Translational Neurodegeneration最新文献

{"title":"Immunosenescence in aging and neurodegenerative diseases: evidence, key hallmarks, and therapeutic implications.","authors":"Zhichun Chen, Zixu Mao, Weiting Tang, Yuxuan Shi, Jun Liu, Yong You","doi":"10.1186/s40035-025-00517-1","DOIUrl":"10.1186/s40035-025-00517-1","url":null,"abstract":"<p><p>Aging is a multifaceted biological process affecting various organ systems. Immunosenescence, a key feature of aging, markedly increases susceptibility to infections, cancers, autoimmune diseases, and also neurodegenerative disorders. Immunosenescence not only accelerates normal aging but also drives the progression of neurodegenerative diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD). However, the lack of a consensus on the mechanistic hallmarks of immunosenescence presents a major barrier to the development and validation of anti-aging therapies. In this review, we propose 11 hallmarks of immunosenescence: genomic instability, telomere attrition, epigenetic dysregulation, stem cell exhaustion, loss of proteostasis, deregulated nutrient-sensing, mitochondrial dysfunction, cellular senescence, chronic inflammation, altered intercellular communication, and microbiome dysbiosis. We also elucidate the intricate interplay between immunosenescence and both normal brain aging and neurodegenerative pathologies, highlighting the pivotal involvement of age-related immune dysregulation in the pathogenesis of neurodegenerative disorders. This mechanistic connection is particularly evident in prototypical neurodegenerative conditions such as AD and PD, where immunosenescence appears to significantly contribute to disease progression and phenotypic manifestations. Given that the ultimate goal of immune aging research is to prevent or alleviate age-related diseases, we also discuss potential hallmark-targeting anti-immunosenescence strategies to delay or even reverse normal aging and neurodegeneration.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"60"},"PeriodicalIF":19.1,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12659517/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145640340","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":"Neurotrophic factor-α1/carboxypeptidase E regulates critical protein networks to rescue neurodegeneration, defective synaptogenesis and impaired autophagy in Alzheimer's disease mice.","authors":"Lan Xiao, Pranav Sharma, Xuyu Yang, Daniel Abebe, Y Peng Loh","doi":"10.1186/s40035-025-00520-6","DOIUrl":"10.1186/s40035-025-00520-6","url":null,"abstract":"<p><strong>Background: </strong>The global aging population is increasingly inflicted with Alzheimer's disease (AD), but a cure is still unavailable. Neurotrophic factor-α1/carboxypeptidase E (NF-α1/CPE) gene therapy has been shown to prevent and reverse memory loss and pathology in AD mouse models. However, the mechanisms of action of NF-α1/CPE are not fully understood. We investigated if a non-enzymatic form of NF-α1/CPE-E342Q is efficient in reversing AD pathology and carried out a proteomic study to uncover the mechanisms of action of NF-α1/CPE in AD mice.</p><p><strong>Methods: </strong>AAV-human NF-α1/CPE or a non-enzymatic form, NF-α1/CPE-E342Q, was delivered into the hippocampus of 3 × Tg-AD male mice. The effects on cognitive function, neurodegeneration, synaptogenesis and autophagy were investigated. A quantitative proteomic analysis of the hippocampus was carried out.</p><p><strong>Results: </strong>Hippocampal delivery of AAV-NF-α1/CPE-E342Q prevented memory loss, neurodegeneration and microglial activation in 3 × Tg-AD mice, indicating that the action is independent of its enzymatic activity. Quantitative proteomic analysis of the hippocampus of 3 × Tg-AD mice revealed differential expression of > 2000 proteins involving many metabolic pathways after NF-α1/CPE gene therapy. Of these, two new proteins, Snx4 and Trim28, which increase Aβ production and tau levels, respectively, were down-regulated by NF-α1/CPE. Western blot analysis verified their reduction in AAV-NF-α1/CPE-treated 3 × Tg-AD mice compared to untreated mice. Our proteomic analysis indicated synaptic organization as the top signaling pathway altered in response to CPE expression. Synaptic markers PSD95 and Synapsin1 were decreased in 3 × Tg-AD mice and were restored with AAV-NF-α1/CPE treatment. Proteomic analysis hypothesized involvement of autophagic signaling pathway. Indeed, multiple protein markers of autophagy were down-regulated in 3 × Tg-AD mice, accounting for impaired autophagy. NF-α1/CPE gene therapy upregulated the levels of these proteins in 3 × Tg-AD mice, thereby reversing autophagic impairment.</p><p><strong>Conclusions: </strong>This study uncovered vast actions of NF-α1/CPE in restoring expression of networks of critical proteins including those necessary for maintaining neuronal survival, synaptogenesis and autophagy, while down-regulating many proteins that promote tau and Aβ accumulation to reverse memory loss and AD pathology in 3 × Tg-AD mice. AAV-NF-α1/CPE gene therapy uniquely targets many metabolic levels, offering a promising holistic approach for AD treatment (Graphical Abstract).