Translational Neurodegeneration最新文献

{"title":"Dysfunction of the neurovascular unit as a temporal driver in Alzheimer's pathogenesis.","authors":"Lifang Wang, Lei Han, Shiping Liu","doi":"10.1186/s40035-026-00548-2","DOIUrl":"10.1186/s40035-026-00548-2","url":null,"abstract":"<p><p>Extensive studies have shown that cerebrovascular dysfunction is a critical factor in the onset and progression of Alzheimer's disease (AD). Neurovascular unit (NVU) is impaired in AD brains, including damage of tight junction between endothelial cells, degeneration of pericytes, activation of astrocytes and microglia, and apoptosis of neurons. As decreased cerebral blood flow is observed before amyloid-beta (Aβ) generation, it is supposed that NVU dysfunction may precede and exacerbate the pathological state of AD neural system, and that the events of NVU dysfunction and Aβ deposition synergistically promote AD progression. Technological breakthroughs of three-dimensional NVU organoids, spatial transcriptomics with single-cell resolution, and development of artificial intelligence technology, such as machine learning and deep learning, offer the possibility of constructing accurate functional structural models. Here we systematically review the NVU dysfunction during AD progression as well as the applications of spatial transcriptomics and organoid technology in NVU studies.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13101311/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147782056","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":"Drug repurposing for disease-modifying effects in multiple system atrophy.","authors":"Seong Ho Jeong, Jin Young Shin, Phil Hyu Lee","doi":"10.1186/s40035-026-00551-7","DOIUrl":"10.1186/s40035-026-00551-7","url":null,"abstract":"<p><p>Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disorder lacking any proven disease-modifying therapy. Drug repurposing offers a strategy to accelerate the development of treatments by utilizing agents originally approved for other indications. This review summarizes repurposed drugs investigated as disease-modifying therapies for MSA, spanning preclinical in vitro and animal studies and clinical trials. We focus on agents targeting key pathogenic mechanisms in MSA-including α-synuclein aggregation (e.g., sirolimus/rapamycin, rifampicin, lithium, nilotinib, epigallocatechin gallate), neuroinflammation (e.g., minocycline, intravenous immunoglobulin), mitochondrial dysfunction and excitotoxicity (e.g., ubiquinol, rasagiline, safinamide, riluzole), and impaired neurotrophic support (e.g., fluoxetine/selective serotonin reuptake inhibitors, insulin, exendin-4). For each, we discuss mechanisms of action, experimental model outcomes, and clinical trial results. While numerous repurposed agents showed promise in MSA models, most failed to demonstrate significant disease-slowing effects in clinical trials. However, ubiquinol has recently emerged as a notable exception, with a Phase 2 randomized controlled trial showing a significant reduction in motor progression compared to placebo-marking the first placebo-controlled evidence of disease modification in MSA. Limitations such as small sample sizes, late-stage patient enrollment, and tolerability issues (e.g., with lithium) have hampered past trials. Nonetheless, ongoing studies and emerging approaches such as combination therapies hold promise. Continued exploration of repurposed therapies, along with improved trial design and biomarker development, is warranted to finally achieve a disease-modifying treatment for MSA.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147730094","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":"NDST3 suppression restores lysosomal acidification and ameliorates amyloid-β and MAPT/tau pathology in Alzheimer's disease.","authors":"Chuanhua Ge, Kun Wang, Huiyuan Tang, Yiling Ke, Huai Wang, Qiang Fu, Yun Xiu, Yongzheng Guo, Yun-Fang Jia, Zhimin Long, Guiqiong He, Qing Tang","doi":"10.1186/s40035-026-00549-1","DOIUrl":"10.1186/s40035-026-00549-1","url":null,"abstract":"<p><strong>Background: </strong>Impairment of lysosomal acidification has recently been identified as a critical driver of amyloid-β and MAPT/tau pathology in Alzheimer's disease (AD). Restoring lysosomal acidification is a promising strategy for AD treatment. N-deacetylase and N-sulfotransferase 3 (NDST3) is a newly discovered tubulin deacetylase that regulates lysosomal acidification by influencing the recruitment of V-ATPase V1 subunits to lysosomes. Nevertheless, the role of NDST3 in AD remains entirely unexplored.</p><p><strong>Methods: </strong>We began by comparing the effects of NDST3 and histone deacetylase 6 (HDAC6), a well-known tubulin deacetylase with established roles in AD, on lysosomal acidification. Using HT22 cell-based models of AD, we knocked down NDST3 to examine its role in lysosomal acidification and degradative function in the context of this disease. We also evaluated the expression profile of NDST3 in both in vitro and in vivo models of AD. Finally, we investigated the consequences of NDST3 suppression on lysosomal acidity and related AD pathological features in the hippocampi of 3 × Tg-AD mice.