Translational Neurodegeneration最新文献

{"title":"Retraction Note: Asiaticoside, a trisaccaride triterpene induces biochemical and molecular variations in brain of mice with parkinsonism","authors":"Uvarajan Sampath, Vanisree Arambakkam Janardhanam","doi":"10.1186/s40035-024-00424-x","DOIUrl":"https://doi.org/10.1186/s40035-024-00424-x","url":null,"abstract":"This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/2047-9158-2-23.","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"41 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141253539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"In vivo diagnosis of TDP-43 proteinopathies: in search of biomarkers of clinical use.","authors":"Juan I López-Carbonero, Irene García-Toledo, Laura Fernández-Hernández, Pablo Bascuñana, María J Gil-Moreno, Jordi A Matías-Guiu, Silvia Corrochano","doi":"10.1186/s40035-024-00419-8","DOIUrl":"10.1186/s40035-024-00419-8","url":null,"abstract":"<p><p>TDP-43 proteinopathies are a heterogeneous group of neurodegenerative disorders that share the presence of aberrant, misfolded and mislocalized deposits of the protein TDP-43, as in the case of amyotrophic lateral sclerosis and some, but not all, pathological variants of frontotemporal dementia. In recent years, many other diseases have been reported to have primary or secondary TDP-43 proteinopathy, such as Alzheimer's disease, Huntington's disease or the recently described limbic-predominant age-related TDP-43 encephalopathy, highlighting the need for new and accurate methods for the early detection of TDP-43 proteinopathy to help on the stratification of patients with overlapping clinical diagnosis. Currently, TDP-43 proteinopathy remains a post-mortem pathologic diagnosis. Although the main aim is to determine the pathologic TDP-43 proteinopathy in the central nervous system (CNS), the ubiquitous expression of TDP-43 in biofluids and cells outside the CNS facilitates the use of other accessible target tissues that might reflect the potential TDP-43 alterations in the brain. In this review, we describe the main developments in the early detection of TDP-43 proteinopathies, and their potential implications on diagnosis and future treatments.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"29"},"PeriodicalIF":10.8,"publicationDate":"2024-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11149336/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141237723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Variability in SOD1-associated amyotrophic lateral sclerosis: geographic patterns, clinical heterogeneity, molecular alterations, and therapeutic implications.","authors":"Miaodan Huang, Yong U Liu, Xiaoli Yao, Dajiang Qin, Huanxing Su","doi":"10.1186/s40035-024-00416-x","DOIUrl":"10.1186/s40035-024-00416-x","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by progressive loss of motor neurons, resulting in global health burden and limited post-diagnosis life expectancy. Although primarily sporadic, familial ALS (fALS) cases suggest a genetic basis. This review focuses on SOD1, the first gene found to be associated with fALS, which has been more recently confirmed by genome sequencing. While informative, databases such as ALSoD and STRENGTH exhibit regional biases. Through a systematic global examination of SOD1 mutations from 1993 to 2023, we found different geographic distributions and clinical presentations. Even though different SOD1 variants are expressed at different protein levels and have different half-lives and dismutase activities, these alterations lead to loss of function that is not consistently correlated with disease severity. Gain of function of toxic aggregates of SOD1 resulting from mutated SOD1 has emerged as one of the key contributors to ALS. Therapeutic interventions specifically targeting toxic gain of function of mutant SOD1, including RNA interference and antibodies, show promise, but a cure remains elusive. This review provides a comprehensive perspective on SOD1-associated ALS and describes molecular features and the complex genetic landscape of SOD1, highlighting its importance in determining diverse clinical manifestations observed in ALS patients and emphasizing the need for personalized therapeutic strategies.