Translational Neurodegeneration最新文献

{"title":"Age-dependent removal of Atg9-containing vesicle accumulations in motoneuron disease models by physical exercise.","authors":"Alexander Veh, Melissa Ewald, Vinicius da Cruz Neris Geßner, Neha Jadhav Giridhar, Amy-Jayne Hutchings, Christian Stigloher, Beyenech Binotti, Katrin Gertrud Heinze, Patrick Lüningschrör","doi":"10.1186/s40035-025-00524-2","DOIUrl":"10.1186/s40035-025-00524-2","url":null,"abstract":"<p><strong>Background: </strong>Atg9-containing vesicles are enriched in synapses and undergo cycles of exo- and endocytosis similarly to synaptic vesicles, thereby linking presynaptic autophagy to neuronal activity. Dysfunction of presynaptic autophagy is a pathophysiological mechanism in motoneuron disease (MND), which leads to impaired synaptic integrity and function. Here, we asked whether boosting neuronal activity by physical exercise modulates the cellular and motor phenotypes of Plekhg5-deficient mice, an MND model with defective presynaptic autophagy.</p><p><strong>Methods: </strong>To characterize the vesicle accumulations in Plekhg5-deficient mice, we performed immunohistochemical staining, electron microscopy, and super-resolution imaging. Following voluntary running wheel exercise, we quantified the histopathological changes within the spinal cord and at neuromuscular junctions using an unbiased machine-learning approach. Additionally, we analyzed the motor performance of the animals by measuring their grip strength. To assess changes in the autophagic flux upon physical exercise in vivo, we utilized mRFP-GFP-LC3 expressing mice. The presence of Atg9-containing vesicle clusters in SOD1^G93A was analyzed to examine the relevance of this pathological feature in a second MND model.</p><p><strong>Results: </strong>We found marked accumulations of Atg9-containing vesicles at presynaptic sites of Plekhg5-deficient mice, which could be cleared by four weeks of voluntary running wheel exercise in young but surprisingly not in aged Plekhg5-deficient mice. However, physical exercise in aged mice led to synaptic vesicle sorting into the Atg9-containing vesicle accumulations without their removal. In line with these findings, short-term voluntary exercise triggered motoneuron autophagy in young but not old mice. Pointing to a broader role of Atg9-containing vesicles in the pathophysiology of MND, we also found Atg9-containing vesicle accumulations in SOD1^G93A mice, a well-established ALS model. Strikingly, physical exercise in presymptomatic SOD1^G93A mice resulted in a reduction of the vesicle accumulations.</p><p><strong>Conclusions: </strong>Our data highlight the essential role of Atg9 in presynaptic autophagy and suggest that boosting autophagy by physical exercise provides a tool to maintain presynaptic function at the early but not late stages of Plekhg5-associated MND and possibly amyotrophic lateral sclerosis.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"69"},"PeriodicalIF":15.2,"publicationDate":"2025-12-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12706973/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145763954","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":"Positive modulation of sigma-1 receptor: a new weapon to mitigate disease progression in amyotrophic lateral sclerosis.","authors":"Julien Le Friec, Hugo Mourier, Simon Couly, Nicolas Cubedo, Kevin Dubois, Johann Meunier, Benjamin Delprat, Arnaud De Zordo-Banliat, Tahar Ayad, David Virieux, Tsung-Ping Su, Christelle Lasbleiz, Tangui Maurice, Jean-Charles Liévens","doi":"10.1186/s40035-025-00527-z","DOIUrl":"10.1186/s40035-025-00527-z","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is characterised by degeneration of motor neurons, leading to muscle weakness and progressive paralysis. Currently, no treatment is available to halt or reverse the progression of the disease. Oxidative stress, mitochondrial dysfunction, accumulation of unfolded proteins and inflammation are interconnected key actors involved in ALS. A potent therapeutic strategy would be to find molecules that break this vicious circle leading to neuronal dysfunction and death. Targeting sigma-1 receptor (S1R) could meet this objective, as this chaperone protein modulates many cell survival mechanisms. So far, the impact of S1R activation in ALS has been studied using specific agonists and mostly on the SOD1 mutation that represents only 2% of patients. In the present study, the impact of two different S1R activators, the reference agonist PRE-084 and the positive modulator OZP002, was compared on two key ALS genes: TDP43 and C9orf72.