Translational Neurodegeneration最新文献

{"title":"Extracellular PHF-tau modulates astrocyte mitochondrial dynamics and mediates neuronal connectivity.","authors":"Valentin Zufferey, Aatmika Barve, Enea Parietti, Luc Belinga, Audrey Bringaud, Yvan Varisco, Kerstin Fabbri, Francesca Capotosti, Paola Bezzi, Nicole Déglon, Pierre Marquet, Nicolas Preitner, Kevin Richetin","doi":"10.1186/s40035-025-00474-9","DOIUrl":"https://doi.org/10.1186/s40035-025-00474-9","url":null,"abstract":"<p><strong>Background: </strong>Tau is an intracellular protein that plays a crucial role in stabilizing microtubules. However, it can aggregate into various forms under pathological conditions and be secreted into the brain parenchyma. While the consequences of tau aggregation within neurons have been extensively studied, the effects of extracellular paired helical filaments of tau (ePHF-tau) on neurons and astrocytes are still poorly understood.</p><p><strong>Methods: </strong>This study examined the effect of human ePHF-tau (2N4R) on primary cultures of rat neuroglia, focusing on changes in neurites or synapses by microscopy and analysis of synaptosome and mitochondria proteomic profiles after treatment. In addition, we monitored the behavior of mitochondria in neurons and astrocytes separately over three days using high-speed imaging and high-throughput acquisition and analysis.</p><p><strong>Results: </strong>ePHF-tau was efficiently cleared by astrocytes within two days in a 3D neuron-astrocyte co-culture model. Treatment with ePHF-tau led to a rapid increase in synaptic vesicle production and active zones, suggesting a potential excitotoxic response. Proteomic analyses of synaptosomal and mitochondrial fractions revealed distinct mitochondrial stress adaptations: astrocytes exhibited elevated mitochondrial biogenesis and turnover, whereas neuronal mitochondria displayed only minor oxidative modifications. In a mixed culture model, overexpression of tau 1N4R specifically in astrocytes triggered a marked increase in mitochondrial biogenesis, coinciding with enhanced synaptic vesicle formation in dendrites. Similarly, astrocyte-specific overexpression of PGC1alpha produced a comparable pattern of synaptic vesicle production, indicating that astrocytic mitochondrial adaptation to ePHF-tau may significantly influence synaptic function.</p><p><strong>Conclusions: </strong>These findings suggest that the accumulation of PHF-tau within astrocytes drives changes in mitochondrial biogenesis, which may influence synaptic regulation. This astrocyte-mediated adaptation to tauopathy highlights the potential role of astrocytes in modulating synaptic dynamics in response to tau stress, opening avenues for therapeutic strategies aimed at astrocytic mechanisms in the context of neurodegenerative diseases.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"13"},"PeriodicalIF":10.8,"publicationDate":"2025-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143693380","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":"Improving vulnerable Calbindin1^- neurons in the ventral hippocampus rescues tau-induced impairment of episodic memory.","authors":"Huiyang Lei, Jingru Lv, Fuqiang Zhang, Linyu Wei, Kun Shi, Jiale Liu, Ting He, Rui Xiong, Fei Sun, Tongkai Zhong, Jingqi Zhao, Dan Ke, Qun Wang, Peiran Jiang, Ai-Min Bao, Jian-Zhi Wang, Ying Yang","doi":"10.1186/s40035-025-00473-w","DOIUrl":"10.1186/s40035-025-00473-w","url":null,"abstract":"<p><strong>Background: </strong>Intraneuronal accumulation of hyperphosphorylated tau is a hallmark of Alzheimer's disease (AD). Given the significant correlation between tau pathology and memory loss in AD patients, identifying vulnerable brain regions, particularly susceptible neuron types in these regions, will advance our understanding of AD onset and shed light on therapeutic strategies to manage its progression.</p><p><strong>Methods: </strong>Immunofluorescent staining was employed to identify the brain regions and neuron types vulnerable to tau pathology in AD. A combination of chemogenetics, electrophysiological recording, in vivo Ca²⁺ recording, and a modified temporal-order discrimination behavior test was utilized to investigate the toxicity of tau accumulation to susceptible neurons in the dorsal part of the ventral hippocampus. Proteomics, phosphoproteomics, and molecular targeting were used to explore the underlying mechanisms of neuron susceptibility to tau accumulation in AD. The beneficial effects of microtubule affinity regulating kinase 4 (MARK4) knockdown and administration of DEPhosphorylation TArgeting Chimera (DEPTAC) were evaluated in AD mice with tau pathology.