Molecular Neurodegeneration最新文献

{"title":"Mitochondria transfer in neurological disorders: the key role of neuroglia.","authors":"Jie Jiao, Hui Chen, Alexei Verkhratsky, Yixun Su, Chenju Yi","doi":"10.1186/s13024-026-00953-1","DOIUrl":"10.1186/s13024-026-00953-1","url":null,"abstract":"<p><p>Mitochondria transfer has emerged as a distinctive mechanism for intercellular communication and neuronal homeostasis. Neurones, owing to their unique bioenergetic demands, are particularly vulnerable to mitochondrial dysfunction, a shared pathogenetic feature across many neurological conditions, including neurodegenerative disorders, cerebrovascular diseases, and brain injuries. Intercellular transfer of mitochondria represents a potential adaptive mechanism rectifying compromised mitochondrial function. Neuroglial cells, especially astrocytes and microglia, frequently act as mitochondrial donors, supplying functional mitochondria to stressed neurones to restore bioenergetic capacity and influence disease trajectories. However, mitochondria transfer is intrinsically context dependent and can exert opposing effects. In addition to providing metabolic support, damaged mitochondria may also be transferred, propagating pathological signals, and exacerbating tissue injury. Moreover, in advanced disease states, mitochondrial malfunction often affects all cell types in the nervous system, including neuroglia, limiting the availability of healthy endogenous mitochondrial donors. This review critically examines mitochondria transfer in neurological diseases, with a focus on glial contribution and underlying mechanisms, and outlines key challenges and opportunities for advancing both mechanistic understanding and therapeutic translation.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13371259/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147988378","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":"Phospho-ubiquitin: rewriting the ubiquitin code.","authors":"Tauseef R Butt","doi":"10.1186/s13024-026-00947-z","DOIUrl":"10.1186/s13024-026-00947-z","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13480194/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147982561","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":"Pharmacological restoration of impaired autophagy in retinal ganglion cells prevents abnormal mitochondrial accumulation and glaucomatous neurodegeneration.","authors":"Prabhavathi Maddineni, Balasankara Reddy Kaipa, Bindu Kodati, Karthikeyan Kesavan, Linya Li, J Cameron Millar, Sam Yacoub, Ramesh B Kasetti, Abbot F Clark, Gulab S Zode","doi":"10.1186/s13024-026-00950-4","DOIUrl":"10.1186/s13024-026-00950-4","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Progressive loss of retinal ganglion cells (RGCs) and degeneration of optic nerve (ON) axons are the key pathological hallmarks of glaucoma, the leading cause of irreversible blindness. Elevated intraocular pressure (IOP), primarily due to dysfunction of the trabecular meshwork (TM), remains the most significant and only known modifiable risk factor. However, vision loss persists in some patients despite effective IOP control, highlighting the critical need to elucidate the mechanisms driving glaucomatous neurodegeneration. Emerging evidence links mitochondrial dysfunction to glaucomatous neurodegeneration, yet the precise mechanisms remain poorly defined. Here, we investigate whether defective autophagy/mitophagy, which removes damaged mitochondria, contributes to mitochondrial accumulation, oxidative stress, and neurodegeneration in glaucoma. We further explore the therapeutic potential of enhancing autophagy to improve mitochondrial turnover, mitigate RGC loss, and preserve visual function.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;Glucocorticoid (GC)-induced and myocilin (MYOC)-associated glaucoma mouse models were used to assess the expression of mitochondrial markers (TOM20/COX IV), oxidative DNA damage (8-OHdG), and mitophagy/autophagy-related proteins (p62, LC3, Phospho-ubiquitin (Ser65), and LAMP1) in retinal tissues. Transmission electron microscopy (TEM) was employed to analyze mitochondrial accumulation in glaucomatous ON. Mitophagy flux was assessed at early and late stages of neurodegeneration using mitophagy reporter Mt-Keima mice. The effect of RGC-specific autophagy deficiency on mitochondrial accumulation and neurodegeneration was further investigated using Atg5&lt;sup&gt;flox/flox&lt;/sup&gt; mice, in which Atg5 deletion was induced by AAV2-Cre delivery. Additionally, the therapeutic effect of enhancing autophagy with Torin 2 to restore mitochondrial turnover and prevent glaucomatous neurodegeneration was evaluated in both GC-induced and myocilin-associated glaucoma models, as well as in ex vivo human retinal explants.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;Chronic IOP elevation led to increased mitochondrial accumulation, oxidative DNA damage, and impaired mitophagy/autophagy in glaucomatous retina. TEM analysis further confirmed the accumulation of structurally abnormal mitochondria in glaucomatous ON. In Mt-Keima mice, chronic IOP elevation significantly reduced mitophagy flux prior to RGC loss, indicating that mitophagy impairment precedes neurodegeneration. RGC-specific Atg5 deletion induced the accumulation of damaged mitochondria, leading to neurodegeneration in Atg5 &lt;sup&gt;flox/flox&lt;/sup&gt; mice. Notably, pharmacological restoration of impaired autophagy with Torin 2 prevented mitochondrial accumulation and preserved the structural and functional integrity of RGCs and their axons in glaucoma mouse models and ex vivo human retinal explant cultures.