Ageing and neurodegenerative diseases最新文献

{"title":"Advantages and differences among various animal models of Huntington’s disease","authors":"Zhu Yu, Wenhao Yang, Sen Yan","doi":"10.20517/and.2024.13","DOIUrl":"https://doi.org/10.20517/and.2024.13","url":null,"abstract":"Treating and preventing neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, dementia with Lewy bodies, amyotrophic lateral sclerosis, frontotemporal dementia, and Huntington’s disease have become significant challenges in the field of neurological research. In the early stages of neurodegenerative disease research, scientists often choose appropriate animal models to delve deeper into their molecular pathological mechanisms and macroscopic clinical manifestations. Selecting the right animal model is a crucial step in initiating and advancing this research process. This article focuses on analyzing various animal models used in the field of neurodegenerative diseases in recent years, with a particular focus on Huntington’s disease. It discusses in detail the advantages and disadvantages of different animal models in experimental research, as well as the pathological features and clinical manifestations they exhibit.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"11 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141920504","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Age-related energetic reprogramming in glial cells: possible correlations with Parkinson’s disease","authors":"Boling Chu, Hongling Xiang, Han Wang, Yuting Lin, Rui Li, Jing Hu, Hao Qian","doi":"10.20517/and.2024.11","DOIUrl":"https://doi.org/10.20517/and.2024.11","url":null,"abstract":"Glial cells populate the central nervous system and undertake indispensable roles in safeguarding and maintaining optimal neuronal performance. Throughout life, the brain undergoes inevitable changes that impact both neurons and glial cells. Concurrent with age-related neurodegenerative diseases, such as Alzheimer’s disease (AD) and Parkinson’s disease (PD), metabolic dysfunctions in glial cells are consistently observed. Though widely debated, the idea of treating neurodegenerative disorders by manipulating brain bioenergetics warrants further exploration. This review discusses the distinctive metabolic characteristics of central nervous system (CNS) glia, the metabolic deviations that occur in glial cells in the aging brain, and the ramifications of metabolic rewiring within glia on neurodegenerative disorders, specifically PD. We focus on astrocytes and microglia due to their substantial transformations under aging and diseased states, known as reactivation. Special attention is given to clarifying the complex relationships between dysregulated glial energy metabolism and brain disorders. By discussing both classic theories and current advances in this field, we aim to shed light on promising therapeutic horizons anchored in the strategic calibration of glial metabolic configurations.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"189 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141828764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Fibril-forming motif of non-expanded ataxin-3 revealed by scanning proline mutagenesis","authors":"Sheng-Rong Meng, Chao Ma, Jie Chen, Li-Qiang Wang, Hong-Yu Hu, Yi Liang","doi":"10.20517/and.2023.15","DOIUrl":"https://doi.org/10.20517/and.2023.15","url":null,"abstract":"Aims: The misfolding of ataxin-3 in neurons is the hallmark of a neurodegenerative disease, spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD). Ataxin-3 consists of a N-terminal Josephin domain and a C-terminal polyglutamine (polyQ) tract. The length of the polyQ tract is positively correlated with the disease. The aggregation of ataxin-3 in vitro is a two-step process, with the first step involving the aggregation of the Josephin domain and the second step involving an expanded polyQ tract. However, the fibril-forming motif of the Josephin domain is not well understood.\u0000 Methods: In this study, we employed 3D profile algorithm and scanning proline mutagenesis to identify the fibril-forming motif of non-expanded ataxin-3.\u0000 Results: By using thioflavin T fluorescence kinetics, sarkosyl-insoluble SDS-PAGE, transmission electron microscopy (TEM), and Fourier transform infrared spectroscopy (FTIR), we identified the fibril-forming motif of the Josephin domain of non-expanded ataxin-3 as 79VISNAL84.\u0000 Conclusions: We demonstrated that the proline mutation in the fibril-forming motif of the Josephin domain could inhibit the aggregation of expanded ataxin-3, which shows some therapeutic promise.