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.
{"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}
Elisabeth C. DeMarco, Jason Longhurst, Leslie Hinyard
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.
帕金森病（PD）是一种由运动症状和非运动症状（包括抑郁和焦虑）组成的神经退行性疾病。抑郁、焦虑和运动症状之间的关系尚不十分清楚。此外，对帕金森氏症患者（PwP）和非帕金森氏症患者的焦虑和抑郁进行直接比较的情况也很少。本研究确定了帕金森病患者和非帕金森病患者在状态焦虑和特质焦虑方面的差异，检查了抑郁症对两组患者焦虑的影响，并探讨了帕金森病患者抑郁、焦虑和运动症状之间的关系。42 名帕金森病患者和 56 名非帕金森病对比参与者的数据来自一项非随机、非治疗的纵向观察研究。研究评估了焦虑（状态-特质焦虑量表 (STAI)）、抑郁（老年抑郁筛查）和运动症状（运动障碍协会-统一帕金森病评分量表第三部分）。在焦虑或抑郁方面，帕金森病患者与非帕金森病患者之间没有明显的统计学差异。无论帕金森病状态如何，抑郁都与 STAI 评分升高有关（P < 0.001）。与非抑郁症患者相比，抑郁症患者的运动症状负担更大（中位数 [IQR]: 25.00 [21.00, 38.50] vs. 20.00 [16.00, 23.00]; P = 0.064）。根据抑郁和帕金森病状况对参与者进行分组后，他们的状态焦虑和特质焦虑在统计学上存在显著差异。虽然焦虑似乎与帕金森病患者的运动症状无关，但抑郁可能与更大的运动症状负担有关。我们需要进一步研究抑郁、焦虑和运动障碍之间的关系。
{"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}
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.
端粒是位于染色体末端的重要 DNA 蛋白复合物，在防止染色体融合、重组和降解方面发挥着关键作用，从而确保基因组的稳定性。当端粒达到极限缩短长度时，就会激活DNA损伤检查点，停止细胞分裂，引发复制衰老。端粒酶由核糖核酸（RNA）和蛋白质组成，可以合成端粒重复序列，延长端粒。研究表明，端粒长度（TL）和端粒酶活性与衰老、与衰老相关的退行性疾病和肿瘤密切相关。神经退行性疾病（NDDs）是由遗传和环境因素引起的主要衰老相关疾病之一，具有起病隐匿、诊断困难、疾病进展不可逆、缺乏有效治疗等特点，给社会和家庭带来沉重负担。目前，许多研究都注意到了NDD中白细胞端粒长度（LTL）和端粒酶活性的变化，这表明端粒和端粒酶在NDD发病机制中起着至关重要的作用。本综述探讨了端粒长度与 NDD 之间的关系，研究了作为潜在治疗靶点的端粒酶，并讨论了用于 NDD 诊断和治疗的新兴生物标记物和干预策略。
{"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}
Pub Date : 2024-01-01Epub Date: 2024-08-06DOI: 10.20517/and.2024.18
Disa Basu, Nannan Yang, Jinhui Ding, Lupeng Wang, Zhenhua Liu, Beisha Tang, Huaibin Cai
Parkinson's disease (PD) is a prevalent degenerative movement disorder largely attributed to the dysfunction of dopamine transmission in the basal ganglia. However, the role of the endocannabinoid (eCB) system (ECS) in PD pathology and symptomatology is often overlooked in discussions. Recent research, including our own, has identified multiple homozygous loss-of-function variants in diacylglycerol lipase β (DAGLB), an enzyme involved in the synthesis of 2-arachidonoyl-glycerol (2-AG) - the most abundant eCB in the brain - in individuals with early-onset autosomal recessive Parkinsonism. These genetic findings strongly link eCB deficiency with the etiopathogenesis of PD. Exploring the roles of DAGLB and 2-AG signaling in PD and dopamine transmission could provide a new perspective on PD treatments, focusing on the function of the ECS and the pathophysiological implications of its disruption.
