Molecular Therapy最新文献

Exploring the therapeutic potential of human iPSC-NPC-based therapy in MPS IIIA 探索基于人ipsc - npc治疗MPS IIIA的治疗潜力

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-10-21 DOI: 10.1016/j.ymthe.2026.10.006

Emma Schindhelm,Troy C. Lund

引用次数: 0

Targeting the bad neighbors: Precision nanotherapy for the adipose stromal niche 靶向坏邻居：脂肪基质生态位的精确纳米疗法

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-10-21 DOI: 10.1016/j.ymthe.2026.10.004

Daniel Gallego-Perez,Kristin I. Stanford

引用次数: 0

IL-12-producing iPSC-derived antigen-presenting cells enhance antitumor immunity and enable off-the-shelf immunotherapy. 产生il -12的ipsc衍生抗原提呈细胞增强抗肿瘤免疫，使现成的免疫治疗成为可能。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-16 DOI: 10.1016/j.ymthe.2026.10.017

Masateru Yamamoto, Rong Zhang, Tsuyoshi Kobayashi, Yilan Li, Huaigeng Xu, Hiroaki Mashima, Keigo Saito, Masahiro Kariya, Masamichi Ide, Yuichiro Hagiya, Eri Fukuda, Sena Uemura, Yuki Osako, Ryo Nakaki, Tetsuya Nakatsura, Satoshi Fukushima, Shin Kaneko, Akitsu Hotta, Hideki Ohdan, Yasushi Uemura

{"title":"IL-12-producing iPSC-derived antigen-presenting cells enhance antitumor immunity and enable off-the-shelf immunotherapy.","authors":"Masateru Yamamoto, Rong Zhang, Tsuyoshi Kobayashi, Yilan Li, Huaigeng Xu, Hiroaki Mashima, Keigo Saito, Masahiro Kariya, Masamichi Ide, Yuichiro Hagiya, Eri Fukuda, Sena Uemura, Yuki Osako, Ryo Nakaki, Tetsuya Nakatsura, Satoshi Fukushima, Shin Kaneko, Akitsu Hotta, Hideki Ohdan, Yasushi Uemura","doi":"10.1016/j.ymthe.2026.10.017","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.10.017","url":null,"abstract":"Effective activation of cancer-reactive T cells by antigen-presenting cells (APCs) is essential for tumor elimination. However, dendritic cell (DC)-based cancer vaccines often yield inconsistent clinical outcomes due to patient-dependent variability. We established IL-12-producing proliferative myeloid cells (IL12-pMCs) from mouse induced pluripotent stem cells (iPSCs) as a standardized APC platform. These cells stably secrete IL-12, express costimulatory molecules, and enhance the priming and expansion of antigen-specific CD8+ T cells, while also activating NK cells. Upon tumor antigen loading and in vivo administration, IL12-pMCs induced robust IFN-related gene signatures in tumors, promoted infiltration of effector cells, suppressed immunosuppressive populations, and showed potent antitumor efficacy, with further enhancement when combined with immune checkpoint inhibitors (ICIs). For clinical application, we generated human IL12-pMCs from iPSCs with selective HLA expression to enable antigen-specific CD8+ T cell priming while minimizing alloreactivity. This system offers a potent, off-the-shelf APC platform for next-generation cancer immunotherapy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207377","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}

引用次数: 0

Lentiviral gene therapy corrects the metabolic and immune abnormalities in purine nucleoside phosphorylase-deficient mice. 慢病毒基因疗法纠正嘌呤核苷磷酸化酶缺陷小鼠的代谢和免疫异常。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-16 DOI: 10.1016/j.ymthe.2026.10.015

Robyn Loves, Matilde Leon-Ponte, Arundhati G Nair, Lorand Cimpean, Angitha Mriduraj, Weixin Min, Philipp John-Neek, Michael Rothe, Axel Schambach, Santhosh Dhanraj, Chetankumar S Tailor, Eyal Grunebaum

