Translational Neurodegeneration最新文献

{"title":"Cholesterol nose-to-brain delivery as a possible therapeutic strategy in Huntington's disease.","authors":"Monica Favagrossa, Alice Passoni, Marta Valenza, Daria Di Prisco, Giulia Birolini, Michela Villa, Andrea Scolz, Laura Pasetto, Valentina Bonetto, Chiara Zuccato, Caterina Mariotti, Renzo Bagnati, Elena Cattaneo, Laura Colombo, Mario Salmona","doi":"10.1186/s40035-026-00569-x","DOIUrl":"10.1186/s40035-026-00569-x","url":null,"abstract":"<p><strong>Background: </strong>Huntington's disease (HD) is a genetically dominant neurodegenerative disorder characterized by several pathological mechanisms, including the disruption of brain cholesterol homeostasis. In several HD animal models, brain cholesterol biosynthesis and levels are reduced. Since circulating cholesterol cannot reach the brain, providing exogenous cholesterol has been shown to improve HD phenotypes. However, the methods used for cholesterol delivery were invasive and not easily transferable to clinical practice.</p><p><strong>Methods: </strong>Cholesterol-enriched liposomes were developed by using freeze-and-thaw methods and were administered to R6/2 mice through a single or repeated intranasal administrations. Deuterated-cholesterol was used to discriminate exogenous from endogenous cholesterol. Exogenous cholesterol accumulation and distribution, as well as the levels of cholesterol precursors and metabolites, were measured using mass spectrometry. Behavioral tests, real-time PCR analysis, and immunostaining of mutant HTT (muHTT) aggregates were performed to verify the therapeutic effects of liposomes. Plasma neurofilament levels were measured by Simoa-Quanterix assay.</p><p><strong>Results: </strong>We developed and characterized freeze-and-thaw liposomes. Then, we demonstrate that the exogenous cholesterol can spread throughout the entire brain following intranasal administration of cholesterol-enriched liposomes. Furthermore, repeated intranasal treatments with liposomes result in a full restoration of cognitive decline, and delayed the onset of coordination and motor impairment as well as the loss of muscular strength in the early stages of the disease. Cholesterol supplementation also reduced the plasma level of neurofilament light chain and promoted the clearance of muHTT aggregates.</p><p><strong>Conclusions: </strong>The findings support the effectiveness of cholesterol supplementation as a therapeutic strategy for HD and indicate the translational potential of nose-to-brain cholesterol delivery.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13435458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148674032","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":"Brain insulin resistance as a driver of proteinopathy in neurodegeneration: from cell-type-specific mechanisms to targeted therapeutics.","authors":"Man Xiang, Si-Yu Cao, Xue-Heng Sun, Jing-Wen Hu, Ming-Zhe Lv, Jia-Yi Li, Wen Li","doi":"10.1186/s40035-026-00573-1","DOIUrl":"10.1186/s40035-026-00573-1","url":null,"abstract":"<p><p>Neurodegenerative diseases are increasingly linked to systemic metabolic dysfunction, with brain insulin resistance (BIR) positioned as a central mediator. Yet translating this insight into effective therapies has proven remarkably difficult. This review argues that BIR-driven neurodegeneration should be interpreted at two distinct but interconnected levels: cell-type-specific disruption of brain homeostasis by BIR, and the direct, mechanistic role of BIR in driving the proteinopathies that define Alzheimer's and Parkinson's diseases. We first show how BIR produces distinct functional deficits across neurons, astrocytes, microglia, and oligodendrocytes, impairing synaptic plasticity, metabolic coupling, immunometabolic homeostasis, and myelination, resulting in a cellular milieu that favors proteinopathy. We then map molecular pathways through which BIR directly distrubs the metabolism of amyloid-β, tau, and α-synuclein. We further examine how islet amyloid polypeptide cross-seeds cerebral amyloid pathology, suggesting a direct molecular interaction between the peripheral drivers of BIR and protein aggregation. In this framework, BIR functions not as a passive risk factor, but as an active, upstream driver of proteostatic collapse. Cellular dysfunction combined with proteostatic failure, defines the therapeutic target space. We evaluate interventions accordingly, distinguishing those that primarily restore cellular function from those that enhance protein clearance, and those that achieve both. For each strategy, we assess the translational evidence, critically appraising the barriers that have limited their clinical success, including patient heterogeneity, narrow therapeutic windows, and inadequate central nervous system delivery. By integrating cell-type-specific biology with proteostatic mechanisms and a clinically oriented therapeutic framework, this review aims to provide a foundation for multi-target strategies that address the BIR-neurodegeneration axis at its mechanistic roots.