</p><p><strong>Results: </strong>NDST3 differs from HDAC6 in the subcellular spatial patterns of catalyzing microtubule deacetylation but parallels HDAC6 in regulating lysosomal pH. In HT22 cells with APP695^Swe overexpression, knockdown of NDST3 lowered lysosomal pH by promoting the assembly of the V-ATPase holoenzyme on the lysosomal membrane and enhanced the autophagic degradation of aberrant Aβ and MAPT/tau. Notably, NDST3 levels were found to be elevated in the brains of AD models and patients. Reducing NDST3 expression in the hippocampi of 3 × Tg-AD mice facilitated lysosomal reacidification, which decreased the abnormal accumulation of amyloid plaques and MAPT/tau tangles, mitigated neuronal damage, and ameliorated cognitive deficits.</p><p><strong>Conclusions: </strong>Our study identified NDST3 as a key factor regulating lysosomal acidity in AD. Suppressing NDST3 restores lysosomal function in AD and protects against AD pathology, highlighting NDST3 as a promising therapeutic target for AD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13097816/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147782087","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":"Tau conformation, distribution and PET imaging correlations in progressive supranuclear palsy.","authors":"Chong Dong, Jing-Hong Ma, Hong-Wen Qiao, Gilles D Tamagnan, Piu Chan, Shu-Ying Liu","doi":"10.1186/s40035-026-00545-5","DOIUrl":"10.1186/s40035-026-00545-5","url":null,"abstract":"<p><p>Progressive supranuclear palsy (PSP) is a primary tauopathy characterized by aggregation of pathological tau. Recent advances in cryo-electron microscopy have enabled the classification of tauopathies at near-atomic resolution, revealing disease-specific tau filament conformations. These microstructural differences may influence the intracellular localization, intercellular propagation, and spatial distribution of tau pathology, as well as the microscopic binding profiles and macroscopic imaging signatures of tau positron emission tomography (PET) tracers. This review focuses on PSP by delineating its specific tau architecture and cellular and spatial distributions and how they differ in comparison with other major tauopathies and by critically discussing the clinical utility and limitations of tau PET. Through this integrative perspective, we aim to bridge neuropathological insights with in vivo PET findings.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13015156/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147515072","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":"Deciphering the microenvironment of adult neurogenesis: a perspective from neurodegenerative diseases.","authors":"Zheng-Kai Lao, Nan-Jie Xu","doi":"10.1186/s40035-026-00546-4","DOIUrl":"10.1186/s40035-026-00546-4","url":null,"abstract":"<p><p>Neurodegenerative diseases are characterized by progressive neuron loss and brain atrophy. While conventional studies focused on neuronal death as the primary cause of these diseases, accumulating evidence suggests that impaired neurogenesis, particularly the dysfunction of adult neural stem cells (NSCs), may also contribute significantly to disease pathogenesis. Adult neurogenesis occurs primarily in two adult NSC niches. These specialized niches are enriched with complex cytokine networks, neuronal activity, and non-cellular components such as the extracellular matrix. Understanding the regulation of NSCs in the adult brain and how their dysregulation exacerbates neurodegeneration provides novel insights into therapeutic strategies. This review proposes that dysfunction of the NSC microenvironment, rather than neuronal death alone, may drive neurodegeneration, and that restoring this microenvironment offers a novel research direction of stem cell-based therapies.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13011702/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147515108","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":"Axonopathy: mechanisms and potential therapeutic targets for neurodegenerative diseases.","authors":"Ruinan Shen, Kijung Sung, Jianqing Ding, Chengbiao Wu","doi":"10.1186/s40035-026-00543-7","DOIUrl":"10.1186/s40035-026-00543-7","url":null,"abstract":"<p><p>Axons are unique structural and functional features of nerve cells, which play a critical role in regulating neuronal homeostasis. Dysfunction and degeneration of axons (axonopathy) has been established as an early and prominent contributing mechanism to the pathogenesis of neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis. In this review, we briefly summarize the structure and function of axons, and highlight recent advances in the understanding of the role of axons in health and disease. We argue that axons are a potential target for developing novel therapies for neurodegenerative diseases.