Alzheimer’s disease, neural stem cells and neurogenesis: cellular phase at single-cell level

Alzheimer’s disease cannot be cured as of yet.Our current understanding on the causes of Alzheimer’s disease is limited.To develop treatments,experimental models that represent a particular cellular phase of the disease and more rigorous scrutiny of the cellular pathological mechanisms are crucial.In recent years,Alzheimer’s disease research underwent a paradigm shift.According to this tendency,Alzheimer’s disease is increasingly being conceived of a disease where not only neurons but also multiple cell types synchronously partake to manifest the pathology.Knowledge on every cell type adds an alternative approach and hope for the efforts towards the treatment.Neural stem cells and their neurogenic ability are making an appearance as a new aspect of the disease manifestation based on the recent findings that neurogenesis reduces dramatically in Alzheimer’s disease patients compared to healthy individuals.Therefore,understanding how neural stem cells can form new neurons in Alzheimer’s disease brains holds an immense potential for clinics.However,this provocative idea requires further evidence and tools for investigation.Recently,single cell sequencing appeared as a revolutionary tool to understand cellular programs in unprecedented resolution and it will undoubtedly facilitate comprehensive investigation of different cell types in Alzheimer’s disease.In this mini-review,we will touch upon recent studies that use single cell sequencing for investigating cellular response in Alzheimer’s disease and some consideration pertaining to the utilization of neural regeneration for Alzheimer’s disease research.

The role of DJ-1 complexes and catecholamine metabolism： relevance for familial and idiopathic Parkinson＇s disease

Autosomal recessive mutations in the PARK7 gene,which encodes for the protein DJ-1,result in a loss of function and are a cause of familial Parkinson’s disease（PD）,while increased wild-type DJ-1protein levels are associated with some forms of cancer.Several functions of DJ-1 have been described,with the greatest evidence indicating that DJ-1 is a redox-sensitive protein involved in the regulation of oxidative stress and cell survival.

星形胶质细胞转录组分析指导的脑卒中靶标鉴定

星形胶质细胞支持正常的脑功能,但在卒中等病理条件下,星形胶质细胞反应性激活,其也可能参与神经退行性改变。反应性星形胶质细胞增生对机体有益或有害,与环境背景有关,但其分子基础仍未得到充分解释。借助RiboTag技术,我们在特异性地短暂性大脑中动脉闭塞(tMCAO)72h后的小鼠星形胶质细胞中,纯化翻译mRNA,构建卒中特异性星形胶质细胞翻译组数据库。我们发现,与对照组脑组织相比,tMCAO后的反应性星形胶质细胞显示与A2表型相关的转录物的富集,这与神经保护相关。星形胶质细胞也会上调大量潜在的神经毒性基因。我们共鉴定了1003个基因和38个转录因子的差异表达,其中Stat3,Sp1和Spi1变化最明显。为了进一步探索Stat3介导的通路对卒中发病机制的影响,我们选择星形胶质细胞特异性条件性缺失Stat3的小鼠制造tMCAO模型,发现这些小鼠的局灶性缺血卒中体积减少,且梗死72h后小鼠的运动结果改善。综上所述,本研究扩展了新兴的星形胶质细胞特异性靶向卒中治疗数据库,并肯定了星形胶质细胞是脑功能的关键保障细胞。

Cerebrospinal fluid neurogranin as a new player in prion disease diagnosis and prognosis

Neurogranin (Ng) and its role as Alzheimer’s disease (AD) biomarker: Ng is a calmodulin-binding protein mainly expressed in cerebral structures such as the cortex,hippocampus and striatum.It is mainly located in the dendritic processes,particularly in post-synaptic compartments,but also in the cytosolic compartment,being likely involved in the regulation of the intracellular calcium-calmodulin signaling pathway (Represa et al.,1990).In the last decade,a plethora of studies have demonstrated that cerebrospinal fluid (CSF) Ng is increased in AD patients and in individuals with an ADlike CSF profile (Kester et al.,2015a).This increase seems to be disease-specific because other neurodegenerative conditions including frontotemporal dementia,Lewy body dementia,Parkinson’s disease,progressive supranuclear palsy,multiple system atrophy or Huntington’s disease,present CSF Ng concentrations similar to controls (Wellington et al.,2016).Ng levels in CSF appear to be elevated in mild cognitive impairment (MCI)-affected individuals who progress to AD and are highly related to memory and cognitive function (Kester et al.,2015a;Tarawneh et al.,2016),which indicates that this protein may serve as an early AD biomarker with diagnostic utility in pre-dementia disease stages,and with prognostic utility to predict cognitive decline and MCI-to-AD conversion.