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;Our study indicates impaired autophagy ","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13242679/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147959998","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":"TDP-43: [GU]-ardian of the transcriptome.","authors":"Irika R Sinha, Abigail L Atkinson, Katherine E Irwin, Jonathan P Ling, Philip C Wong","doi":"10.1186/s13024-026-00944-2","DOIUrl":"10.1186/s13024-026-00944-2","url":null,"abstract":"<p><p>TDP-43 is a ubiquitously expressed, primarily nuclear DNA/RNA-binding protein implicated in neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and Alzheimer's disease (AD). In this review, we examine the structure and regulation of TDP-43, how these features influence its localization and functional activity, and how their disruption may contribute to disease. Among TDP-43's diverse functions, splicing repression of nonconserved RNA sequences termed cryptic exons has emerged as especially central to human disease. TDP-43 nuclear depletion and cytoplasmic aggregation are well-established pathological features in affected neurons and glia of neurodegenerative diseases, and accumulating evidence suggests that loss of TDP-43-mediated splicing repression occurs presymptomatically in disease. Advances in RNA-sequencing have enabled systematic identification of cryptic exon inclusion as a sensitive marker of TDP-43 dysfunction. Here, we synthesize current knowledge of TDP-43 biology and curate datasets from human tissues and experimental models, focusing on cryptic splicing to provide a resource for leveraging cryptic exon biology to better understand, detect, and target TDP-43 dysfunction.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13343711/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147942187","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":"LRRK2 and GBA1 in Lewy body diseases: neuropathological subtypes at opposite ends of a spectrum?","authors":"Vedika Jha,Lorraine V Kalia","doi":"10.1186/s13024-026-00939-z","DOIUrl":"https://doi.org/10.1186/s13024-026-00939-z","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"91 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-04-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147753250","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":"Plasma proteomic signatures of preclinical Alzheimer's disease in clinically unimpaired older adults.","authors":"Alexandra N Trelle,Karly A Cody,Tran T Nguyen,Joseph R Winer,Skylar Weiss,Isha Sai,Tyler Ward,Gloria Cheng,Divya Channappa,Justin Mendiola,Amal Al-Rajhi,Keerthana Raghuraman,Sharon J Sha,Edward N Wilson,Tony Wyss-Coray,Holden T Maecker,Anthony D Wagner,Elizabeth C Mormino","doi":"10.1186/s13024-026-00941-5","DOIUrl":"https://doi.org/10.1186/s13024-026-00941-5","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"4 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147739061","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":"Obesity-driven phosphatidylethanolamine dysregulation impairs neuroimmune crosstalk and accelerates Alzheimer's pathogenesis.","authors":"Li Yang,Jianting Sheng,Shaohua Qi,Zheng Yin,Michael Chan,Yuliang Cao,Hong Zhao,Zhihao Wan,Bill Chan,Ju Young Ahn,Xiaohui Yu,Matthew Vasquez,Shan Xu,Xianlin Han,Weiming Xia,Willa A Hsueh,Stephen T C Wong","doi":"10.1186/s13024-026-00943-3","DOIUrl":"https://doi.org/10.1186/s13024-026-00943-3","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147684814","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":"Regional diffusion imaging measures to disentangle SVD-related hypertensive arteriopathy versus cerebral amyloid angiopathy.","authors":"Sheelakumari Raghavan, Scott A Przybelski, Robel K Gebre, Audrey Low, Mingzhao Hu, Robert I Reid, B Gwen Windham, Heather J Wiste, Angela J Fought, Michael G Kamykowski, Aivi T Nguyen, Melissa E Murray, Val J Lowe, Clifford R Jr Jack, Ronald C Petersen, Jonathan Graff-Radford, Prashanthi Vemuri","doi":"10.1186/s13024-026-00942-4","DOIUrl":"10.1186/s13024-026-00942-4","url":null,"abstract":"<p><p>BACKGROUND: Detecting and distinguishing early changes due to the two key subtypes of cerebral small vessel disease (SVD), hypertensive arteriopathy (HA) and cerebral amyloid angiopathy (CAA), has significant clinical implications. Our goal was to develop and validate dMRI signatures associated with HA-SVD and CAA-SVD proxies and assess their clinical utility using Alzheimer’s disease and SVD biomarkers, pathology, and cognition. METHODS: Two independent cohorts with baseline dMRI scans, T2* gradient-echo MRI, and vascular risk measures were analyzed: Mayo Clinic Study of Aging (MCSA, N = 1080) and Alzheimer’s Disease Neuroimaging Initiative (ADNI, N = 549). In MCSA, regional dMRI measures associated with proxies of HA-SVD (hypertension) and CAA-SVD (lobar cerebral microbleeds) were identified using logistic regression models. The top regional features were then