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-03-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13011709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147515105","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":"Molecular mechanisms of exercise-induced improvements in Alzheimer's disease: a focus on lipid homeostasis.","authors":"Jianfan Zhou, Xianliang Zhang, Shuting Yin, Shuan Xue, Qiang He, Si Chen, Xiangli Xue","doi":"10.1186/s40035-026-00537-5","DOIUrl":"10.1186/s40035-026-00537-5","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is the most prevalent type of dementia, and its pathophysiological mechanisms involve multiple factors, including genomic factors, metabolomic factors, and environmental factors. Lipid dysregulation occurs both centrally and peripherally in patients with AD, and the severity is closely associated with disease progression. Applied studies based on genome-wide association studies, genomic analyses, lipidomic analyses, mass spectrometry, and machine learning, have identified lipids as a key potential target for early diagnosis and intervention in AD. However, due to the complexity of AD pathogenesis and the considerable structural and functional diversities of lipids, pharmacological therapies that target lipid homeostasis have shown limited effectiveness in ameliorating AD pathology and are often accompanied by side effects. In contrast, exercise, a holistic intervention with multitarget effects, can modulate the levels of multiple lipids simultaneously and slow the progression of AD with minimal side effects. However, the mechanisms require further clarification. This review summarizes alterations and mechanisms of action of lipids-including fatty acids, triglycerides, glycerophospholipids, sphingolipids, and cholesterol-in AD and further outlines the possible molecular mechanisms through which exercise influences AD through modulation of lipid metabolism. We also review the recent clinical research on lipid-targeting drugs for AD, and propose a hypothesis that lipids may act as a mediator of the peripheral-central crosstalk between exercise and AD. Additionally, how different apolipoprotein E genotypes may affect the response to exercise in AD is explored. These insights provide a theoretical basis for nonpharmacological interventions for AD and offer an important reference for the development of lipid-related therapeutic targets.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-03-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13007380/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147499211","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":"Ultrasonic repression of TRPA1-dependent astrocyte reactivity confers neuroprotection in models of Lewy body dementia.","authors":"Ji Hun Kim, Keunhyung Lee, Minseok Koo, Doeun Kim, Jin Kyung Hong, Jeong-Yun Choi, Han Seok Ko, Joo-Ho Shin, Joo Min Park, Jinhyoung Park, Yunjong Lee","doi":"10.1186/s40035-026-00544-6","DOIUrl":"10.1186/s40035-026-00544-6","url":null,"abstract":"<p><strong>Background: </strong>The pathology of Lewy body dementia (LBD) features neuronal α-synuclein (α-syn) accumulation and astrocytic hyperactivation in cognitive brain circuits. Ultra-low-intensity ultrasound (ULIUS) modulates astrocyte function via transient receptor potential ankyrin 1 (TRPA1) and has been investigated for therapeutic applications in neurodegenerative diseases.</p><p><strong>Methods: </strong>The therapeutic efficacy and mechanisms of ULIUS were evaluated in primary cultured astrocytes and neuron-glia cocultures treated with α-syn preformed fibrils (PFFs), as well as in an LBD model induced by hippocampal α-syn PFF injection into neuronal α-syn-A53T transgenic mice. Astrocytic TRPA1 was modulated under pathologic conditions with ULIUS or a pharmacologic TRPA1 antagonist to determine calcium responses and transcriptional regulation of Trpa1 and inflammation-related genes. Neuropathological analyses for Lewy-like inclusions, neurodegeneration, and inflammation were performed in LBD mouse brains, with or without ULIUS. Spatial learning and memory were assessed using the Barnes maze.</p><p><strong>Results: </strong>Repeated transcranial ULIUS application was safe in long-term use and, unlike prolonged stronger ultrasound, did not cause hippocampal inflammation or neurodegeneration. It also prevented neuroinflammation and Lewy-like pathologies, rescuing cognitive impairment in LBD mice. ULIUS abolished α-syn-induced elevation of TRPA1, toll-like receptors-2 (TLR2), interleukin-1β, and tumor necrosis factor-α in LBD mouse brains. Mechanistically, both ULIUS and TRPA1 inhibitor blocked the sustained TRPA1-dependent calcium increase and the expression of inflammation-associated transcripts in α-syn PFF-treated astrocytes.</p><p><strong>Conclusions: </strong>Our findings provide mechanistic insights into the reciprocal TRPA1-TLR2 signaling pathway in α-syn-induced astrocyte pathology and underscore the disease-modifying potential of focused transcranial ULIUSm on astrocytes for the treatment of LBD. This study establishes a novel therapeutic strategy to alleviate neuroinflammation and cognitive decline associated with LBD. The demonstration of its long-term safety further supports ULIUS as a promising therapeutic strategy.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12973804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147435676","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":"Gut-initiated alpha synuclein fibrils drive parkinsonism phenotypes: temporal mapping of REM sleep behavior disorder-like and other non-motor symptoms.","authors":"Daniel Dautan, Wojciech Paslawski, Sergio G Montejo, Daniel C Doyon, Valentina I Brioschi, Roberta Marongiu, Michael G Kaplitt, Rong Chen, Valina L Dawson, Xiaoqun Zhang, Ted M Dawson, Per Svenningsson","doi":"10.1186/s40035-026-00536-6","DOIUrl":"10.1186/s40035-026-00536-6","url":null,"abstract":"<p><strong>Background: </strong>Parkinson's disease (PD) is a progressive neurodegenerative disorder marked by both motor and non-motor symptoms. Although non-motor features such as gastrointestinal and sleep disturbances often precede motor impairments and are critical to PD pathogenesis, the mechanisms underlying their onset and progression remain insufficiently characterized.