{"title":"Lentiviral gene therapy corrects the metabolic and immune abnormalities in purine nucleoside phosphorylase-deficient mice.","authors":"Robyn Loves, Matilde Leon-Ponte, Arundhati G Nair, Lorand Cimpean, Angitha Mriduraj, Weixin Min, Philipp John-Neek, Michael Rothe, Axel Schambach, Santhosh Dhanraj, Chetankumar S Tailor, Eyal Grunebaum","doi":"10.1016/j.ymthe.2026.10.015","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.10.015","url":null,"abstract":"Purine nucleoside phosphorylase (PNP) deficiency impairs purine metabolism leading to severe T cell defects, which can be corrected by allogeneic hematopoietic stem cell (HSC) transplant, however the associated complications are significant. Therefore, autologous gene therapy is an attractive alternative treatment option. Here, we present a third-generation self-inactivating lentiviral vector expressing the human PNP gene under the control of the elongation factor-1 alpha short promoter (LVV-EFS-PNP), which was delivered ex vivo to HSCs and was tested for its ability to correct the abnormalities in PNP-deficient (Pnp-/-) mice. The LVV-EFS-PNP vector demonstrated effective gene transfer, without jeopardizing hematopoietic colony formation in vitro. In vivo, Pnp-/- mice transplanted with Pnp-/- lineage-negative cells transduced with LVV-EFS-PNP achieved sustained correction of the immune and metabolic abnormalities, including restoration of thymocyte development, T cell proliferation, and T cell-dependent and independent antibody responses. Importantly, genotoxicity assessments demonstrated that LVV-EFS-PNP had a low transformation potential and did not significantly dysregulate gene expression signature linked to vector-induced transformation, similar to other clinically used lentiviruses. These results demonstrate the safety and efficacy of gene therapy using LVV-EFS-PNP in a pre-clinical model of PNP deficiency, providing evidence for a promising new treatment strategy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207342","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}

引用次数: 0

The allogeneic eDN70(-) CAR-T Cells Without TCR or MHC Editing Exhibit Enhanced Persistence and Function. 未经TCR或MHC编辑的同种异体eDN70(-) CAR-T细胞表现出增强的持久性和功能。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-16 DOI: 10.1016/j.ymthe.2026.10.016

Wuling Li, Yanmin Xu, Zhi Yang, Juanjuan Shan, Huailong Xu, Huiyu Chen, Junjie Shen, Cheng Qian, Wenwei Yin

{"title":"The allogeneic eDN70(-) CAR-T Cells Without TCR or MHC Editing Exhibit Enhanced Persistence and Function.","authors":"Wuling Li, Yanmin Xu, Zhi Yang, Juanjuan Shan, Huailong Xu, Huiyu Chen, Junjie Shen, Cheng Qian, Wenwei Yin","doi":"10.1016/j.ymthe.2026.10.016","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.10.016","url":null,"abstract":"Allogeneic CAR-T therapy offers an \"off-the-shelf\" alternative to autologous CAR-T, but faces graft-versus-host rejection (GVH) and host-versus-graft rejection (HVG). Conventional TCR/MHC elimination compromises persistence and increase NK susceptibility. Here, we developed a next-generation UCAR-T strategy that avoids TCR/MHC disruption while addressing donor-cell alloreactivity and host-mediated rejection. First, we eliminated CD4/CD8 to reduce alloreactivity while preserving TCR integrity and potentially TCR/CD3-mediated fitness, although in vivo xGvHD protection remains to be determined. In parallel, we identified CD70 as a marker selectively upregulated on alloreactive immune cells, enabling targeted removal of HVG-driving subsets. Because CD70 is also induced during T-cell activation and further enhanced following CD4/CD8 knockout, we additionally deleted CD70 to prevent fratricide, generating a CD4/CD8/CD70 triple-negative UCAR-T backbone (eDN70(-) UCAR-T). As proof-of-concept, we incorporated both CD19- and CD70-targeting CARs to generate eDN70(-)19/70CAR-T cells, which showed superior expansion, reduced exhaustion, and greater resistance to HVG pressure. Furthermore, these cells demonstrated durable tumor control and robust recall responses in vivo, with preliminary tissue-level safety from the high-dose study. Collectively, our findings establish eDN70(-) UCAR-T cells as a versatile platform capable of overcoming the persistence limitations of current allogeneic CAR-T therapies, with the CD19/CD70 dual-target configuration serving as a representative implementation of this strategy.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207415","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}