</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"59"},"PeriodicalIF":19.1,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12648813/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145606199","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":"Attenuating α-synuclein pathology in mice with in situ engineered astrocytes.","authors":"Xiao-Yu Du, Jing Zhou, Jie Zhu, Lun Zhang, Shuai Lu, Shi-Yu Liang, Fang Cui, Hao-Han Zhang, Fei Chen, Ming-Yue Jiao, Ya-Ru Huang, Xiao-Lin Yu, Rui-Tian Liu","doi":"10.1186/s40035-025-00518-0","DOIUrl":"10.1186/s40035-025-00518-0","url":null,"abstract":"<p><strong>Background: </strong>α-Synuclein oligomers (α-synOs) contribute to the initiation and progression of Parkinson's disease (PD) by promoting neuronal death and activating glial cells. Clearing α-synOs while maintaining tissue homeostasis is a promising therapeutic strategy for PD.</p><p><strong>Methods: </strong>We genetically engineered astrocytes with an anti-α-synO chimeric antigen receptor (CAR) consisting of a single-chain variable fragment targeting α-synOs and a truncated MerTK receptor, to direct their phagocytic activity against α-synOs.</p><p><strong>Results: </strong>CAR-engineered astrocytes (CAR-A) showed significantly enhanced phagocytosis of α-synOs due to effective activation of Rac1, Cdc42 and RhoA and markedly decreased the release of pro-inflammatory cytokines by inhibiting the NF-κB and cytokine receptor signaling pathways. Consistently, in situ CAR-A significantly ameliorated the motor and cognitive deficits of A53T mice by clearing α-synOs, creating a non-inflammatory microenvironment and restoring the viability of dopaminergic neurons.</p><p><strong>Conclusions: </strong>CAR-A-based strategy is an effective treatment for PD-like mouse model. This in situ CAR-A technology provides an innovative and feasible strategy to treat PD and other brain disorders.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"58"},"PeriodicalIF":15.2,"publicationDate":"2025-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12632020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145557871","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":"Transplantation of hiPSC-derived pericytes rescues Alzheimer's disease phenotypes in APOE4/4 mice through IGF2-rich apoptotic vesicles.","authors":"Chuanfeng Xiong, Yao Tang, Junhua Chen, Mingming Fan, Lan Wei, Zhaoran Dong, Xingqiang Lai, Xuejiao Men, Qiumin Chen, Dairui Li, Wenjin Ye, Yuanchen Ma, Xiaoyong Chen, Weijun Huang, Zhengqi Lu, Hong Chen, Yunfeng Shen, Yanming Chen, Andy Peng Xiang, Weiqiang Li","doi":"10.1186/s40035-025-00512-6","DOIUrl":"10.1186/s40035-025-00512-6","url":null,"abstract":"<p><strong>Background: </strong>Effective therapies for Alzheimer's disease (AD) remain to be developed. APOE4 is the strongest genetic risk factor for late-onset AD. Pericyte degeneration and blood-brain barrier (BBB) disruption are thought to be early biomarkers of AD and contribute to cognitive decline in APOE4 carriers, representing potential therapeutic targets. Our previous studies have shown that pericyte transplantation is one of the most effective strategies for BBB restoration, exhibiting great therapeutic potential for APOE4-related BBB damage and AD phenotypes.</p><p><strong>Methods: </strong>APOE4/4 mice were treated with pericytes derived from APOE3/3 human induced pluripotent stem cells (hiPSCs). Behavioral tests, AD pathologies, and BBB integrity were assessed. Subsequently, temporal and spatial distribution of the transplanted pericytes was analyzed using tdTomato⁺ lentivirus labeling. Next, therapeutic effects of apoptotic vesicles (ApoVs) generated from APOE3/3 pericytes were evaluated in APOE4/4 pericytes in vitro. Additionally, transcriptomic and proteomic profiling were performed to identify key effector molecules in pericyte-derived ApoVs. Finally, the therapeutic effects of ApoVs derived from pericytes were evaluated in APOE4/4 mice.</p><p><strong>Results: </strong>Early, multiple transplantations of pericytes derived from APOE3/3 hiPSCs robustly rescued cognitive decline and AD pathologies, restored BBB integrity, and prevented in situ pericyte degeneration in aged APOE4/4 mice. Intriguingly, ApoVs released from the infused cells, rather than the transplanted pericytes, were predominantly distributed in the brain, which were ingested by in situ APOE4/4 pericytes and then promoted functional recovery. We further characterized insulin growth factor-2 (IGF-2) as a key factor in APOE3/3 pericyte-derived ApoVs. Infusion of the in vitro generated ApoVs from APOE3/3 pericytes demonstrated distinct therapeutic effects in APOE4/4 mice, which were reversed by IGF2 knockout.