</p><p><strong>Methods: </strong>To investigate the sequential development of motor and non-motor symptoms in a model of experimental parkinsonism, we injected alpha-synuclein (αSyn) preformed fibrils (PFFs) into the duodenum and antrum of wild-type mice, establishing a gut-brain axis model of PD. We performed whole-brain anatomical mapping of αSyn-PFF propagation and assessed behavioral alterations at multiple time points post-injection. Correlations between anatomical spread and behavioral changes, particularly sleep, were further validated through SNCA overexpression or local αSyn-PFF injections in the substantia nigra, combined with dual-wavelength fiber photometry, behavioral assays, and histological analyses.</p><p><strong>Results: </strong>Injection of αSyn-PFFs into the gastrointestinal tract of wild-type mice led to a progressive spread of pathological αSyn throughout the central nervous system, in temporal association with distinct motor and non-motor phenotypes. These findings provide translational validity of the gut-brain model, mirroring the clinical progression seen in many PD patients. In two established αSyn-based PD models, dual-wavelength fiber photometry that monitors dopamine and acetylcholine release in the striatum, demonstrated a central role for dopamine dysfunction in modulating sleep architecture, particularly in relation to REM sleep without atonia, consistent with REM sleep behavior disorder (RBD)-like manifestations in PD.</p><p><strong>Conclusion: </strong>This work provides a detailed characterization of the progressive and multisystem nature of experimental parkinsonism, highlighting the interplay between αSyn pathology, gut-brain signaling, and the onset of non-motor disturbances, with a particular focus on RBD-like alterations in sleep.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12973632/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147435665","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":"SSEA3 and CD105 positivity are associated with the treatment potency of human neural crest-derived nasal turbinate stem cells for Alzheimer's disease.","authors":"Jung Yeon Lim, Jung Eun Lee, Minho Lee, Haewon Shim, Sang In Park, Soon A Park, Sin-Soo Jeun, Sheng-Min Wang, Sunghwan Kim, Seung Ho Yang, Hyun Kook Lim, Sung Won Kim","doi":"10.1186/s40035-026-00539-3","DOIUrl":"10.1186/s40035-026-00539-3","url":null,"abstract":"<p><strong>Background: </strong>Stem cells have the potential to treat Alzheimer's disease (AD), but clinical outcomes are unpredictable due to inter-donor differences in stem cell properties. This study aimed to determine whether the pluripotency marker SSEA3 and the mesenchymal marker CD105 positivity are associated with the therapeutic efficacy of human neural crest-derived nasal turbinate stem cells (NTSCs) for AD.</p><p><strong>Methods: </strong>The therapeutic effects of NTSCs obtained from different donors, with varying percentages of SSEA3⁺/CD105⁺ cells, were explored in 5 × FAD transgenic AD mice and cerebral organoids derived from induced pluripotent stem cells (iPSC) of three AD patients. Neuropathological changes associated with AD were examined, including expression of beta-amyloid, inflammation, and neuronal survival. Cognitive functions were evaluated by the Morris water maze (MWM) test.</p><p><strong>Results: </strong>NTSCs from different donors improved cognitive function and AD-related neuropathology to varying degrees, depending on the percentage of SSEA3⁺/CD105⁺ cells. Compared with NTSCs with a lower percentage of SSEA3⁺/CD105⁺ cells (NTSCs-L), NTSCs with a higher percentage of SSEA3⁺/CD105⁺ cells (NTSCs-H) showed greater properties in vitro, including proliferative capacity, multilineage differentiation potency, and secretion of neuroprotective cytokines. These properties were comparable to those of pure SSEA3⁺/CD105⁺ cells isolated from NTSCs (NTSCs-SC). Both NTSCs-H and NTSCs-SC improved cognitive function and reduced cerebral Aβ deposition, inflammation, and neuronal death in AD model mice. Furthermore, NTSCs-H and NTSCs-SC decreased Aβ aggregates, tau hyperphosphorylation, neuronal death, microglial numbers, and inflammatory cytokine levels in AD cerebral organoids. However, there was no significant difference in AD-related pathological changes between NTSCs-H and NTSCs-SC treatment groups.</p><p><strong>Conclusions: </strong>Our findings suggest that SSEA3/CD105 positivity is a potential marker of NTSC therapeutic efficacy for the treatment of AD. Future studies should focus on enhancing the therapeutic potential of SSEA3⁺/CD105⁺ NTSCs by improving their functional efficacy and consistency, and advancing their use in clinical settings.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12955099/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147344444","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}