通过星形胶质细胞转录组分析寻找脑卒中治疗靶标

星形胶质细胞支持正常的脑功能,但当它们在卒中等病理条件下变得具有反应性时也可能促成神经退行性病变。然而,反应性星形胶质细胞增生的有益和有害特性之间依赖于背景的相互作用的分子基础仍然未被完全理解。我们使用RiboTag技术,在短暂性大脑中动脉闭塞(tMCAO)72 h后的小鼠星形胶质细胞中特异性地纯化翻译m RNA,从而产生卒中特异性星形胶质细胞翻译组数据库。与对照组大脑相比,t MCAO后的反应性星形胶质细胞显示与A2表型相关的转录物富集,这与神经保护相关。我们还发现,星形胶质细胞也会上调大量潜在的神经毒性基因。本研究共鉴定了1,003个基因和38个转录因子的差异表达,其中Stat3,Sp1和Spi1是最显著的。为了进一步探索Stat3介导的途径对卒中发病机制的影响,我们对星形胶质细胞特异性条件性缺失Stat3的小鼠进行tMCAO处理,发现局灶性缺血72 h后的小鼠脑梗死体积减小,运动功能改善。综上所述,本研究扩展了新兴的星形胶质细胞特异性靶向卒中治疗数据库,支持星形胶质细胞在生理和病理条件下均对脑功能提供了关键保障作用的观点。

Prediction of Outcomes in Mini-Basketball Training Program for Preschool Children with Autism Using Machine Learning Models

In recent years evidence has emerged suggesting that Mini-basketball training program(MBTP)can be an effec-tive intervention method to improve social communication(SC)impairments and restricted and repetitive beha-viors(RRBs)in preschool children suffering from autism spectrum disorder(ASD).However,there is a considerable degree if interindividual variability concerning these social outcomes and thus not all preschool chil-dren with ASD profit from a MBTP intervention to the same extent.In order to make more accurate predictions which preschool children with ASD can benefit from an MBTP intervention or which preschool children with ASD need additional interventions to achieve behavioral improvements,further research is required.This study aimed to investigate which individual factors of preschool children with ASD can predict MBTP intervention out-comes concerning SC impairments and RRBs.Then,test the performance of machine learning models in predict-ing intervention outcomes based on these factors.Participants were 26 preschool children with ASD who enrolled in a quasi-experiment and received MBTP intervention.Baseline demographic variables(e.g.,age,body,mass index[BMI]),indicators of physicalfitness(e.g.,handgrip strength,balance performance),performance in execu-tive function,severity of ASD symptoms,level of SC impairments,and severity of RRBs were obtained to predict treatment outcomes after MBTP intervention.Machine learning models were established based on support vector machine algorithm were implemented.For comparison,we also employed multiple linear regression models in statistics.Ourfindings suggest that in preschool children with ASD symptomatic severity(r=0.712,p<0.001)and baseline SC impairments(r=0.713,p<0.001)are predictors for intervention outcomes of SC impair-ments.Furthermore,BMI(r=-0.430,p=0.028),symptomatic severity(r=0.656,p<0.001),baseline SC impair-ments(r=0.504,p=0.009)and baseline RRBs(r=0.647,p<0.001)can predict intervention outcomes of RRBs.Statistical models predicted 59.6%of variance in post-treatment SC impairments(MSE=0.455,RMSE=0.675,R2=0.596)and 58.9%of variance in post-treatment RRBs(MSE=0.464,RMSE=0.681,R2=0.589).Machine learning models predicted 83%of variance in post-treatment SC impairments(MSE=0.188,RMSE=0.434,R2=0.83)and 85.9%of variance in post-treatment RRBs(MSE=0.051,RMSE=0.226,R2=0.859),which were better than statistical models.Ourfindings suggest that baseline characteristics such as symptomatic severity of 144 IJMHP,2022,vol.24,no.2 ASD symptoms and SC impairments are important predictors determining MBTP intervention-induced improvements concerning SC impairments and RBBs.Furthermore,the current study revealed that machine learning models can successfully be applied to predict the MBTP intervention-related outcomes in preschool chil-dren with ASD,and performed better than statistical models.Ourfindings can help to inform which preschool children with ASD are most likely to benefit from an MBTP intervention,and they might provide a reference for the development of personalized intervention programs for preschool children with ASD.