{"title":"Beyond dopamine: exploring endocannabinoids in Parkinson's disease.","authors":"Disa Basu, Nannan Yang, Jinhui Ding, Lupeng Wang, Zhenhua Liu, Beisha Tang, Huaibin Cai","doi":"10.20517/and.2024.18","DOIUrl":"10.20517/and.2024.18","url":null,"abstract":"<p><p>Parkinson's disease (PD) is a prevalent degenerative movement disorder largely attributed to the dysfunction of dopamine transmission in the basal ganglia. However, the role of the endocannabinoid (eCB) system (ECS) in PD pathology and symptomatology is often overlooked in discussions. Recent research, including our own, has identified multiple homozygous loss-of-function variants in diacylglycerol lipase β (DAGLB), an enzyme involved in the synthesis of 2-arachidonoyl-glycerol (2-AG) - the most abundant eCB in the brain - in individuals with early-onset autosomal recessive Parkinsonism. These genetic findings strongly link eCB deficiency with the etiopathogenesis of PD. Exploring the roles of DAGLB and 2-AG signaling in PD and dopamine transmission could provide a new perspective on PD treatments, focusing on the function of the ECS and the pathophysiological implications of its disruption.</p>","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"4 3","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12797192/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145971597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
SHANK3 is a protein primarily found in the postsynaptic density (PSD) of excitatory synapses in the brain. Heterozygous mutations in the shank3 gene have been linked to autism spectrum disorder (ASD) and intellectual disability. There are various animal models carrying mutant SHANK3 that have provided valuable insights into the pathogenesis of ASD. In this review, we will discuss these animal models, with a specific focus on the neuropathology observed in shank3 mouse and monkey models. These models are particularly important as they share closer similarities to humans and are capable of more accurately recapitulating the neuropathological features observed in individuals with ASD. Mice with mutations in the shank3 gene exhibit deficits in social behavior, communication, and repetitive behaviors, which are core features of ASD and support the link between SHANK3 and ASD. However, studies of monkey models with SHANK3 targeting by CRISPR/Cas9 have demonstrated that, unlike mice with completely knocked-out shank3 genes, the monkey model with complete deletion of SHANK3 displays a reduction in the number of neuronal cells. This review discusses the species-specific neuropathology in SHANK3/shank3 knockout mice and monkeys. The differences in neuropathology in SHANK3/shank3 mutant mouse and monkey models suggest that non-human primate models are highly valuable for investigating the mechanism of neurodegeneration that may selectively occur in primate brains.
{"title":"Neuropathological insights from SHANK3 mutant animal models","authors":"Jia-Wei Zhang, Da-Jian He, Xiao-Jiang Li","doi":"10.20517/and.2023.18","DOIUrl":"https://doi.org/10.20517/and.2023.18","url":null,"abstract":"SHANK3 is a protein primarily found in the postsynaptic density (PSD) of excitatory synapses in the brain. Heterozygous mutations in the shank3 gene have been linked to autism spectrum disorder (ASD) and intellectual disability. There are various animal models carrying mutant SHANK3 that have provided valuable insights into the pathogenesis of ASD. In this review, we will discuss these animal models, with a specific focus on the neuropathology observed in shank3 mouse and monkey models. These models are particularly important as they share closer similarities to humans and are capable of more accurately recapitulating the neuropathological features observed in individuals with ASD. Mice with mutations in the shank3 gene exhibit deficits in social behavior, communication, and repetitive behaviors, which are core features of ASD and support the link between SHANK3 and ASD. However, studies of monkey models with SHANK3 targeting by CRISPR/Cas9 have demonstrated that, unlike mice with completely knocked-out shank3 genes, the monkey model with complete deletion of SHANK3 displays a reduction in the number of neuronal cells. This review discusses the species-specific neuropathology in SHANK3/shank3 knockout mice and monkeys. The differences in neuropathology in SHANK3/shank3 mutant mouse and monkey models suggest that non-human primate models are highly valuable for investigating the mechanism of neurodegeneration that may selectively occur in primate brains.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"23 45","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139148338","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}
Adult-onset idiopathic dystonia is thought to be an autosomal dominant disorder with markedly reduced penetrance and heterogeneous clinical presentation. It has been known for a long time that age may affect the clinical phenomenology of the condition, at least in terms of the site of dystonia onset. The aim of this paper is to understand whether age and aging may play a role in the natural history of adult-onset idiopathic dystonia and in the mechanisms underlying its development and progression. Aging may increase abnormalities in cortical/subcortical excitability manifested by patients with different forms of adult-onset idiopathic dystonia, thus enhancing susceptibility to dystonia development, worsening spasm severity, at least in blepharospasm, and favoring perhaps the spread of dystonia to near body sites. The relationship between age of onset and site of onset in adult-onset idiopathic dystonia (AOID) might reflect age- and body-site-specific environmental risk factors that would drive the variable clinical expression of individuals carrying dystonia-susceptibility gene(s).