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-08-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13430798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148670251","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":"Transaldolase 1 contributes to pentose phosphate pathway disruption and synaptic dysfunction in Alzheimer's disease.","authors":"Xiaoyu Hu, Ying Yu, Haorui Luo, Jiabing Li, Xiaofei Zhang, Gang Wang, Jianping Li, Juan Li, Hongzhuan Chen, Yu Qiu","doi":"10.1186/s40035-026-00567-z","DOIUrl":"10.1186/s40035-026-00567-z","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline and synaptic dysfunction. Increasing evidence suggests that impaired glucose utilization is a major contributor to AD pathogenesis. Neurons preferentially use glucose through the pentose phosphate pathway (PPP). In AD, the flux through the PPP is significantly reduced; however, the underlying mechanism is still elusive. This study was aimed to elucidate how PPP was affected in AD and its contribution to the AD pathogenesis.</p><p><strong>Methods: </strong>Proteomic analyses of temporal cortex synaptosomes from AD patients and controls were conducted to identify dysregulated pathways and significantly affected proteins. Functional analysis was performed by knockdown or restoration of protein expression in primary cultured neurons, as well as in wild-type and 5 × FAD mice. Pseudotargeted metabolomics and biochemical, molecular, electrophysiological and behavioral assessments were performed to evaluate metabolic characteristics, redox status, mitochondrial function, synaptic plasticity and cognition.</p><p><strong>Results: </strong>Proteomic analysis of synaptic compartments identified glucose metabolism as the most significantly dysregulated functional network in AD. Further, transaldolase 1 (TALDO1), a rate-limiting enzyme in the PPP, was identified as a key enzyme affected in AD. TALDO1 was markedly downregulated at the early stage of AD. Downregulation of TALDO1 reduced glucose metabolism by inhibiting the PPP, TCA cycle and oxidative phosphorylation, causing broad metabolic collapse. Further, downregulation of TALDO1 depleted the nicotinamide adenine dinucleotide phosphate and glutathione pools, weakening antioxidant defense, thus resulting in mitochondria impairment and reduced energy supply. These collectively drive synaptic dysfunction and cognitive decline. Conversely, restoring TALDO1 expression in 5 × FAD mice improved glucose uptake, mitigated oxidative stress, restored metabolic homeostasis, and rescued neuronal and cognitive functions.</p><p><strong>Conclusion: </strong>These findings identify TALDO1 as a key regulator of the impaired PPP in AD and may represent a promising therapeutic target for restoring neuronal metabolic homeostasis and function.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13418138/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148621476","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":"Neuroinflammation in Alzheimer's and Parkinson's diseases: pathogenic mechanisms and therapeutic strategies.","authors":"Qin-Qin Wang, Qing-Qing Sun, Yong-Shun Guo, Shu Yin, Jia-Wei Zhou","doi":"10.1186/s40035-026-00571-3","DOIUrl":"10.1186/s40035-026-00571-3","url":null,"abstract":"<p><p>Neuroinflammation is increasingly recognized as a key contributor and amplifier associated with the pathogenesis of Alzheimer's disease (AD) and Parkinson's disease (PD). Neuroinflammation occurs throughout various stages of these diseases with expanding complexity. Currently, no effective therapies exist that specifically target neuroinflammatory processes in these disorders. In this review, we synthesize current understanding of central and peripheral inflammatory mechanisms implicated in both diseases. We illustrate how endogenous pathological triggers, such as amyloid-β (Aβ) peptide, hyperphosphorylated tau, and α-synuclein, activate glial cells, contributing to chronic neuroinflammation that exacerbates neurodegeneration. Additionally, peripheral factors, including systemic inflammation, environmental exposures, and gut-brain axis interactions, are discussed for their roles in modulating neuroinflammatory