引用次数: 0

Beyond Excitotoxicity: Glutamate-Independent Mechanisms Underlie Noise-Induced Synaptopathy and Compromise Gene Therapy for Hereditary Deafness. 超越兴奋毒性：遗传耳聋的噪音诱导突触病变和妥协基因治疗的谷氨酸独立机制。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-16 DOI: 10.1016/j.ymthe.2026.10.018

Changyun Yu, Hongen Xu, Ling Tong, Weijun Zhou, Mengli Zhang, Haiyan Zhou, Jinming Yin, Jiali Wang, Jingjie Han, Ying Cao, Jiake Zhao, Yueyu Wen, Wenxue Tang, Shuangshuang Lu, Liang Wang, Xingle Zhao

{"title":"Beyond Excitotoxicity: Glutamate-Independent Mechanisms Underlie Noise-Induced Synaptopathy and Compromise Gene Therapy for Hereditary Deafness.","authors":"Changyun Yu, Hongen Xu, Ling Tong, Weijun Zhou, Mengli Zhang, Haiyan Zhou, Jinming Yin, Jiali Wang, Jingjie Han, Ying Cao, Jiake Zhao, Yueyu Wen, Wenxue Tang, Shuangshuang Lu, Liang Wang, Xingle Zhao","doi":"10.1016/j.ymthe.2026.10.018","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.10.018","url":null,"abstract":"Noise-induced hearing loss (NIHL) is classically attributed to glutamate excitotoxicity, yet the precise requirement for synaptic glutamate release remains untested using genetic approaches. Here, we investigated noise-induced cochlear damage using Vglut3 knockout (Vglut3-KO) mice, which lack glutamatergic transmission from inner hair cells. Following 116 dB SPL noise exposure, wild-type (WT) mice exhibited permanent threshold shifts, persistent ABR wave I amplitude reduction, and significant loss of both ribbon synapses and outer hair cells (OHC) in the basal turn. Unexpectedly, Vglut3-KO mice also exhibited significant synapse loss despite their inability to release glutamate, revealing glutamate-independent mechanisms of synaptopathy. Proteomic analysis of noise-exposed cochleae identified 62 differentially expressed proteins enriched in synaptic and extracellular matrix pathways, including upregulation of Rps6ka1, Cplx2, and Cdk5, and downregulation of Ppa2. Comparative profiling of Vglut3-KO mice further revealed 233 differentially expressed proteins, with widespread downregulation of synaptic, mitochondrial, and ECM pathways. Importantly, noise exposure severely compromised AAV8-Vglut3 gene therapy efficacy in Vglut3-KO mice: while unexposed mutants achieved complete functional recovery, noise-exposed animals failed to attain normal hearing thresholds, with VGLUT3 expression restored across all cochlear turns as confirmed by immunofluorescence. These findings demonstrate that high-intensity noise induces synaptopathy through both excitotoxic and non-excitotoxic mechanisms involving synaptic and ECM disruption, and that acoustic trauma creates persistent OHC loss limiting gene therapy outcomes, underscoring the need for comprehensive otoprotective strategies in hereditary deafness patients awaiting treatment.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207350","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}

引用次数: 0

A natural compound derivative targeting HADHA disrupts mitochondrial homeostasis and suppresses renal cell carcinoma. 针对HADHA的天然化合物衍生物破坏线粒体稳态并抑制肾细胞癌。

IF 11.4 1区医学

Molecular Therapy Pub Date : 2026-10-16 DOI: 10.1016/j.ymthe.2026.10.014

Ara Jo, Sanjeevram Dhandapani, Ziqin Wang, Hyeryeon Jung, Hongjun Jang, Morgan A Bailey, Andrew Tran, Brandon Tsai, Jinjae Park, Hyejin Lee, Hye-Jin Park, Yoojin Lim, Dolce Feenaghty, Victor M Moncada, Damu Wu, Keaton Chien, Nancy Chen, Yunsol Jo, Jiazheng Miao, Zhujun Yao, Jihoon Lee, Karthigayan Shanmugasundaram, Gang Greg Wang, Andrew Armstrong, Daniel George, David Howell, Jiaoti Huang, Michael C Fitzgerald, Jiyong Hong, Jung Wook Park

