists,respectively.The overall prevalence rates of WO and dyskinesia were 46.5%(95%CI 44.0%-48.9%)and 10.3%(95%CI 8.8%-11.8%),respectively.The mean score of WOQ-9 for those with WO was 3.8(SD=1.8),with movement slowness being the most common motor symptoms and pain/aching being the most common non-motor symptoms.Better improvement of motor symptoms(n=354,87.8%)and long-term disease control and drug selection(n=288,71.5%)were the two most frequently considered factors when movement disorders specialists adjusted therapeutic strategies for patients with WO.Conclusions:This survey provided the first multi-center epidemiological data of motor complications among PD patients on L-dopa therapy from China's Mainland.WO prevalence rate among Chinese PD patients was in line with,while dyskinesia prevalence rate was lower than previous reports from other Countries.

Transplantation of bone marrow mesenchymal stem cells improves cognitive deficits and alleviates neuropathology in animal models of Alzheimer’s disease: a meta-analytic review on potential mechanisms

Background Alzheimer’s disease is a neurodegenerative disorder.Therapeutically,a transplantation of bone marrow mesenchymal stem cells(BMMSCs)can play a beneficial role in animal models of Alzheimer’s disease.However,the relevant mechanism remains to be fully elucidated.Main body Subsequent to the transplantation of BMMSCs,memory loss and cognitive impairment were significantly improved in animal models with Alzheimer’s disease(AD).Potential mechanisms involved neurogenesis,apoptosis,angiogenesis,inflammation,immunomodulation,etc.The above mechanisms might play different roles at certain stages.It was revealed that the transplantation of BMMSCs could alter some gene levels.Moreover,the differential expression of representative genes was responsible for neuropathological phenotypes in Alzheimer’s disease,which could be used to construct gene-specific patterns.Conclusions Multiple signal pathways involve therapeutic mechanisms by which the transplantation of BMMSCs improves cognitive and behavioral deficits in AD models.Gene expression profile can be utilized to establish statistical regression model for the evaluation of therapeutic effect.The transplantation of autologous BMMSCs maybe a prospective therapy for patients with Alzheimer’s disease.

Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system

Background:Amyloid beta peptide(Aβ)is the main component of extraneuronal senile plaques typical of Alzheimer’s disease(AD)brains.Although Aβis produced by normal neurons,it is shown to accumulate in large amounts within neuronal lysosomes in AD.We have recently shown that under normal conditions the majority of Aβis localized extralysosomally,while oxidative stress significantly increases intralysosomal Aβcontent through activation of macroautophagy.It is also suggested that impaired Aβsecretion and resulting intraneuronal increase of Aβcan contribute to AD pathology.However,it is not clear how Aβis distributed inside normal neurons,and how this distribution is effected when Aβsecretion is inhibited.Methods:Using retinoic acid differentiated neuroblastoma cells and neonatal rat cortical neurons,we studied intracellular distribution of Aβby double immunofluorescence microscopy for Aβ40 or Aβ42 and different organelle markers.In addition,we analysed the effect of tetanus toxin-induced exocytosis inhibition on the intracellular distribution of Aβ.Results:Under normal conditions,Aβwas found in the small cytoplasmic granules in both neurites and perikarya.Only minor portion of Aβwas colocalized with trans-Golgi network,Golgi-derived vesicles,early and late endosomes,lysosomes,and synaptic vesicles,while the majority of Aβgranules were not colocalized with any of these structures.Furthermore,treatment of cells with tetanus toxin significantly increased the amount of intracellular Aβin both perikarya and neurites.Finally,we found that tetanus toxin increased the levels of intralysosomal Aβalthough the majority of Aβstill remained extralysosomally.Conclusion:Our results indicate that most Aβis not localized to Golgi-related structures,endosomes,lysosomes secretory vesicles or other organelles,while the suppression of Aβsecretion increases intracellular intra-and extralysosomal Aβ.