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"50 17","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141358532","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Automatically targeting the dorsolateral subthalamic nucleus for functional connectivity-guided rTMS therapy","authors":"N. Zhao, Yang Qiao, J. Yue, Ying Jing, Qiu Ge, Meng Zhang, Jianguo Zhang, Yuan Zhen, Yu-Tao Xiang, Jue Wang, Yuding Zang","doi":"10.20517/and.2023.31","DOIUrl":"https://doi.org/10.20517/and.2023.31","url":null,"abstract":"Aim: Many resting-state functional magnetic resonance imaging (rs-fMRI) studies have provided evidence that repetitive transcranial magnetic stimulation (rTMS) exerts treatment effects via functional connectivity (FC) from a superficial stimulation target to a deep effective region. The dorsolateral subthalamic nucleus (DL-STN) is an effective target in deep brain stimulation surgery for Parkinson’s disease (PD), but its targeting highly depends on well-trained neurosurgeons and is not easily used for FC-guided rTMS. We aimed to devise a method for automatically localizing the DL-STN, and further develop a one-stop plug-in of rs-fMRI FC analysis to assist future individualized FC-guided rTMS.\u0000 Methods: Based on structural and iron-sensitive MRI of 78 participants, two raters defined the DL-STN coordinates with very high reliability. The averaged coordinates in the standard Montreal Neurological Institute (MNI) space were: left DL-STN, x: -11.89 ± 0.82, y: -14.51 ± 1.00, and z: -6.40 ± 1.01 and the right DL-STN, x: 12.53 ± 0.77, y: -13.97 ± 0.86, and z: -6.57 ± 0.99. As the individual distances from the averaged coordinates were less than 3 mm (within one voxel for most rs-fMRI studies) for all 78 participants, we defined the average coordinates as AutoSTN. We then developed a one-stop plug-in named Connectivity and Coordinates Converting Assistant Toolbox (CC-CAT) and performed AutoSTN FC analysis.\u0000 Results: The AutoSTN seed showed significant FC with the motor cortices in all participants.\u0000 Conclusion: The AutoSTN-based rs-fMRI FC could guide future rTMS on PD. The one-stop plug-in CC-CAT can be used for any FC-guided rTMS treatment.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"113 46","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140985561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Re-energising the brain: glucose metabolism, Tau protein and memory in ageing and dementia","authors":"Miranda Robbins","doi":"10.20517/and.2023.57","DOIUrl":"https://doi.org/10.20517/and.2023.57","url":null,"abstract":"Memory naturally declines as we age, but the rapid loss of memory can be distressing for people living with Alzheimer’s disease (AD). How memories are formed and retrieved in the brain is not fully understood; it is thought to require plasticity to the synapses connecting neurons in a network of engram cells. Plasticity may occur either through changes to the volume and location of molecules and organelles within the synapse, or gross structural changes of synapses. Memory naturally declines as we age, as do many of the mechanisms required for learning and memory, such as changes in concentrations of the cytoskeletal structural protein Microtubule-Associated Protein Tau, reduced brain glucose metabolism, and sensitivities to insulin. The biggest risk factor for developing AD is ageing, yet only few studies try to reconcile the natural decline in functions we see with ageing with the dramatic impairment of these pathways in AD, such as Tau protein and energy homeostasis by neurons. This review will therefore explain the changes to metabolism, Tau protein, and memory impairment during ageing, and explore the latest research that links these processes to neurodegeneration seen in AD, and other Tauopathies. Understanding how ageing and dementia diverge may offer an important and underutilised avenue for therapeutic interventions to target metabolism in both “healthy” ageing and disease.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"44 6","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-05-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141010552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Aging and Parkinson’s disease: a complex interplay of vulnerable neurons, the immune system and the blood-brain barrier","authors":"J. Bendig, Anika Frank, Heinz Reichmann","doi":"10.20517/and.2023.36","DOIUrl":"https://doi.org/10.20517/and.2023.36","url":null,"abstract":"Aging is the biggest risk factor for Parkinson’s disease (PD) and a particular vulnerability of dopaminergic neurons in the substantia nigra to aging-associated effects has been firmly established. More recent work has revealed an