Prion-induced neurotoxicity: Possible role for cell cycle activity and DNA damage response

Protein misfolding neurodegenerative diseases arisethrough neurotoxicity induced by aggregation of host proteins. These conditions include Alzheimer's disease, Huntington's disease, Parkinson's disease, motor neuron disease, tauopathies and prion diseases. Collectively, these conditions are a challenge to society because of the increasing aged population and through the real threat to human food security by animal prion diseases. It is therefore important to understand the cellular and molecular mechanisms that underlie protein misfolding--induced neurotoxicity as this will form the basis for designing strategies to alleviate their burden. Prion diseases are an important paradigm for neurodegenerative conditions in general since several of these maladies have now been shown to display prion--like phenomena. Increasingly, cell cycle activity and the DNA damage response are recognised as cellular events that participate in the neurotoxic process of various neurodegenerative diseases, and their associated animal models, which suggests they are truly involved in the pathogenic process and are not merely epiphenomena. Here we review the role of cell cycle activity and the DNA damage response in neurodegeneration associated with protein misfolding diseases, and suggest that these events contribute towards prion--induced neurotoxicity. In doing so, we highlight PrP transgenic Drosophila as a tractable model for the genetic analysis of transmissible mammalian prion disease.

Fused in sarcoma-amyotrophic lateral sclerosis as a novel member of DNA single strand break diseases with pure neurological phenotypes

Accumulation of DNA damage and genomic instability are believed to have crucial effects in neurodegenerative conditions such as Alzheimer’s disease,Parkinson’s disease,Huntington’s disease,premature aging diseases as well as amyotrophic lateral sclerosis(ALS)and frontotemporal dementia(FTD).Until recently these studies were largely correlative in nature,though raising the possibility that defects in the DNA damage response(DDR)underlie neurodegenerative diseases.

Associations between meeting 24-hour movement guidelines and quality of life among children and adolescents with autism spectrum disorder

Background:The Canadian 24-hour movement behavior(24-HMB)guidelines suggest that a limited amount of screen time use,an adequate level of physical activity(PA),and sufficient sleep duration are beneficial for ensuring and optimizing the health and quality of life(QoL)of children and adolescents.However,this topic has yet to be examined for children and adolescents with autism spectrum disorder(ASD)specifically.The aim of this cross-sectional observational study was to examine the associations between meeting 24-HMB guidelines and several QoLrelated indicators among a national sample of American children and adolescents with ASD.Methods:Data were taken from the 2020 U.S.National Survey of Children’s Health dataset.Participants(n=956)aged 617 years and currently diagnosed with ASD were included.The exposure of interest was adherence to the 24-HMB guidelines.Outcomes were QoL indicators,including learning interest/curiosity,repeating grades,adaptive ability,victimization by bullying,and behavioral problems.Categorical variables were described with unweighted sample counts and weighted percentages.Age,sex,race,preterm birth status,medication,behavioral treatment,household poverty level,and the educational level of the primary caregivers were included as covariates.Odds ratio(OR)and 95%confidence interval(95%CI)were used to present the strength of association between adherence to 24-HMB guidelines and QoL-related indicators.Results:Overall,452 participants(45.34%)met 1 of the 3 recommendations,216(22.65%)met 2 recommendations,whereas only 39 participants(5.04%)met all 3 recommendations.Compared with meeting none of the recommendations,meeting both sleep duration and PA recommendations(OR=3.92,95%CI:1.639.48,p<0.001)or all 3 recommendations(OR=2.11,95%CI:1.034.35,p=0.04)was associated with higher odds of showing learning interest/curiosity.Meeting both screen time and PA recommendations(OR=0.15,95%CI:0.040.61,p<0.05)or both sleep duration and PA recommendations(OR=0.24,95%CI:0.070.87,p<0.05)was associated with lower odds of repeating any grades.With respect to adaptive ability,participants who met only the PA recommendation of the 24-HMB were less likely to have difficulties dressing or bathing(OR=0.11,95%CI:0.020.66,p<0.05)than those who did not.For participants who met all 3 recommendations(OR=0.38,95%CI:0.150.99,p=0.05),the odds of being victimized by bullying was lower.Participants who adhered to both sleep duration and PA recommendations were less likely to present with severe behavioral problems(OR=0.17,95%CI:0.040.71,p<0.05)than those who did not meet those guidelines.Conclusion:Significant associations were found between adhering to 24-HMB guidelines and selected QoL indicators.These findings highlight the importance of maintaining a healthy lifestyle as a key factor in promoting and preserving the QoL of children with ASD.