{"title":"Adult-onset idiopathic dystonia: phenotype and mechanism changes “as time goes by”","authors":"Giovanni Defazio, A. Muroni","doi":"10.20517/and.2023.32","DOIUrl":"https://doi.org/10.20517/and.2023.32","url":null,"abstract":"Adult-onset idiopathic dystonia is thought to be an autosomal dominant disorder with markedly reduced penetrance and heterogeneous clinical presentation. It has been known for a long time that age may affect the clinical phenomenology of the condition, at least in terms of the site of dystonia onset. The aim of this paper is to understand whether age and aging may play a role in the natural history of adult-onset idiopathic dystonia and in the mechanisms underlying its development and progression. Aging may increase abnormalities in cortical/subcortical excitability manifested by patients with different forms of adult-onset idiopathic dystonia, thus enhancing susceptibility to dystonia development, worsening spasm severity, at least in blepharospasm, and favoring perhaps the spread of dystonia to near body sites. The relationship between age of onset and site of onset in adult-onset idiopathic dystonia (AOID) might reflect age- and body-site-specific environmental risk factors that would drive the variable clinical expression of individuals carrying dystonia-susceptibility gene(s).","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"11 15","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-12-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138603447","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}
Essential Tremor (ET) is a very common neurological condition that increases with age. Tremor progresses in severity and body distribution with aging. Patients with ET may develop clinical signs of cerebellar dysfunction. Other neurological signs may be seen as well, but their association with ET has not been fully solidified. Pathological changes in the cerebellum are seen with ET, although describing ET as a neurodegenerative disease is still premature. Links to other neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease can be seen but may simply reflect co-incidental co-morbidities of aging.
{"title":"Essential tremor and ageing","authors":"Nicki Niemann, Holly A. Shill","doi":"10.20517/and.2023.35","DOIUrl":"https://doi.org/10.20517/and.2023.35","url":null,"abstract":"Essential Tremor (ET) is a very common neurological condition that increases with age. Tremor progresses in severity and body distribution with aging. Patients with ET may develop clinical signs of cerebellar dysfunction. Other neurological signs may be seen as well, but their association with ET has not been fully solidified. Pathological changes in the cerebellum are seen with ET, although describing ET as a neurodegenerative disease is still premature. Links to other neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease can be seen but may simply reflect co-incidental co-morbidities of aging.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"42 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136262638","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}
Sachin Kammula, Sulagna Tripathi, Ning Wang, Valina L. Dawson, Ted M. Dawson, Xiaobo Mao
Alzheimer’s disease (AD) is a prevalent neurodegenerative disease characterized by irreversible neural degeneration and cognitive decline. The prion-like propagation of the β-amyloid (Aβ) and tau proteins leads to the formation of protein plaques and, subsequently, neuronal dysfunction, contributing significantly to AD pathogenesis. Although effective AD treatments remain elusive, targeting tau protein aggregation has emerged as a promising therapeutic approach. However, recent anti-tau antibody trials have shown limited success in improving cognition, underscoring the need for a more advanced, multifaceted approach to address multiple mechanisms of tau pathology. This review examines the role of tau protein in the context of AD, with a particular focus on potential therapeutic interventions. Emphasis is placed on the modulation of tau protein expression, tau post-translational modifications and aggregation, receptor-mediated uptake and extracellular release pathways, neural inflammatory response pathways, intercellular organelle exchange, mitochondrial function, microtubule stability, and nuclear factor expression as critical intervention points. Despite the challenges faced in ongoing anti-tau clinical efforts, a comprehensive strategy targeting multiple pathways involved in tau pathology, by using either combinations of existing drugs or novel multitarget drugs, holds promise. By gaining a deeper understanding of the complex mechanisms underlying tau pathology, researchers can develop innovative therapeutic strategies to combat AD.