</p><p><strong>Conclusions: </strong>APOE3/3 pericytes or APOE3/3 pericyte-derived IGF2-rich ApoVs may offer promising therapeutic strategies for APOE4-associated AD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"57"},"PeriodicalIF":15.2,"publicationDate":"2025-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12613509/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145507264","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":"Harnessing cervical lymphatic mechanics to enhance amyloid clearance: a paradigm shift in Alzheimer's therapeutics?","authors":"Wei Wang, Junhui Lv, Zihao Xu, Shuxu Yang, Jin Wang, Weidong Le","doi":"10.1186/s40035-025-00521-5","DOIUrl":"10.1186/s40035-025-00521-5","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"56"},"PeriodicalIF":15.2,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12590745/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145453190","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":"Roles of TREM2 in Alzheimer's disease.","authors":"Xiaoshan Qi, Kedong Zhu, Wei Ke, Junjie Wang, Shanping Mao, Guiqin Chen","doi":"10.1186/s40035-025-00515-3","DOIUrl":"10.1186/s40035-025-00515-3","url":null,"abstract":"<p><p>Variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene have been demonstrated to increase the risk of late-onset Alzheimer's disease (AD) and Nasu-Hakola disease. As a type I transmembrane receptor, TREM2 is predominantly expressed in microglia within the central nervous system. Extensive research over the past decade has consistently established the critical role of TREM2 in AD pathogenesis, encompassing its regulation of microglial inflammatory responses, amyloid-β deposition, and tau pathology. Notably, the soluble TREM2 fragment (sTREM2) is emerging as a promising candidate biomarker for clinical progression of AD, as evidenced by human studies. Despite these advances, the precise roles of membrane-bound TREM2 and sTREM2 in AD pathogenesis remain incompletely elucidated. Novel mouse models and technological innovations have enabled therapeutic approaches targeting TREM2 for neuroprotection. This review summarizes this progress and highlights areas for future research towards the development of TREM2-directed therapeutics.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"55"},"PeriodicalIF":15.2,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12577446/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145409690","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":"Shared burden of ultra-rare genetic variants across a spectrum of motor neuron diseases.","authors":"Gang Wu, Wenan Chen, Joanne Wuu, Angita Jain, Jason Myers, Isabell Cordts, Evadnie Rampersaud, Jeannine M Heckmann, Melissa Nel, Volkan Granit, Jeffrey Statland, Andrea Swenson, John Ravits, Corey T McMillan, Lauren Elman, James Caress, Ted M Burns, Erik P Pioro, Jaya Trivedi, Jonathan Katz, Carlayne Jackson, Samuel Maiser, David Walk, Yuen So, Jacob L McCauley, Matthew C Baker, J Paul Taylor, Stephan Zuchner, Rosa Rademakers, Marka van Blitterswijk, Michael Benatar","doi":"10.1186/s40035-025-00516-2","DOIUrl":"10.1186/s40035-025-00516-2","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"54"},"PeriodicalIF":19.1,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12570777/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145393363","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":"SIK2-mediated phosphorylation of GABARAPL2 facilitates autophagosome-lysosome fusion and rescues neurodegeneration in an Alzheimer's disease model.","authors":"Xiaoman Dai, Ziling Ye, Chen Wang, Yufei Huang, Yun Chen, Tianqing Han, Weijie Gao, Xin Wu, Jing Zhang, Xiaochun Chen","doi":"10.1186/s40035-025-00514-4","DOIUrl":"10.1186/s40035-025-00514-4","url":null,"abstract":"<p><strong>Background: </strong>Defective autophagic flux is implicated in Alzheimer's disease (AD), but the molecular mechanisms underlying this process are not fully understood. Salt-inducible kinase 2 (SIK2) is associated with autophagic function. However, its specific involvement in autophagic flux regulation and AD pathogenesis remains unclear.</p><p><strong>Methods: </strong>We evaluated hippocampal SIK2 expression and its age-related changes in postmortem AD patients and 5 × FAD mice by bioinformatics analysis, immunofluorescence, qPCR, and Western blotting. To investigate the functional role of SIK2, we employed adeno-associated virus-mediated SIK2 knockdown and overexpression in combination with behavioral tests (Morris water maze), electrophysiological recordings (long-term potentiation, LTP), and ultrastructural analysis (electron microscopy) to evaluate cognitive function and synaptic plasticity. Autophagic flux was measured using LC3B/p62 turnover assays, mRFP-GFP-LC3 tandem fluorescence assay, and transmission electron microscopy. Mechanistic insights were gained through co-immunoprecipitation assay, GST-pull down assay, phosphoproteomics, and site-directed mutagenesis. Additionally, phosphorylation-mimetic (S72E) and non-phosphorylatable (S72A) mutants of GABA type A receptor-associated protein-like 2 (GABARAPL2) were intrahippocampally delivered to 5 × FAD mice to explore their effects.