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"28"},"PeriodicalIF":10.8,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11138100/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141176467","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The relation of synaptic biomarkers with Aβ, tau, glial activation, and neurodegeneration in Alzheimer's disease.","authors":"Yi-Ting Wang, Nicholas J Ashton, Stijn Servaes, Johanna Nilsson, Marcel S Woo, Tharick A Pascoal, Cécile Tissot, Nesrine Rahmouni, Joseph Therriault, Firoza Lussier, Mira Chamoun, Serge Gauthier, Ann Brinkmalm, Henrik Zetterberg, Kaj Blennow, Pedro Rosa-Neto, Andréa L Benedet","doi":"10.1186/s40035-024-00420-1","DOIUrl":"10.1186/s40035-024-00420-1","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"27"},"PeriodicalIF":12.6,"publicationDate":"2024-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11131272/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141158019","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CSF biomarkers of reactive glial cells are associated with blood-brain barrier leakage and white matter lesions.","authors":"Linbin Dai, Xinyi Lv, Zhaozhao Cheng, Yan Wu, Xianliang Chai, Jiong Shi, Yong Shen, Qiong Wang, Feng Gao","doi":"10.1186/s40035-024-00422-z","DOIUrl":"10.1186/s40035-024-00422-z","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"26"},"PeriodicalIF":12.6,"publicationDate":"2024-05-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11112808/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141088765","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Considerations for biomarker strategies in clinical trials investigating tau-targeting therapeutics for Alzheimer's disease.","authors":"Lewis K Penny, Richard Lofthouse, Mohammad Arastoo, Andy Porter, Soumya Palliyil, Charles R Harrington, Claude M Wischik","doi":"10.1186/s40035-024-00417-w","DOIUrl":"10.1186/s40035-024-00417-w","url":null,"abstract":"<p><p>The use of biomarker-led clinical trial designs has been transformative for investigating amyloid-targeting therapies for Alzheimer's disease (AD). The designs have ensured the correct selection of patients on these trials, supported target engagement and have been used to support claims of disease modification and clinical efficacy. Ultimately, this has recently led to approval of disease-modifying, amyloid-targeting therapies for AD; something that should be noted for clinical trials investigating tau-targeting therapies for AD. There is a clear overlap of the purpose of biomarker use at each stage of clinical development between amyloid-targeting and tau-targeting clinical trials. However, there are differences within the potential context of use and interpretation for some biomarkers in particular measurements of amyloid and utility of soluble, phosphorylated tau biomarkers. Given the complexities of tau in health and disease, it is paramount that therapies target disease-relevant tau and, in parallel, appropriate assays of target engagement are developed. Tau positron emission tomography, fluid biomarkers reflecting tau pathology and downstream measures of neurodegeneration will be important both for participant recruitment and for monitoring disease-modification in tau-targeting clinical trials. Bespoke design of biomarker strategies and interpretations for different modalities and tau-based targets should also be considered.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 1","pages":"25"},"PeriodicalIF":12.6,"publicationDate":"2024-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11107038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141076776","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Agomirs upregulating carboxypeptidase E expression rescue hippocampal neurogenesis and memory deficits in Alzheimer’s disease","authors":"Dongfang Jiang, Hongmei Liu, Tingting Li, Song Zhao, Keyan Yang, Fuwen Yao, Bo Zhou, Haiping Feng, Sijia Wang, Jiaqi Shen, Jinglan Tang, Yu-Xin Zhang, Yun Wang, Caixia Guo, Tie-Shan Tang","doi":"10.1186/s40035-024-00414-z","DOIUrl":"https://doi.org/10.1186/s40035-024-00414-z","url":null,"abstract":"Adult neurogenesis occurs in the subventricular zone (SVZ) and the subgranular zone of the dentate gyrus in the hippocampus. The neuronal stem cells in these two neurogenic niches respond differently to various physiological and pathological stimuli. Recently, we have found that the decrement of carboxypeptidase E (CPE) with aging impairs the maturation of brain-derived neurotrophic factor (BDNF) and neurogenesis in the SVZ. However, it remains unknown whether these events occur in the hippocampus, and