{"title":"Unraveling the tau puzzle: a review of mechanistic targets and therapeutic interventions to prevent tau pathology in Alzheimer’s disease","authors":"Sachin Kammula, Sulagna Tripathi, Ning Wang, Valina L. Dawson, Ted M. Dawson, Xiaobo Mao","doi":"10.20517/and.2023.20","DOIUrl":"https://doi.org/10.20517/and.2023.20","url":null,"abstract":"Alzheimer’s disease (AD) is a prevalent neurodegenerative disease characterized by irreversible neural degeneration and cognitive decline. The prion-like propagation of the β-amyloid (Aβ) and tau proteins leads to the formation of protein plaques and, subsequently, neuronal dysfunction, contributing significantly to AD pathogenesis. Although effective AD treatments remain elusive, targeting tau protein aggregation has emerged as a promising therapeutic approach. However, recent anti-tau antibody trials have shown limited success in improving cognition, underscoring the need for a more advanced, multifaceted approach to address multiple mechanisms of tau pathology. This review examines the role of tau protein in the context of AD, with a particular focus on potential therapeutic interventions. Emphasis is placed on the modulation of tau protein expression, tau post-translational modifications and aggregation, receptor-mediated uptake and extracellular release pathways, neural inflammatory response pathways, intercellular organelle exchange, mitochondrial function, microtubule stability, and nuclear factor expression as critical intervention points. Despite the challenges faced in ongoing anti-tau clinical efforts, a comprehensive strategy targeting multiple pathways involved in tau pathology, by using either combinations of existing drugs or novel multitarget drugs, holds promise. By gaining a deeper understanding of the complex mechanisms underlying tau pathology, researchers can develop innovative therapeutic strategies to combat AD.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"277 2","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136262063","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}
Stroke has become the second leading cause of death and disability worldwide. Its morbidity and mortality are on the rise, seriously jeopardizing the health and quality of life of the elderly. A growing number of studies have identified ferroptosis as an important mechanism of pathological cell death during stroke and other acute brain injuries, and studies have demonstrated that ferroptosis inhibitors and ion chelators are effective in improving neurological damage and related cerebral ischemia manifestations in the development of stroke. This suggests that there are potential targets in the ferroptosis pathway to regulate stroke. The synergistic effect of Chinese herbs with multiple components, multiple pathways, and multiple targets is a unique advantage for stroke prevention and treatment. The aim of this article is to describe the role and influence of Chinese herbs in the pathology of ferroptosis injury in stroke, and to provide evidence that Chinese herbs can treat or reduce neurological injury after stroke by targeting ferroptosis.