used to compute composite dMRI indices for HA-SVD and CAA-SVD. These dMRI indices were validated in ADNI and in an independent pathology sample of MCSA (N = 147). In MCSA, we also computed standard global SVD indices from diffusion and FLAIR MRI and compared them with dMRI indices to reflect SVD subtypes. Next, we evaluated the association of these indices with cognitive performance (global, attention, and memory) using regression models, after adjusting demographics, white matter hyperintensities (WMH) and amyloid. RESULTS: Hypertension was associated with reduced microstructural integrity predominantly in fronto-parieto-projection pathways, whereas lobar microbleeds were associated with occipito-parietal damage. These differential tract association patterns with HA-SVD and CAA-SVD proxies were less pronounced in ADNI. In the community-dwelling MCSA cohort with higher prevalence of vascular disease, dMRI indices provided more differentiated associations with both proxies of SVD than global SVD indices, underscoring added value for etiology-specific identification. As expected, CAA-SVD indices were more strongly associated with occipital WMH and amyloid burden and were linked to CAA pathology scores. CAA-SVD indices also had greater association with memory performance, independent of amyloid and WMH. Conversely, HA-SVD indices were robustly associated with post-mortem Kalaria scales and attention scores. CONCLUSIONS: Using three datasets, (population-based sample, independent cohort, pathology sample), we found that regional dMRI signatures can capture distinct SVD processes of HA and CAA. These dMRI signatures offer potential for early differential identification of SVD subtypes and can aid in guiding clinical decision making and prevention. </p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13185335/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147675180","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":"PLCG2 signaling and genetic resilience in Alzheimer's disease.","authors":"Andy P Tsai,Amara K Martin,Andrew Mi,Ava E Yeh,Eduardo Ramirez Lopez,Tony Wyss-Coray","doi":"10.1186/s13024-026-00935-3","DOIUrl":"https://doi.org/10.1186/s13024-026-00935-3","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"58 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-03-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147518438","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":"Molecular characterization of humanized APOE mouse models reveals source and genotype dependent differences.","authors":"Na Wang, Gefei Yu, Zhen Wang, Alla Alnobani, Suren Jeevaratnam, Xue Zhang, Meghan McReynolds, Yuzhou Chang, Fangfang Qi, William Tauer, Cassandra Rosenberg, Melissa Wren, Tadafumi C Ikezu, Yuka A Martens, Minghui Wang, Bin Zhang, Gregory W Carter, Michael Sasner, David M Holtzman, Junmin Peng, Long-Jun Wu, Takahisa Kanekiyo, Chia-Chen Liu, Guojun Bu","doi":"10.1186/s13024-026-00940-6","DOIUrl":"10.1186/s13024-026-00940-6","url":null,"abstract":"<p><p>BACKGROUND: Humanized APOE targeted-replacement (TR) mice are essential tools for studying apoE isoform effects in Alzheimer’s disease (AD) and other apoE-related disorders. Despite their widespread use, existing APOE mouse models, generated with different gene targeting strategies, have not been directly compared in terms of apoE isoform expression, lipid profiles, and transcriptomic signatures. Such differences could impact how we interpret APOE genotype-related outcomes, as well as related underlying molecular mechanisms. METHODS: We conducted a comprehensive molecular comparison of humanized APOE mouse models from three sources: Taconic Biosciences (TAC), the Cure Alzheimer’s Fund (CAF), and The Jackson Laboratory (JAX). We assessed apoE protein and transcript levels, peripheral plasma lipid composition, and bulk brain transcriptomics. ApoE isoform levels were evaluated by biochemical and proteomic measurements. Peripheral lipids, including low-density lipoprotein (LDL), high-density lipoprotein (HDL), cholesterol, and triglycerides, were also measured. We employed complementary bioinformatics analyses to evaluate brain transcriptomes and identify differentially expressed genes (DEGs) and networks based on source, APOE genotype, and sex. RESULTS: We found that apoE isoforms exhibited differential levels among the three sources in the brain, liver, and plasma. Peripheral lipoproteins and lipids, including LDL, HDL, cholesterol, and triglycerides, also showed distinct concentrations in each source and genotype. Importantly, we identified distinct brain transcriptional signatures among these mouse models, which were influenced by source, APOE genotype, and sex. Finally, our analysis revealed specific differentially expressed genes and pathways impacted by source, genotype, and sex. CONCLUSIONS: Our findings highlight APOE genotype- and source-dependent variations in apoE isoform levels, lipid profiles, and molecular pathways. This study underscores the importance of consistency and caution in choosing and utilizing humanized APOE mouse models, offering molecular insights into key apoE-related outcomes.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13185305/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147513496","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}