what the role of CPE is in the adult hippocampal neurogenesis in the context of Alzheimer’s disease (AD). In vivo screening was performed to search for miRNA mimics capable of upregulating CPE expression and promoting neurogenesis in both neurogenic niches. Among these, two agomirs were further assessed for their effects on hippocampal neurogenesis in the context of AD. We also explored whether these two agomirs could ameliorate behavioral symptoms and AD pathology in mice, using direct intracerebroventricular injection or by non-invasive intranasal instillation. Restoration of CPE expression in the hippocampus improved BDNF maturation and boosted adult hippocampal neurogenesis. By screening the miRNA mimics targeting the 5’UTR region of Cpe gene, we developed two agomirs that were capable of upregulating CPE expression. The two agomirs significantly rescued adult neurogenesis and cognition, showing multiple beneficial effects against the AD-associated pathologies in APP/PS1 mice. Of note, noninvasive approach via intranasal delivery of these agomirs improved the behavioral and neurocognitive functions of APP/PS1 mice. CPE may regulate adult hippocampal neurogenesis via the CPE–BDNF–TrkB signaling pathway. This study supports the prospect of developing miRNA agomirs targeting CPE as biopharmaceuticals to counteract aging- and disease-related neurological decline in human brains.","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"26 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140800362","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Focusing on mitochondria in the brain: from biology to therapeutics","authors":"Nanshan Song, Shuyuan Mei, Xiangxu Wang, Gang Hu, Ming Lu","doi":"10.1186/s40035-024-00409-w","DOIUrl":"https://doi.org/10.1186/s40035-024-00409-w","url":null,"abstract":"Mitochondria have multiple functions such as supplying energy, regulating the redox status, and producing proteins encoded by an independent genome. They are closely related to the physiology and pathology of many organs and tissues, among which the brain is particularly prominent. The brain demands 20% of the resting metabolic rate and holds highly active mitochondrial activities. Considerable research shows that mitochondria are closely related to brain function, while mitochondrial defects induce or exacerbate pathology in the brain. In this review, we provide comprehensive research advances of mitochondrial biology involved in brain functions, as well as the mitochondria-dependent cellular events in brain physiology and pathology. Furthermore, various perspectives are explored to better identify the mitochondrial roles in neurological diseases and the neurophenotypes of mitochondrial diseases. Finally, mitochondrial therapies are discussed. Mitochondrial-targeting therapeutics are showing great potentials in the treatment of brain diseases.","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"13 32 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140608669","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of the brain renin-angiotensin system in Parkinson´s disease","authors":"Jose Luis Labandeira-Garcia, Carmen M. Labandeira, Maria J. Guerra, Ana I. Rodriguez-Perez","doi":"10.1186/s40035-024-00410-3","DOIUrl":"https://doi.org/10.1186/s40035-024-00410-3","url":null,"abstract":"The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs, including the brain, have a local paracrine RAS. Mutual regulation between the dopaminergic system and RAS has been observed in several tissues. Dysregulation of these interactions leads to renal and cardiovascular diseases, as well as progression of dopaminergic neuron degeneration in a major brain center of dopamine/angiotensin interaction such as the nigrostriatal system. A decrease in the dopaminergic function induces upregulation of the angiotensin type-1 (AT1) receptor activity, leading to recovery of dopamine levels. However, AT1 receptor overactivity in dopaminergic neurons and microglial cells upregulates the cellular NADPH-oxidase-superoxide axis and Ca2+ release, which mediate several key events in oxidative stress, neuroinflammation, and α-synuclein aggregation, involved in Parkinson's disease (PD) pathogenesis. An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivity. Consistent with this, an imbalance in RAS activity towards the pro-oxidative/pro-inflammatory AT1 receptor axis has been observed in the substantia nigra and striatum