Combination of novel RNA sequencing and sophisticated network modeling to reveal a common denominator in amyotrophic lateral sclerosis?

Amyotrophic lateral sclerosis (ALS) is one of the most dreadful neurodegenerative diseases leading to death within 1-5 years after symptom onset.The majority of ALS cases are sporadic(sALS),while the remaining 5-10%are familial(fALS).Genetic discoveries have identified ALScausative mutations in more than 30 genes so far(Chia et al.,2018).Indeed,the four most common mutations observed in ALS genes in Europe are the hexanucleotide expansion repeat in Chromosome9 Open Reading Frame 72 (C9ORF72),Cu-Zn superoxide dismutase 1 (SOD1),tra nsactive response DNA Binding protein 43kDa (TARDBP)and fused in sa rcoma (FUS).

Single cell whole-genome sequencing of brain cells:age-and cell-type specific mutational profiles

In a recent study published in Cell,Ganz et al.shed new light on the mutational landscape of brain cells,particularly neurons and oligodendrocytes(OLs).1 Utilizing a combination of optimized single-cell whole-genome sequencing with single-nucleus chromatin accessibility and gene expression analysis,they profiled somatic mutations in 86 OLs from 13 neurotypical individuals,spanning in age from infants to elderly.Neurons investigated were 56,derived from 19(including 12 overlapping)individuals(Fig.1).

Breaking barriers:noncanonical inflammasome executes blood–brain barrier disruption

In a landmark study recently published in Nature,1 Wei and colleagues demonstrate that the activation of GSDMD by the cytosolic lipopolysaccharide(LPS)sensor caspase-11 triggers blood–brain barrier(BBB)breakdown upon LPS challenge independent of TLR4-induced cytokine release.Their work identifies the noncanonical inflammasome and GSDMD pore formation as a potential target for treating central nervous system(CNS)disorders associated with inflammatory BBB dysfunction.

Legacy of the discovery of the T-cell receptor: 40 years of shaping basic immunology and translational work to develop novel therapies

Forty years have passed since the groundbreaking achievement of cloning T-cell receptor genes [1, 2]. The rich narrative that sets the stage for this significant event is incredibly striking, and its profound legacy in contemporary immunology and medical science is truly remarkable.

Enhanced diagnostic workup increases pathological findings in patients with acute ischaemic stroke:results of the prospective HEBRAS study