{"title":"Potential effects of Chinese herbs on iron metabolism for the treatment of stroke","authors":"Wen-Juan Guo, Hai-Ling Ding, Qi-Hui Zhang","doi":"10.20517/and.2023.02","DOIUrl":"https://doi.org/10.20517/and.2023.02","url":null,"abstract":"Stroke has become the second leading cause of death and disability worldwide. Its morbidity and mortality are on the rise, seriously jeopardizing the health and quality of life of the elderly. A growing number of studies have identified ferroptosis as an important mechanism of pathological cell death during stroke and other acute brain injuries, and studies have demonstrated that ferroptosis inhibitors and ion chelators are effective in improving neurological damage and related cerebral ischemia manifestations in the development of stroke. This suggests that there are potential targets in the ferroptosis pathway to regulate stroke. The synergistic effect of Chinese herbs with multiple components, multiple pathways, and multiple targets is a unique advantage for stroke prevention and treatment. The aim of this article is to describe the role and influence of Chinese herbs in the pathology of ferroptosis injury in stroke, and to provide evidence that Chinese herbs can treat or reduce neurological injury after stroke by targeting ferroptosis.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"161 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136308271","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}
Microglia are the resident immune cells of the central nervous system (CNS) and play pivotal roles in nervous development, homeostasis, and various neurological diseases. Most of the previous understanding of microglia came from rodents or a limited number of postmortem microglia. However, as significant differences between murine and human microglia have been verified, it has become increasingly apparent that rodents cannot accurately recapitulate human genetics and pathology, thus hindering the translation of microglial findings from rodents to humans. In addition, primary human microglia are notoriously difficult to obtain and lack the scalability required for many high-throughput assays. Fortunately, recent advances in microglia generation from human pluripotent stem cells (hPSCs) have enabled exciting new avenues to decipher or revisit microglial biology in the human context. Given the complex interactions between microglia and other CNS cells, hPSC-derived microglia-like cells (MGLs) were further engrafted within hPSC-derived brain organoids (BOs), which largely lack microglia due to their different embryonic origins, to study human microglial functions in either health and disease state closer to brain microglia. This is a rapidly evolving field, especially in the last five years, that has begun to yield novel insights into the genetics of human microglia and their unique role in neurological diseases. In this review, we will summarize the versatile applications of hPSC-derived MGLs and microglia-containing BOs. Specifically, we will discuss their applications in disease modeling, omics and systematic analysis, interaction with other CNS cell types, as well as transplantation-based human-mouse chimerism.
{"title":"The versatile applications of human pluripotent stem cell-derived microglia and microglia-containing brain organoids","authors":"Junjiao Wu, Yu Tang","doi":"10.20517/and.2023.01","DOIUrl":"https://doi.org/10.20517/and.2023.01","url":null,"abstract":"Microglia are the resident immune cells of the central nervous system (CNS) and play pivotal roles in nervous development, homeostasis, and various neurological diseases. Most of the previous understanding of microglia came from rodents or a limited number of postmortem microglia. However, as significant differences between murine and human microglia have been verified, it has become increasingly apparent that rodents cannot accurately recapitulate human genetics and pathology, thus hindering the translation of microglial findings from rodents to humans. In addition, primary human microglia are notoriously difficult to obtain and lack the scalability required for many high-throughput assays. Fortunately, recent advances in microglia generation from human pluripotent stem cells (hPSCs) have enabled exciting new avenues to decipher or revisit microglial biology in the human context. Given the complex interactions between microglia and other CNS cells, hPSC-derived microglia-like cells (MGLs) were further engrafted within hPSC-derived brain organoids (BOs), which largely lack microglia due to their different embryonic origins, to study human microglial functions in either health and disease state closer to brain microglia. This is a rapidly evolving field, especially in the last five years, that has begun to yield novel insights into the genetics of human microglia and their unique role in neurological diseases. In this review, we will summarize the versatile applications of hPSC-derived MGLs and microglia-containing BOs. Specifically, we will discuss their applications in disease modeling, omics and systematic analysis, interaction with other CNS cell types, as well as transplantation-based human-mouse chimerism.","PeriodicalId":93251,"journal":{"name":"Ageing and neurodegenerative diseases","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89392193","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}
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