</p><p><strong>Results: </strong>In postmortem brains of AD patients, we observed robust accumulation of hyperphosphorylated tau in the anterior hippocampal CA1 region, particularly in its Calbindin1^- (Calb1^-) neurons, as opposed to the posterior hippocampal CA1 region and Calb1⁺ neurons. The susceptibility of Calb1^- neurons to phospho-tau accumulation was also observed in P301L mice, especially in the dorsal part of ventral (anterior in human) hippocampal CA1 (dvCA1). In P301L mice, dvCA1 displayed distinct protein and phosphorylated protein networks compared with dorsal CA1, accompanied by overactivation of MARK4. Overexpressing human tau in Calb1^- neurons in the dvCA1 (dvCA1^Calb1- neurons) specifically impairs the temporal-order discrimination of objects. Meanwhile, tau accumulation significantly inhibited the excitability and firing patterns of dvCA1^Calb1- neurons associated with temporal-order discrimination. Knocking down MARK4 or reducing hyperphosporylated tau via DEPTAC in P301L mice significantly ameliorated AD-like tau pathology in dvCA1^Calb1- neurons and improved temporal-order discrimination of objects.</p><p><strong>Conclusion: </strong>These findings highlight the crucial role of dvCA1^Calb1- neurons in the early stage of tau pathology and demonstrate the potential of targeting phosphorylated tau through MARK4 knockdown or DEPTAC administration to counter the vulnerability of dvCA1^Calb1- neurons and, consequently, ameliorate episodic memory deficits in AD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"12"},"PeriodicalIF":10.8,"publicationDate":"2025-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11877784/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143558182","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":"Chronic subthalamic nucleus deep brain stimulation reduces pathological TrkB aggregates in a Parkinson's disease rat model.","authors":"Tobias Petschner, Katarina Hofman, Jia Zhi Chen, Thomas Andreska, Daniel Wolf, Susanne Knorr, Robert Blum, Muthuraman Muthuraman, Uwe Gbureck, Jens Volkmann, Michael Sendtner, Chi Wang Ip","doi":"10.1186/s40035-025-00472-x","DOIUrl":"10.1186/s40035-025-00472-x","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"11"},"PeriodicalIF":10.8,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11843761/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143469351","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":"Parkinson's disease and glucose metabolism impairment.","authors":"Liangjing Chen, Chunyu Wang, Lixia Qin, Hainan Zhang","doi":"10.1186/s40035-025-00467-8","DOIUrl":"10.1186/s40035-025-00467-8","url":null,"abstract":"<p><p>Parkinson's disease (PD) is the second most common neurodegenerative disorder. PD patients exhibit varying degrees of abnormal glucose metabolism throughout disease stages. Abnormal glucose metabolism is closely linked to the PD pathogenesis and progression. Key glucose metabolism processes involved in PD include glucose transport, glycolysis, the tricarboxylic acid cycle, oxidative phosphorylation, the pentose phosphate pathway, and gluconeogenesis. Recent studies suggest that glucose metabolism is a potential therapeutic target for PD. In this review, we explore the connection between PD and abnormal glucose metabolism, focusing on the underlying pathophysiological mechanisms. We also summarize potential therapeutic drugs related to glucose metabolism based on results from current cellular and animal model studies.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"10"},"PeriodicalIF":10.8,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11831814/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143442085","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 C. elegans gba-3 gene encodes a glucocerebrosidase that exacerbates α-synuclein-mediated impairments in deletion mutants.","authors":"Ning Liu, Rongzhen Li, Xiaobing Huang, Merja Lakso, Garry Wong","doi":"10.1186/s40035-024-00463-4","DOIUrl":"10.1186/s40035-024-00463-4","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"9"},"PeriodicalIF":10.8,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11823175/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143411098","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":"AMPA receptor diffusional trapping machinery as an early therapeutic target in neurodegenerative and neuropsychiatric disorders.","authors":"Daniel Choquet, Patricio Opazo, Hongyu Zhang","doi":"10.1186/s40035-025-00470-z","DOIUrl":"10.1186/s40035-025-00470-z","url":null,"abstract":"<p><p>Over the past two decades, there has been a growing