responses. Notably, the underappreciated roles of oligodendrocyte precursor cells and oligodendrocytes in neuroimmune crosstalk are also highlighted. Advanced methodologies, including glial cell imaging, single-cell transcriptomics, and human induced pluripotent stem cell-derived organoid models, are providing unprecedented insights into the molecular and cellular mechanisms underlying neuroinflammation. Finally, we evaluate emerging therapeutic strategies and ongoing clinical trials targeting neuroinflammatory pathways and analyze the potential of immunomodulatory approaches to slow disease progression. This comprehensive review emphasizes that precise targeting of neuroinflammation represents a tractable strategy for developing effective disease‑modifying treatments for AD and PD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13417865/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148607845","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 the Allen Human Brain Atlas in Alzheimer's disease and Parkinson's disease.","authors":"Yi Xiao, Shichan Wang, Yanbing Hou, Huifang Shang","doi":"10.1186/s40035-026-00566-0","DOIUrl":"10.1186/s40035-026-00566-0","url":null,"abstract":"<p><p>Alzheimer's disease (AD) and Parkinson's disease (PD) are the two most common age-related neurodegenerative disorders. Allen Human Brain Atlas (AHBA) provides high-resolution transcriptomic data across 102 brain regions with multi-site sampling from healthy controls, promoting the use of brain-wide transcriptomic data for imaging transcriptomics and cross-modal model construction. Increasingly, researchers are utilizing brain-wide transcriptomic datasets to investigate the transcriptome correlates of the neuroimage phenotypes in AD and PD. Leveraging the AHBA, researchers have analyzed the transcriptomic correlations of regional susceptibility to Aβ deposition, tau deposition, α-synuclein propagation, and disease-related multiple-dominal neuroimage phenotypes. These studies revealed that transcriptomic pathways related to metabolism, immunity, neurotransmission, and synaptic function play critical roles in the neuroimage phenotype of AD and PD. By incorporating transcriptomic data modeling, subsequent analyses further confirmed that transcriptomic differences provide the molecular basis for the varying susceptibility observed across brain regions. The analytical approaches of imaging transcriptomics, multimodal data integration strategies, and model construction methods used in AD and PD provide a novel perspective for exploration and can be extended to other neurodegenerative diseases. Future research is expected to utilize brain-wide transcriptomic data to uncover the gene expression mechanisms driving neurodegenerative disease phenotypes.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148580196","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":"Functional analysis of late-onset Alzheimer's disease risk genes in Caenorhabditis elegans identifies regulators of neuronal aging.","authors":"Swapnil G Waghmare, Meera M Krishna, Emily C Maccoux, Ariel L Franitza, Brian A Link, Lezi E","doi":"10.1186/s40035-026-00564-2","DOIUrl":"10.1186/s40035-026-00564-2","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13393840/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148563066","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":"Protein kinase CK2α' as a dual modulator of neuroimmune signaling and synaptic dysfunction in tauopathy.","authors":"Angel White, Peter Gavrilyuk, Persephone Gu, Rafael Falcon-Moya, Reid Thurston, Amal Fickak, Nicholas B Rozema, Prarthana Keshavaram, Scott Vermilyea, Riley Schlichte, Joyce Meints, Ying Zhang, Alfonso Araque, Michael K Lee, Rocio Gomez-Pastor","doi":"10.1186/s40035-026-00563-3","DOIUrl":"10.1186/s40035-026-00563-3","url":null,"abstract":"<p><strong>Background: </strong>Tauopathies are a group of neurodegenerative diseases characterized by tau accumulation, neuroinflammation, and synaptic dysfunction, yet effective treatments remain elusive. Protein kinase CK2 is a holoenzyme composed of two regulatory (CK2β) and two catalytic subunits (CK2α and CK2α') and has been linked to multiple aspects of tau pathology. However, genetic evidence defining the specific contributions of CK2 subunits to tau phosphorylation and tauopathy remains lacking. Elucidating subunit-specific roles is critical for the rational development of CK2-targeted therapies.