important role of non-neuronal systems such as the blood-brain barrier (BBB) or the immune system in the pathogenesis of PD. Effects of aging on the immune system include a chronic inflammatory state termed inflammaging and immunosenescence. Both processes are connected to a higher pro-inflammatory potency and negatively affect the maintenance of self-tolerance. The BBB gets increasingly dysfunctional with advancing age and its endothelial cells display a more pro-inflammatory phenotype while the transport of important plasma proteins to the brain is impaired. The immune system and the BBB are heavily interdependent and are both essential for the homeostasis of especially vulnerable dopaminergic neurons. The degeneration of dopaminergic neurons can, in turn, influence the BBB or the immune system, potentially creating a vicious cycle. In this review, we aim to develop a multisystem perspective on aging and PD by incorporating the aging immune system and aging BBB into the pathophysiological processes. Given the current evidence, it seems likely that a combination of multimodal effects of aging on the levels of SN pars compacta (SNc) dopaminergic neurons, the immune system, and the BBB increase the risk of developing PD.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"2 14","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140375263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deregulation of mitochondrial reverse electron transport alters the metabolism of reactive oxygen species and NAD+/NADH and presents a therapeutic target in Alzheimer’s disease","authors":"Suman Rimal, Wen Li, Tejender Pal Khaket, Yu Li, Ishaq Tantray, Yanping Li, Sunil Bhurtel, L. Grinberg, Salvatore Spina, Maria Inmaculada Cobos Sillero, William W Seeley, Su Guo, Bingwei Lu","doi":"10.20517/and.2024.07","DOIUrl":"https://doi.org/10.20517/and.2024.07","url":null,"abstract":"Aim: Oxidative stress and NAD+/NADH imbalance caused by alterations in reactive oxygen species (ROS) and NAD(H) metabolism are pathological features associated with normal aging and age-related diseases including Alzheimer’s disease (AD). How abnormalities in ROS and NAD(H) metabolism occur under these pathological conditions is not well understood, nor is it known whether they are mechanistically linked and can be therapeutically targeted together. The aim of this study is to identify the cause of aberrant ROS and NAD(H) metabolism and test its role in the pathogenesis of AD.\u0000 Methods: Reverse electron transport (RET) along mitochondrial complex I can occur under certain thermodynamic conditions, leading to excessive ROS generation and NAD+ conversion to NADH, and thus lowered NAD+/NADH ratio. Brain samples from AD patients and mouse AD models were used to assess the status of RET by measuring ROS and NAD+/NADH ratio in brain lysates and purified mitochondria respiring under RET conditions. A small molecule RET inhibitor was used to treat APP(swe)/PS1(deltaE9) and 5xFAD mouse models and human induced pluripotent stem cell (iPSC)-derived neuronal model of AD. Effects on behavior and AD-related neuropathology were examined. The biochemical mechanism underlying RET alteration was examined by protein-protein interaction studies.\u0000 Results: RET is aberrantly activated in transgenic AD mouse brains and in individuals with AD. Pharmacological inhibition of RET reduced amyloid burden and neuroinflammation and rescued cognitive and behavioral deficits in the APP(swe)/PS1(deltaE9) and 5xFAD mouse models. In human AD iPSC-derived neurons, RET inhibition reduced amyloid aggregation, tau hyperphosphorylation, and early endosomal defects. Mechanistically, the AD-associated amyloid precursor protein C-terminal fragment (APP.C99) was found to interact with complex I proteins to promote RET.\u0000 Conclusion: RET is aberrantly activated in AD, causing altered ROS and NAD+/NADH metabolism. Pharmacological inhibition of RET is beneficial in mouse and human iPSC models of AD. RET activation represents a key pathological driver and a rational therapeutic target for AD and possibly other age-related neurodegenerative diseases.