{"title":"A natural compound derivative targeting HADHA disrupts mitochondrial homeostasis and suppresses renal cell carcinoma.","authors":"Ara Jo, Sanjeevram Dhandapani, Ziqin Wang, Hyeryeon Jung, Hongjun Jang, Morgan A Bailey, Andrew Tran, Brandon Tsai, Jinjae Park, Hyejin Lee, Hye-Jin Park, Yoojin Lim, Dolce Feenaghty, Victor M Moncada, Damu Wu, Keaton Chien, Nancy Chen, Yunsol Jo, Jiazheng Miao, Zhujun Yao, Jihoon Lee, Karthigayan Shanmugasundaram, Gang Greg Wang, Andrew Armstrong, Daniel George, David Howell, Jiaoti Huang, Michael C Fitzgerald, Jiyong Hong, Jung Wook Park","doi":"10.1016/j.ymthe.2026.10.014","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.10.014","url":null,"abstract":"Metastatic renal cell carcinoma (RCC) remains a lethal malignancy, and therapeutic resistance to current targeted and immune-based therapies highlights the need for new treatment strategies. Here, we identify C18-epi-brasilibactin A (CBA) as a selective inhibitor of RCC. High-throughput screening of a compound library derived from natural-products revealed that CBA potently suppresses RCC cell proliferation while sparing normal renal epithelial and liver cells. Mechanistically, CBA induces cell-cycle arrest, apoptosis, and DNA damage. Transcriptomic and functional analyses showed that CBA disrupts mitochondrial homeostasis by increasing mitochondrial mass and reactive oxygen species, indicating metabolic stress. Using proteomic approaches, we identified hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha (HADHA), a key enzyme in mitochondrial fatty acid β-oxidation, as a key functional mediator of CBA. Genetic depletion of HADHA phenocopied CBA effects, inducing ROS accumulation, DNA damage response, apoptosis, and growth inhibition in RCC cells. CBA treatment significantly suppressed RCC xenograft growth without systemic toxicity. Consistently, HADHA knockdown inhibited tumor progression, whereas HADHA overexpression enhanced tumor growth, supporting a tumor-supportive role for HADHA in RCC. Together, our findings identify HADHA-dependent mitochondrial metabolism as a functional vulnerability in RCC and establish CBA as a candidate therapeutic agent for targeting metabolic dependencies in metastatic renal cell carcinoma.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2026-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149207327","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}

引用次数: 0

Reprogramming immunosuppressive TMEs with Salmonella-delivered sialidase and COX-2 blockade synergistically enhances cancer immunotherapy 用沙门氏菌传递唾液酸酶和COX-2阻断剂重编程免疫抑制TMEs协同增强癌症免疫治疗

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-10-15 DOI: 10.1016/j.ymthe.2026.08.036

Yongjie Zhu,Ming Cheng,Jinling Liu,Mengqi Xiong,Jun Lan,Kang Han,Shengen Yi,Sheng-Nan Jiang,Wenzhi Tan,Jin Hai Zheng

{"title":"Reprogramming immunosuppressive TMEs with Salmonella-delivered sialidase and COX-2 blockade synergistically enhances cancer immunotherapy","authors":"Yongjie Zhu,Ming Cheng,Jinling Liu,Mengqi Xiong,Jun Lan,Kang Han,Shengen Yi,Sheng-Nan Jiang,Wenzhi Tan,Jin Hai Zheng","doi":"10.1016/j.ymthe.2026.08.036","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.08.036","url":null,"abstract":"Sialic acid is a component of the extracellular matrix that is upregulated in multiple tumors and plays critical roles in tumorigenesis and progression. Sialic acid engages sialic acid-binding immunoglobulin-like lectins (Siglecs) on immune cells to suppress immune activation. Despite the potential of sialylation-targeted therapies to reactivate antitumor immunity, their clinical translation remains limited by suboptimal drug delivery systems and insufficient tumor specificity. To overcome these obstacles, we engineered a sialidase-expressing S. typhimurium and termed it SLpnanH. The engineered avirulent bacteria can express and secrete sialidase in situ upon L-arabinose induction. In highly immunosuppressive tumor microenvironments, SLpnanH manifests very specific tumor-targeting capabilities and expresses sialidase at high levels. This study demonstrates that engineered SLpnanH significantly mitigates the tumor immunosuppressive microenvironment and inhibits tumor growth with markedly elongated animal survival compared with control groups. Furthermore, treatment with SLpnanH promotes the infiltration and activation of CD8+ T cells and dendritic cells (DCs) in the tumor-draining lymph nodes. When combined with a selective cyclooxygenase-2 (COX-2) inhibitor, the therapeutic efficacy of SLpnanH was further enhanced. Collectively, these findings underscore SLpnanH as a promising candidate for cancer immunotherapy, with its antitumor efficacy significantly augmented by the adjunctive application of an FDA-approved COX-2 inhibitor.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"68 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149173051","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}