</p><p><strong>Methods: </strong>To investigate the impact of CK2 in tauopathy, Neuro-2a and primary cell cultures expressing mutant tau were treated with siRNAs targeting the two catalytic subunits of CK2, CK2α and CK2α'. In addition, the PS19 mouse model of tauopathy was bred to be haploinsufficient for the catalytic subunit CK2α'. Changes in pathology and symptomatology were analyzed via immunohistochemistry, immunoblotting, RNA-sequencing, in situ hybridization, electrophysiology, and Barnes Maze.</p><p><strong>Results: </strong>We found that the expression of the catalytic subunit CK2α', but not catalytic CK2α or regulatory CK2β subunits, was elevated in postmortem brains of dementia patients and in the hippocampus of PS19 tauopathy mice, especially in neurons and microglia. Using a haploinsufficient model of CK2α' in PS19 mice, we demonstrated that the PS19:CK2α'^(+/-) mice had significantly decreased phosphorylated tau and total tau burden in the hippocampus and cortex. CK2α' depletion also attenuated microglial activation, pro-inflammatory cytokine production and microglia synaptic engulfment, and enhanced synaptic gene expression, synaptic density, and long-term potentiation. Importantly, CK2α' haploinsufficiency rescued cognitive deficits assessed in the Barnes maze.</p><p><strong>Conclusions: </strong>Here, we show CK2α', one of the two catalytic subunits of CK2, as a novel regulator of tau-mediated neurodegeneration. These effects appear to be mediated through both neuronal and glial functions and may involve CK2α'-dependent modulation of tau phosphorylation as well as neuroinflammatory and immune signaling pathways. These findings identify CK2α' as a mechanistically defined and potentially druggable target for therapeutic strategies aimed at modifying tau-driven neurodegeneration.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13348822/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148424353","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":"Plant-derived mitochondria mitigate aging-related neurodegeneration by reprogramming microglial mitochondrial energy metabolism.","authors":"Yun Teng, Chao Luo, Qingbo Xu, Jingyao Mu, Lucy Teng, Hongjia Qian, Yinan Huang, Minmin Liu, Lifeng Zhang, Juw Won Park, Jae Yeon Hwang, Maiying Kong, Jun Yan, Michael L Merchant, Huang-Ge Zhang","doi":"10.1186/s40035-026-00565-1","DOIUrl":"10.1186/s40035-026-00565-1","url":null,"abstract":"<p><strong>Background: </strong>Intercellular mitochondrial transfer is pivotal in both healthy and pathological states. Supplementing healthy mitochondria is emerging as a promising therapeutic approach for various diseases. Non-immunogenic edible plants, which contain mitochondria, offer a novel avenue for such therapies.</p><p><strong>Methods: </strong>Mitochondria were isolated from several commonly consumed edible plants (P-Mit) using differential centrifugation followed by sucrose gradient ultracentrifugation. The distribution of P-Mit, particularly in the brain, was examined with a mitochondrial membrane-potential dye and an imaging system. As a proof of concept, the molecular interactions underlying turmeric-derived mitochondria (T-Mit) uptake by microglia were elucidated through affinity precipitation coupled with mass spectrometry. By labeling with gold-nanoparticles in a distinct triangular or spherical shape followed by electron microscopy and energy dispersive spectroscopy analysis, we demonstrated the physical fusion of T-Mit and animal mitochondria in microglia. Mitochondrial functions such as superoxide levels, ATP-linked mitochondrial respiration, glycolysis and electron transport chain activity were assessed to determine the impact of T-Mit on aging-related microglial dysfunction. Next-generation small RNA sequencing revealed the underlying mechanism by which T-Mit-derived small RNAs modulate the expression of NADH dehydrogenase (ND) genes in microglia.</p><p><strong>Results: </strong>Orally administered T-Mit travelled from the gut to the brain in aged male mice, where they fused with microglial mitochondria (M-Mit), reprogramming M-Mit energy metabolism and reversing aging-related cognitive dysfunction. Specifically, T-Mit was taken up by microglia via the phagocytic receptor TREM2. Subsequently, T-Mit fused with M-Mit in a mitofusin 1-dependent manner. The T-Mit microRNAs Tae-miR319 and Osa-miR166a-3p then integrated into M-Mit, inhibiting the expression of complex I subunits ND4 and ND5. This inhibition alleviated reverse electron transport (RET) at complex I, reducing reactive oxygen species (ROS) production and facilitating ATP production, ultimately rescuing aging-related cognitive decline. Data from elderly human subjects also showed overactivation of the RET process and overproduction of ROS, accompanied by low ATP levels in microglia.