recognition of the physiological importance and pathological implications surrounding the surface diffusion of AMPA receptors (AMPARs) and their diffusional trapping at synapses. AMPAR surface diffusion entails the thermally powered random Brownian lateral movement of these receptors within the plasma membrane, facilitating dynamic exchanges between synaptic and extrasynaptic compartments. This process also enables the activity-dependent diffusional trapping and accumulation of AMPARs at synapses through transient binding to synaptic anchoring slots. Recent research highlights the critical role of synaptic recruitment of AMPARs via diffusional trapping in fundamental neural processes such as the development of the early phases of long-term potentiation (LTP), contextual fear memory, memory consolidation, and sensory input-induced cortical remapping. Furthermore, studies underscore that regulation of AMPAR diffusional trapping is altered across various neurological disease models, including Huntington's disease (HD), Alzheimer's disease (AD), and stress-related disorders like depression. Notably, pharmacological interventions aimed at correcting deficits in AMPAR diffusional trapping have demonstrated efficacy in restoring synapse numbers, LTP, and memory functions in these diverse disease models, despite their distinct pathogenic mechanisms. This review provides current insights into the molecular mechanisms underlying the dysregulation of AMPAR diffusional trapping, emphasizing its role as a converging point for multiple pathological signaling pathways. We propose that targeting AMPAR diffusional trapping represents a promising early therapeutic strategy to mitigate synaptic plasticity and memory deficits in a spectrum of brain disorders, encompassing but not limited to HD, AD, and stress-related conditions. This approach underscores an integrated therapeutic target amidst the complexity of these neurodegenerative and neuropsychiatric diseases.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"8"},"PeriodicalIF":10.8,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11817889/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400184","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":"Refining α-synuclein seed amplification assays to distinguish Parkinson's disease from multiple system atrophy.","authors":"James A Wiseman, Clinton P Turner, Richard L M Faull, Glenda M Halliday, Birger Victor Dieriks","doi":"10.1186/s40035-025-00469-6","DOIUrl":"10.1186/s40035-025-00469-6","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) and multiple system atrophy (MSA) are two distinct α-synucleinopathies traditionally differentiated through clinical symptoms. Early diagnosis of MSA is problematic, and seed amplification assays (SAAs), such as real-time quaking-induced conversion (RT-QuIC), offer the potential to distinguish these diseases through their underlying α-synuclein (α-Syn) pathology and proteoforms. Currently, SAAs provide a binary result, signifying either the presence or absence of α-Syn seeds. To enhance the diagnostic potential and biological relevance of these assays, there is a pressing need to incorporate quantification and stratification of α-Syn proteoform-specific aggregation kinetics into current SAA pipelines.</p><p><strong>Methods: </strong>Optimal RT-QuIC assay conditions for α-Syn seeds extracted from PD and MSA patient brains were determined, and assay kinetics were assessed for α-Syn seeds from different pathologically relevant brain regions (medulla, substantia nigra, hippocampus, middle temporal gyrus, and cerebellum). The conformational profiles of disease- and region-specific α-Syn proteoforms were determined by subjecting the amplified reaction products to concentration-dependent proteolytic digestion with proteinase K.</p><p><strong>Results: </strong>Using our protocol, PD and MSA could be accurately delineated using proteoform-specific aggregation kinetics, including α-Syn aggregation rate, maximum relative fluorescence, the gradient of amplification, and core protofilament size. MSA cases yielded significantly higher values than PD cases across all four kinetic parameters in brain tissues, with the MSA-cerebellar phenotype having higher maximum relative fluorescence than the MSA-Parkinsonian phenotype. Statistical significance was maintained when the data were analysed regionally and when all regions were grouped.