</p><p><strong>Results: </strong>Our study identified SIK2 as a critical regulator that is progressively downregulated in hippocampal neurons of AD patients and 5 × FAD mice, correlating with spatial memory deficits. Reducing SIK2 levels exacerbates cognitive impairment and amyloid-β (Aβ) plaque burden in mice, whereas restoring SIK2 levels mitigates these deficits, restores LTP amplitude, reverses synaptic ultrastructural pathology, and reduces Aβ deposition. Mechanistically, SIK2 enhances autophagic flux by phosphorylating GABARAPL2 at Ser72, a modification essential for autophagosome-lysosome fusion. Remarkably, hippocampal delivery of the phosphorylation-mimetic GABARAPL2-S72E mutant replicated the beneficial effects of SIK2, alleviating Aβ pathology and synaptic dysfunction in 5 × FAD mice. In contrast, the non-phosphorylatable S72A mutant failed to show any protective effects.</p><p><strong>Conclusions: </strong>These findings establish the SIK2-GABARAPL2 axis as a novel signaling cascade governing autophagic flux through lysosomal fusion competence. Dysfunction in this axis contributes to Aβ deposition in AD, offering new insights into the pathogenic mechanisms underlying autophagosome-lysosome fusion in AD and highlighting its potential as a therapeutic target.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"53"},"PeriodicalIF":15.2,"publicationDate":"2025-10-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12548284/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145347408","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":"Disease-disease interactions: molecular links of neurodegenerative diseases with cancer, viral infections, and type 2 diabetes.","authors":"Yuxi Lin, Je Min Yoo, Yan Li, Yunseok Heo, Masaki Okumura, Hyung-Sik Won, Michele Vendruscolo, Mi Hee Lim, Young-Ho Lee","doi":"10.1186/s40035-025-00507-3","DOIUrl":"10.1186/s40035-025-00507-3","url":null,"abstract":"<p><p>Neurodegenerative disorders, notably Alzheimer's and Parkinson's diseases, are unified by progressive neuronal loss and aberrant protein aggregation. Growing evidence indicates that these conditions are linked to cancer, infectious diseases, and type 2 diabetes through convergent molecular processes. In this review, we examine the mechanistic foundations of these links, focusing on shared features such as protein misfolding and aggregation, chronic inflammation, and dysregulated signalling pathways. We integrate cellular, animal, and human data to illustrate how pathogenic proteins may influence one another through cross-seeding and co-aggregation, and assess the implications of such interactions for disease susceptibility, progression, and treatment response. Understanding these underlying mechanisms may provide a conceptual framework for developing therapeutic approaches that target the molecular basis of multiple complex disorders.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"52"},"PeriodicalIF":15.2,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12532377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145309254","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":"Beyond amyloid: nanobody-mediated neuroinflammatory therapy for Alzheimer's disease.","authors":"Soukaina Amniouel, Jessica Suh, Wei Zheng, Qi Zhang","doi":"10.1186/s40035-025-00513-5","DOIUrl":"10.1186/s40035-025-00513-5","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is one of the most common and devastating neurodegenerative diseases, characterized by accumulation of amyloid-beta (Aβ) plaques, neurofibrillary tangles of tau protein, and persistence of neuroinflammation, leading to progressive cognitive decline, loss of independence, emotional and financial strain on families, and significant societal costs. Current anti-amyloid treatments are partly successful in removing Aβ amyloid, but often lead to increased inflammation. This leads to limited therapeutic efficacy and causes side effects such as amyloid-related imaging abnormalities. In addition, they do not address neuroinflammation in AD patients. In this review, we discuss a new therapeutic strategy that combines single-domain antibodies (sdAbs, nanobodies) against Aβ fibrils and anti-inflammatory drugs and applies them to the regions of neuroinflammation associated with the plaques in AD patients. This strategy aims to control the function of activated microglia and astrocytes, thereby avoiding unnecessary immunosuppression. We also discuss the unique features of sdAbs, including small size, good tissue penetration, and lack of Fc-mediated immune reactions, as well as relevant payloads (i.e., small molecules, biologics, and nanoparticles) and delivery systems. This immunomodulatory therapy targets the plaques specifically and therefore represents a promising opportunity to improve amyloid clearance and target the inflammatory components of AD, potentially improving the therapeutic efficacy of the disease.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"51"},"PeriodicalIF":15.2,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12516901/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145287125","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}