</p><p><strong>Conclusions: </strong>Our findings fundamentally alter our understanding of the regulation of mammalian mitochondrial biology by P-Mit and may lead to P-Mit-based transfer therapy for preventing or treating human mitochondrial disorder-related diseases.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13343874/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148412877","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":"Lysophagy protects against ANXA11 amyloid fibril toxicity and propagation in FTLD.","authors":"Honglin Zheng, Haiyang Luo, Yongting Lu, Yapei Yuan, Na Zhang, Suying Duan, Zongping Xia, Yuming Xu","doi":"10.1186/s40035-026-00561-5","DOIUrl":"10.1186/s40035-026-00561-5","url":null,"abstract":"<p><strong>Background: </strong>Accumulation of Annexin A11 (ANXA11) aggregates is a distinct pathological hallmark of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). While genetic studies have linked ANXA11 mutations (e.g., D40G) to disease, the precise molecular events converting aggregation into neurotoxicity and intercellular propagation remain elusive. We hypothesize that lysosomal integrity serves as a critical checkpoint in ANXA11 proteinopathy and that its failure drives disease progression.</p><p><strong>Methods: </strong>To model the human pathology of ANXA11, we generated pre-formed fibrils (PFFs) of wild-type and FTLD/ALS-linked D40G mutant ANXA11. Human iPSC-derived neurons, 3D cerebral organoids, and bulk RNA-sequencing were employed to investigate neurotoxicity. High-resolution imaging, lentiviral knockdown, and biochemical assays were performed to delineate the lysosomal damage response and the subsequent \"prion-like\" spreading of aggregates.</p><p><strong>Results: </strong>The internalized ANXA11 fibrils accumulated in lysosomes, triggering lysosomal membrane permeabilization (LMP). The D40G mutation exacerbated this toxicity, leading to severe LMP, mitochondrial depolarization, and specific transcriptional downregulation of the dynactin subunit ACTR10. Mechanistically, we identified a protective signaling axis involving p38 MAPK, MK2, and HSP27 that senses ANXA11-induced lysosomal damage and initiates lysophagy. Notably, in human cerebral organoids, failure of this lysophagic clearance facilitated the cytoplasmic escape of ANXA11, thereby accelerating its seeding activity and propagation to neighboring cells. Pharmacological or genetic modulation of this pathway significantly altered neuronal survival.</p><p><strong>Conclusions: </strong>Our study established lysosomal rupture as a primary driver of ANXA11-associated neurodegeneration and validated the p38/MK2/HSP27 axis as a crucial defense mechanism in human neural tissue. These findings provide a novel mechanistic link between lysosomal quality control and ANXA11 propagation, highlighting that enhancing lysophagic flux represents a promising translational strategy to halt the progression of FTLD and ALS.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13310443/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148340366","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":"Metabolic crosstalk in the ageing brain: astrocyte-neuron coupling as a target for homeostatic restoration and therapy.","authors":"Lihui Qian, Yanting Deng, Meiying Song, Zhouyuan Zhang, Jiawei Cheng, Boran Zhu, Minghua Wu, Haosu Zhang, Yue Hu","doi":"10.1186/s40035-026-00562-4","DOIUrl":"10.1186/s40035-026-00562-4","url":null,"abstract":"<p><p>Astrocytes, the most abundant glial cells in the central nervous system, play increasingly recognized roles in metabolic regulation beyond their classical supportive functions. This review summarizes current understanding of astrocyte morphological and molecular heterogeneity, with emphasis on regional metabolic properties across different brain areas. We discuss the primary forms and functional significance of astrocyte-neuron metabolic coupling, focusing on glucose, lipid, and glutamate metabolism, lactate shuttling, as well as the mitochondrial reactive oxygen species signaling. Furthermore, we integrate emerging evidence from animal and preclinical studies linking astrocyte-neuron metabolic coupling to ageing-related diseases. Collectively, these findings highlight how astrocyte-neuron interactions sustain physiological homeostasis and contribute to pathological manifestations, underscoring their significance in both health and ageing-related diseases.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13285538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148303058","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}