of several animal models of high vulnerability to dopaminergic degeneration. Interestingly, autoantibodies against angiotensin-converting enzyme 2 and AT1 receptors are increased in PD models and PD patients and contribute to blood–brain barrier (BBB) dysregulation and nigrostriatal pro-inflammatory RAS upregulation. Therapeutic strategies addressed to the modulation of brain RAS, by AT1 receptor blockers (ARBs) and/or activation of the antioxidative axis (AT2, Mas receptors), may be neuroprotective for individuals with a high risk of developing PD or in prodromal stages of PD to reduce progression of the disease.","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"58 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593608","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CRISPR base editing-mediated correction of a tau mutation rescues cognitive decline in a mouse model of tauopathy","authors":"Min Sung Gee, Eunji Kwon, Myeong-Hoon Song, Seung Ho Jeon, Namkwon Kim, Jong Kil Lee, Taeyoung Koo","doi":"10.1186/s40035-024-00415-y","DOIUrl":"https://doi.org/10.1186/s40035-024-00415-y","url":null,"abstract":"&lt;p&gt;The microtubule-binding protein tau is encoded by &lt;i&gt;MAPT&lt;/i&gt;, located on chromosome 17. Mutations in this gene have been implicated in frontotemporal dementia [1]. Down-regulation of endogenous tau with antisense oligonucleotides (ASOs) specific for human tau or zinc-finger protein transcription factors has been explored in preclinical models of tauopathy [2, 3]. Of particular note, the effects of tau ASOs on mild Alzheimer’s disease are now under assessment in a clinical trial [4]. In addition, CRISPR-mediated gene knockout has been used to regulate the expression of &lt;i&gt;APP&lt;/i&gt; or &lt;i&gt;BACE1&lt;/i&gt; to ameliorate amyloid β and tau pathologies [5, 6]. However, therapeutic approaches to correcting &lt;i&gt;MAPT&lt;/i&gt; mutations that cause tau aggregation in animal models of tauopathy have not yet been studied.&lt;/p&gt;&lt;p&gt;CRISPR RNA-guided base editors have been recently used for targeted base mutagenesis in the genome and have become a promising approach for the treatment of neurological disorders [6]. The recently developed adenine base editor, NG-ABE8e, which is a fusion of SpCas9-NG derived from &lt;i&gt;Streptococcus pyogenes&lt;/i&gt; and an evolved &lt;i&gt;E. coli&lt;/i&gt; TadA monomer that is used in combination with a single-guide RNA (sgRNA), generates A-to-G conversions in the spacer upstream of an NG protospacer adjacent motif (PAM). NG-ABE8e has demonstrated an efficient genome editing ability, targeting a window spanning positions 4–11 in the protospacer [7].&lt;/p&gt;&lt;p&gt;In this study, we examined whether NG-ABE8e could be used to correct a pathogenic &lt;i&gt;MAPT&lt;/i&gt; mutation and thereby reduce tauopathy and cognitive symptoms in the PS19 transgenic mouse model expressing human &lt;i&gt;MAPT-&lt;/i&gt;P301S. To evaluate the ability of NG-ABE8e to correct the &lt;i&gt;MAPT&lt;/i&gt;-P301S mutant allele to the wild-type (WT) sequence, we designed sgRNAs targeting the &lt;i&gt;MAPT&lt;/i&gt;-P301S mutation. The sgRNAs were designed to hybridize with a 19-nt target sequence upstream of a TG PAM to replace the A, located 11 nt distal from the 5′-end of protospacer (Fig. 1a and Additional file 1: Table S1). Next, we evaluated the activity of the sgRNA by using targeted deep sequencing to measure adenine base editing frequencies after transfection of plasmids encoding NG-ABE8e and the sgRNAs into HEK293T cells harboring the P301S mutation (293T-P301S) (Additional file 1: Fig. S1a). The desired A-to-G substitution induced by NG-ABE8e corrected the mutant allele to the WT &lt;i&gt;MAPT&lt;/i&gt; sequence, with an observed editing frequency of 16.6% ± 0.8% in the cells (Additional file 1: Fig. S1b). Bystander editing or indels were not detectable in the protospacer. We also designed sgRNAs to target exon 1 in the mouse &lt;i&gt;Rosa26&lt;/i&gt; gene as an internal control (Additional file 1: Fig. S1c and Table S1). Treatment of NIH3T3 cells with NG-ABE8e and a &lt;i&gt;Rosa26&lt;/i&gt;-targeting sgRNA resulted in a base-editing frequency of 29.4% ± 1.3% (Additional file 1: Fig. S1d).&lt;/p&gt;&lt;figure&gt;&lt;figcaption&gt;&lt;b data-test=\"figure-caption-text\"&gt;Fig. 1&lt;/b&gt;&lt;/figcaptio","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"12 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}