Background Stroke aetiology remains cryptogenic in a relevant proportion of patients with acute ischaemic stroke(AIS).We assessed whether enhanced diagnostic workup after AIS yields a higher rate of prespecified pathological findings compared with routine diagnostic care in-hospital.Methods Hospitalised patients with AIS were prospectively enrolled in the investigator-initiated observational HEart and BRain Interfaces in Acute Ischaemic Stroke(HEBRAS)study at the Charité,Berlin,Germany.Patients with AIS without known atrial fibrillation(AF)underwent cardiovascular MR imaging(CMR),MR-angiography of the aortic arch and prolonged Holter-ECG monitoring on top of routine diagnostic care.Results Among 356 patients with AIS(mean age 66 years,37.6%female),enhanced workup yielded a higher rate of prespecified pathological findings compared with routine care(17.7%vs 5.3%;p<0.001).Consequently,fewer patients were classified as cryptogenic after enhanced diagnostic workup(38.5%vs 45.5%,p<0.001).Routine care included echocardiography in 228(64.0%)patients.CMR was successfully performed in 292(82.0%)patients and revealed more often a prespecified pathological finding compared with routine echocardiography(16.1%vs 5.3%).Furthermore,study-related ECG monitoring(median duration 162 hours(IQR 98–210))detected AF in 16(4.5%)patients,while routine monitoring(median duration 51 hours(IQR 34–74))detected AF in seven(2.0%)patients.Conclusions Enhanced diagnostic workup revealed a higher rate of prespecified pathological findings in patients with AIS compared with routine diagnostic care and significantly reduced the proportion of patients with cryptogenic stroke.Trial registration number NCT02142413.

HMGB1, IL-1α, IL-33 and S100 proteins： dual-function alarmins

Our immune system is based on the close collaboration of the innate and adaptive immune systems for the rapid detection of any threats to the host. Recognition of pathogen-derived molecules is entrusted to specific germline- encoded signaling receptors. The same receptors have now also emerged as efficient detectors of misplaced or altered self-molecules that signal tissue damage and cell death following, for example, disruption of the blood supply and subsequent hypoxia. Many types of endogenous molecules have been shown to provoke such sterile inflammatory states when released from dying cells. However, a group of proteins referred to as alarmins have both intracellular and extracellular functions which have been the subject of intense research. Indeed, alarmins can either exert beneficial cell housekeeping functions, leading to tissue repair, or provoke deleterious uncontrolled inflammation. This group of proteins includes the high-mobility group box 1 protein （HMGB1）, interleukin （IL）-1α, IL-33 and the Ca^2＋-binding S100 proteins. These dual-function proteins share conserved regulatory mechanisms, such as secretory routes, post-translational modifications and enzymatic processing, that govern their extracellular functions in time and space. Release of alarmins from mesenchymal cells is a highly relevant mechanism by which immune cells can be alerted of tissue damage, and alarmins play a key role in the development of acute or chronic inflammatory diseases and in cancer development.

Wntl-regu｜ated genetic networks in midbrain dopaminergic neuron development

Neurons synthesizing the neurotransmitter dopamine exert crucial functions in the mammalian brain. The biggest and most important population of dopamine-synthesizing neurons is located in the mammalian ventral midbrain （VM）, and controls and modulates the exe- cution of motor, cognitive, affective, motivational, and rewarding behaviours. Degeneration of these neurons leads to motor deficits that are characteristic of Parkinson＇s disease, while their dysfunction is involved in the pathogenesis of psychiatric disorders including schizophrenia and addiction. Because the aetiology and therapeutic prospects for these diseases include neurodevelopmental aspects, substantial scientific interest has been focused on deciphering the mechanistic pathways that control the generation and sur- vival of these neurons during embryonic development. Researches during the last decade revealed the pivotal role of the secreted Wntl ligand and its signaUing cascade in the generation of the dopamine-synthesizing neurons in the mammalian VM. Here, we summarize the initial and more recent findings that have unravelled several Wntl-controUed genetic networks required for the proliferation and commitment of VM progenitors to the dopaminergic cell fate during midgestational embryonic stages, and for the correct differentiation of these progenitors into postmitotic dopamine-synthesizing neurons at late midgestational embryonic and foetal stages.