引用次数: 0

Retraction Notice to: Recurrent ZNF83-E293VMutationPromotesBladder Cancer Progression through the NF-κB Pathway via Transcriptional Dysregulation of S100A8 复发性znf83 - e293v突变通过NF-κB途径通过S100A8转录失调促进膀胱癌进展

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-10-15 DOI: 10.1016/j.ymthe.2026.10.013

Zhao J. Lyu,Ying Wang,Jin L. Huang,Miao Chen,Sha Y. Wu,Qian Yan,Yu Zhang,Ying Tang,Chen Jiang,Lei Li,Yi Z. Jia,Yu C. Liu,Hong B. Mei,Feng Wang,Ren H. Li,Ya C. Chen,Xiang Lin,Zhi M. Cai,Xin Y. Guan

引用次数: 0

miR-124 delivery to the hippocampus reduces excitability, enhances neurogenesis and affects microglia in a model of Alzheimer’s disease 在阿尔茨海默病模型中，向海马体递送miR-124可降低兴奋性，增强神经发生并影响小胶质细胞

IF 12.4 1区医学

Molecular Therapy Pub Date : 2026-10-12 DOI: 10.1016/j.ymthe.2026.10.001

Oliver Polzer,Léa Salette,Mae van Wijhe,Talya Levi Siva,Aleksandra Tsonkova,Ayinde Swildens,Rosa E. Randoe,Dilara Ayyildiz,Pascal Chameau,Paul J. Lucassen,Evgenia Salta,Carlos P. Fitzsimons

{"title":"miR-124 delivery to the hippocampus reduces excitability, enhances neurogenesis and affects microglia in a model of Alzheimer’s disease","authors":"Oliver Polzer,Léa Salette,Mae van Wijhe,Talya Levi Siva,Aleksandra Tsonkova,Ayinde Swildens,Rosa E. Randoe,Dilara Ayyildiz,Pascal Chameau,Paul J. Lucassen,Evgenia Salta,Carlos P. Fitzsimons","doi":"10.1016/j.ymthe.2026.10.001","DOIUrl":"https://doi.org/10.1016/j.ymthe.2026.10.001","url":null,"abstract":"MicroRNA-124 (miR-124) has been proposed as therapeutic candidate for Alzheimer's disease (AD), given its regulation of gene networks governing synaptic function, neurogenesis and inflammation. However, its functional role during early disease stages, and the cellular context-dependence of its effects, remain unclear. Here, we investigated the effects of targeted neuronal miR-124 delivery to the hippocampal dentate gyrus (DG) of AppNL-G-F mice. At an earlier ‘presymptomatic’ stage, miR-124 reduced intrinsic excitability of mature granule neurons and induced subtle changes in dendritic architecture. Integrative transcriptomic analyses revealed that predicted miR-124 targets were enriched among downregulated genes involved in synapse organization and cell junction assembly. At the same time, miR-124 increased the number of immature neurons and microglia, indicating structural and functional remodeling of the DG. At a later ‘symptomatic’ disease stage, where AD pathology is established, neuronal miR-124 supplementation reduced DG Aβ40 and Aβ42 levels and decreased local amyloid plaque burden, while also altering the plaque-associated microglial response. Together, these findings identify neuronal miR-124 as a context- and disease-stage-dependent regulator of the DG microenvironment and demonstrate effects extending from neuronal function to other cellular populations and local AD-associated pathology.","PeriodicalId":19020,"journal":{"name":"Molecular Therapy","volume":"38 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2026-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149151815","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}

引用次数: 0