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":" 44","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140212601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetics of Huntington’s disease and related disorders: beyond triplet repeats","authors":"J. Burgunder","doi":"10.20517/and.2023.49","DOIUrl":"https://doi.org/10.20517/and.2023.49","url":null,"abstract":"Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder due to a triplet repeat expansion in the HTT gene. The identification of this gene variation was a lengthy process, but it has since provided an explanation of clinical observations including the variability in age at onset observed across generations (phenomenon of anticipation). Further molecular genetic investigations have allowed the discovery of genes modifying the phenotype presenting differences in terms of age at the onset and course of the disease. Pathogenic gene variations have also been found in other diseases with a similar presentation, such as HD, allowing precise genetic diagnosis. This narrative review examines these data in the context of their historical development. Their implication in our understanding of these disorders and treatment modalities is also highlighted.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140412771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring relationships between state and trait anxiety and depression in patients with Parkinson’s disease and controls: a cross-sectional analysis","authors":"Elisabeth C. DeMarco, Jason Longhurst, Leslie Hinyard","doi":"10.20517/and.2023.33","DOIUrl":"https://doi.org/10.20517/and.2023.33","url":null,"abstract":"Parkinson’s disease (PD) is a neurodegenerative disease comprised of motor and non-motor symptoms, including depression and anxiety. The relationship between depression, anxiety, and motor symptoms is not well understood. Additionally, there are few direct comparisons of anxiety and depression between people with PD (PwP) and those without PD. The present study determined differences in state and trait anxiety between those with and without PD, examined the impact of depression on anxiety in both groups, and explored the relationship between depression, anxiety, and motor symptoms among PwP. Data from 42 PwP and 56 non-PD comparison participants were obtained from a non-randomized, non-treatment longitudinal observational study. Anxiety [State-Trait Anxiety Inventory (STAI)], depression (Geriatric Depression Screen), and motor symptoms (Movement Disorder Society - Unified Parkinson’s Disease Rating Scale part III) were assessed. There were no statistically significant differences between PwP and non-PD comparisons for anxiety or depression. Depression was associated with elevated STAI scores (P < 0.001) regardless of PD status. Depressed PwP displayed greater motor symptom burden compared to non-depressed PwP (median [IQR]: 25.00 [21.00, 38.50] vs. 20.00 [16.00, 23.00]; P = 0.064). There were statistically significant differences in both state and trait anxiety when participants were grouped by depression and PD status. While anxiety does not appear to be correlated with motor symptoms in people with PD, depression may be associated with greater motor symptom burden. Further study is needed to explore the relationship between depression, anxiety, and motor impairment in PwP.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"54 ","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140482577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Potential roles of telomeres and telomerase in neurodegenerative diseases","authors":"Jun Shao, Jing Wang, Bo Li, Chuanbin Liu","doi":"10.20517/and.2023.41","DOIUrl":"https://doi.org/10.20517/and.2023.41","url":null,"abstract":"Telomeres, essential DNA-protein complexes located at chromosome ends, play a critical role in preventing chromosome fusion, recombination, and degradation, thus ensuring genomic stability. When telomeres reach a limiting shortened length, they will activate DNA damage checkpoints, stop cell division and trigger replicative senescence. Telomerase is composed of RNA and protein, which can synthesize telomeres repeat sequences, and elongate telomeres. Studies have shown that telomere length (TL) and telomerase activity are closely involved in aging, aging-related degenerative diseases, and tumors. Neurodegenerative diseases (NDDs) are one of the major aging-related diseases caused by both genetic and environmental factors, characterized by insidious onset, difficult diagnosis, irreversible disease progression, and lack of effective treatments, which brings a heavy burden to society and families. Currently, many studies have noted variations in leukocyte telomere length (LTL) and telomerase activity in NDDs, suggesting a vital role for telomeres and telomerase in NDD pathogenesis. This review explores the relationship between TL and NDDs, examines telomerase as a potential therapeutic target, and discusses emerging biomarkers and intervention strategies for NDD diagnosis and treatment.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"2 10","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139525052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}