</p><p><strong>Conclusions: </strong>Our RT-QuIC protocol and analysis pipeline can distinguish between PD and MSA, and between MSA phenotypes. MSA α-Syn seeds induce faster propagation and exhibit higher aggregation kinetics than PD α-Syn, mirroring the biological differences observed in brain tissue. With further validation of these quantitative parameters, we propose that SAAs could advance from a yes/no diagnostic to a theranostic biomarker that could be utilised in developing therapeutics.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"7"},"PeriodicalIF":10.8,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11804046/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371222","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":"Second-generation anti-amyloid monoclonal antibodies for Alzheimer's disease: current landscape and future perspectives.","authors":"Byeong-Hyeon Kim, Sujin Kim, Yunkwon Nam, Yong Ho Park, Seong Min Shin, Minho Moon","doi":"10.1186/s40035-025-00465-w","DOIUrl":"10.1186/s40035-025-00465-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most common type of dementia. Monoclonal antibodies (MABs) serve as a promising therapeutic approach for AD by selectively targeting key pathogenic factors, such as amyloid-β (Aβ) peptide, tau protein, and neuroinflammation. Specifically, based on their efficacy in removing Aβ plaques from the brains of patients with AD, the U.S. Food and Drug Administration has approved three anti-amyloid MABs, aducanumab (Aduhelm®), lecanemab (Leqembi®), and donanemab (Kisunla™). Notably, lecanemab received traditional approval after demonstrating clinical benefit, supporting the Aβ cascade hypothesis. These MABs targeting Aβ are categorized based on their affinity to diverse conformational features of Aβ, including monomer, fibril, protofibril, and plaque forms of Aβ as well as pyroglutamate Aβ. First-generation MABs targeting the non-toxic monomeric Aβ, such as solanezumab, bapineuzumab, and crenezumab, failed to demonstrate clinical benefit for AD in clinical trials. In contrast, second-generation MABs, including aducanumab, lecanemab, donanemab, and gantenerumab directed against pathogenic Aβ species and aggregates have shown that reducing Aβ deposition can be an effective strategy to slow cognitive impairment in AD. In this review, we provide a comprehensive overview of the current status, mechanisms, outcomes, and limitations of second-generation MABs for the clinical treatment of AD. Moreover, we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"6"},"PeriodicalIF":10.8,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11771116/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143047804","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":"Correction: Inflammasomes in neurodegenerative diseases.","authors":"Qianchen Wang, Songwei Yang, Xuan Zhang, Shanshan Zhang, Liping Chen, Wanxue Wang, Naihong Chen, Jiaqing Yan","doi":"10.1186/s40035-025-00468-7","DOIUrl":"10.1186/s40035-025-00468-7","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"5"},"PeriodicalIF":10.8,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11755795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143029705","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":"Application of antisense oligonucleotide drugs in amyotrophic lateral sclerosis and Huntington's disease.","authors":"Kaili Ou, Qingqing Jia, Dandan Li, Shihua Li, Xiao-Jiang Li, Peng Yin","doi":"10.1186/s40035-025-00466-9","DOIUrl":"10.1186/s40035-025-00466-9","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD) are diverse in clinical presentation and are caused by complex and multiple factors, including genetic mutations and environmental factors. Numerous therapeutic approaches have been developed based on the genetic causes and potential mechanisms of ALS and HD. Currently, available treatments for various neurodegenerative diseases can alleviate symptoms but do not provide a definitive cure. Gene therapy, which aims to modify or express specific proteins for neuroprotection or correction, is considered a powerful tool in managing neurodegenerative conditions. To date, antisense oligonucleotide (ASO) drugs targeting the pathological genes associated with ALS and HD have shown promising results in numerous animal studies and several clinical trials. This review provides a comprehensive overview of the development, mechanisms of action, limitations, and clinical applications of ASO drugs in neurodegenerative diseases, with a specific focus on ALS and HD therapeutic strategies.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"4"},"PeriodicalIF":10.8,"publicationDate":"2025-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11748355/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012281","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}