A new paradigm for diagnosis of neurodegenerative diseases: peripheral exosomes of brain origin

Neurodegenerative diseases are a heterogeneous group of maladies, characterized by progressive loss of neurons. These diseases involve an intricate pattern of cross-talk between different types of cells to maintain specific signaling pathways. A component of such intercellular cross-talk is the exchange of various types of extracellular vesicles (EVs). Exosomes are a subset of EVs, which are increasingly being known for the role they play in the pathogenesis and progression of neurodegenerative diseases, e.g., synucleinopathies and tauopathies. The ability of the central nervous system exosomes to cross the blood-brain barrier into blood has generated enthusiasm in their study as potential biomarkers. However, the lack of standardized, efficient, and ultra-sensitive methods for the isolation and detection of brain-derived exosomes has hampered the development of effective biomarkers. Exosomes mirror heterogeneous biological changes that occur during the progression of these incurable illnesses, potentially offering a more comprehensive outlook of neurodegenerative disease diagnosis, progression and treatment. In this review, we aim to discuss the challenges and opportunities of peripheral biofluid-based brain-exosomes in the diagnosis and biomarker discovery of Alzheimer’s and Parkinson’s diseases. In the later part, we discuss the traditional and emerging methods used for the isolation of exosomes and compare their advantages and disadvantages in clinical settings.

Longitudinal diffusion tensor magnetic resonance imaging analysis at the cohort level reveals disturbed cortical and callosal microstructure with spared corticospinal tract in the TDP-43^(G298S) ALS mouse model

Background:In vivo diffusion tensor imaging(DTI)of the mouse brain was used to identify TDP-43 associated alterations in a mouse model for amyotrophic lateral sclerosis(ALS).Methods:Ten mice with TDP-43^(G298S) overexpression under control of the Thy1.2 promoter and 10 wild type(wt)underwent longitudinal DTI scans at 11.7 T,including one baseline and one follow-up scan with an interval of about 5months.Whole brain-based spatial statistics(WBSS)of DTI-based parameter maps was used to identify longitudinal alterations of TDP-43^(G298S) mice compared to wt at the cohort level.Results were supplemented by tractwise fractional anisotropy statistics(TFAS)and histological evaluation of motor cortex for signs of neuronal loss.Results:Alterations at the cohort level in TDP-43^(G298S) mice were observed cross-sectionally and longitudinally in motor areas M1/M2 and in transcallosal fibers but not in the corticospinal tract.Neuronal loss in layer V of motor cortex was detected in TDP-43^(G298S) at the later(but not at the earlier)timepoint compared to wt.Conclusion:DTI mapping of TDP-43^(G298S) mice demonstrated progression in motor areas M1/M2.WBSS and TFAS are useful techniques to localize TDP-43^(G298S) associated alterations over time in this ALS mouse model,as a biological marker.

A natural history comparison Check for updates of SOD1-mutant patients with amyotrophic lateral sclerosis between Chinese and German populations

Currently,there is no effective treatment for amyotrophic lateral sclerosis(ALS),despite the limited efficacy of riluzole[1]and edaravone[2].SOD1(coding for the Cu/Zn superoxide dismutase)is the second most frequent genetic cause for ALS only after C9orf72 in patients with European ancestry while being the most frequent in Asian ALS populations[3],Multiple therapeutic approaches have targeted SOD1-related ALS,including the antisense oligonucleotide tofersen with promising results in a recent phase I/II trial[4].

α-Synuclein conformers reveal link to clinical heterogeneity ofα-synucleinopathies

α-Synucleinopathies,such as Parkinson’s disease(PD),dementia with Lewy bodies(DLB)and multiple system atrophy,are a class of neurodegenerative diseases exhibiting intracellular inclusions of misfoldedα-synuclein(αSyn),referred to as Lewy bodies or oligodendroglial cytoplasmic inclusions(Papp-Lantos bodies).Even though the specific cellular distribution of aggregatedαSyn differs in PD and DLB patients,both groups show a significant pathological overlap,raising the discussion of whether PD and DLB are the same or different diseases.Besides clinical investigation,we will focus in addition on methodologies,such as protein seeding assays(real-time quaking-induced conversion),to discriminate between different types ofα-synucleinopathies.This approach relies on the seeding conversion properties of misfoldedαSyn,supporting the hypothesis that different conformers of misfoldedαSyn may occur in different types ofα-synucleinopathies.Understanding the pathological processes influencing the disease progression and phenotype,provoked by differentαSyn conformers,will be important for a personalized medical treatment in future.