</p><p><strong>Methods: </strong>The dissociation of S1R from Binding immunoglobulin Protein (BiP) was determined using ELISA. OZP002 toxicity was compared to PRE-084 on zebrafish larvae with increasing concentrations. The efficacy of OZP002 and PRE-084 was evaluated on the locomotor escape response of zebrafish expressing mutant TDP43 or one C9orf72 toxic dipeptide. Their effects on NRF2 target gene expression were studied by qPCR. The beneficial effect was further examined on the locomotor performances of TDP43^A315T mice using rotarod and beam walking tests. We also performed analysis on motor neuron loss and glial reactivity.</p><p><strong>Results: </strong>OZP002 is a positive modulator of S1R, that increases the dissociation of the S1R-BiP complex induced by orthosteric agonists. S1R activation by both OZP002 and PRE-084 restored the locomotor response of ALS zebrafish expressing either TDP43 or one C9orf72 toxic dipeptide. The neuroprotection was due at least in part to the NRF2 cascade stimulation but not with a direct interaction. More importantly, OZP002 and PRE-084 prevented locomotor defects and degeneration of spinal motor neurons in TDP43^A315T transgenic mice. Astroglial and microglial reactivities were also reduced by both activators.</p><p><strong>Conclusions: </strong>We here emphasize the therapeutic value of S1R activation in mitigating ALS pathology. Additionally, we show that the positive modulators pave the way for the development of new S1R-activating compounds for ALS treatment.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"68"},"PeriodicalIF":15.2,"publicationDate":"2025-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12703938/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757432","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":"Lipofuscin accumulation in aging and neurodegeneration: a potential \"timebomb\" overlooked in Alzheimer's disease.","authors":"Godfried Dougnon, Hideaki Matsui","doi":"10.1186/s40035-025-00529-x","DOIUrl":"10.1186/s40035-025-00529-x","url":null,"abstract":"<p><p>Lipofuscin, a marker of aging, is the accumulation of autofluorescent granules within microglia and postmitotic cells such as neurons. Lipofuscin has traditionally been regarded as an inert byproduct of cellular degradation. However, recent findings suggest that lipofuscin may play a role in modulating age-related neurodegenerative processes, and several questions remain unanswered. For instance, why do lipofuscin granules accumulate preferentially in aged neurons and microglia? What happens to these pigments upon neuronal demise? Particularly in neurodegenerative diseases like Alzheimer's disease (AD), why does amyloid β (Aβ) deposition usually begin in late adulthood or during aging? Why do lipofuscin and amyloid plaques appear preferentially in grey matter and rarely in white matter? In this review, we argue that lipofuscin should be revisited not as a simple biomarker of aging, but as a potential modulator of neurodegenerative diseases. We synthesize emerging evidence linking lipofuscin to lysosomal dysfunction, oxidative stress, lipid peroxidation and disease onset-mechanisms critically implicated in neurodegeneration. We also explore the potential interactions of lipofuscin with Aβ and their spatial location, and summarize evidence showing that lipofuscin may influence disease progression via feedback loops affecting cellular clearance and inflammation. Finally, we propose future research directions toward better understanding of the mechanisms of lipofuscin accumulation and improved lysosomal waste clearance in aging.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"67"},"PeriodicalIF":15.2,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12699879/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145744816","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":"Microglia in the crosstalk between peripheral and central nervous systems in Parkinson's disease.","authors":"Tianbai Li, Tao Qiu, Fei Jiang, Huaibin Cai, Weidong Le","doi":"10.1186/s40035-025-00531-3","DOIUrl":"10.1186/s40035-025-00531-3","url":null,"abstract":"<p><p>Parkinson's disease (PD) is increasingly recognized as a multisystem disorder involving pathological α-synuclein (α-syn) accumulation and widespread neuroimmune dysregulation. Microglia, the resident immune cells in the central nervous system (CNS), are pivotal mediators of the bidirectional communication between the CNS and peripheral systems. In addition to sensing neuronal injury and α-syn pathology, microglia dynamically respond to peripheral immune signals, including circulating cytokines, immune cell infiltration, and microbial metabolites, through pattern recognition receptors such as Toll-like and NOD-like receptors. Furthermore, microglia regulate blood-brain barrier integrity, modulate peripheral immune cell recruitment, interact with meningeal lymphatic vessels, and contribute to the propagation of α-syn within the CNS and along the gut-brain axis. However, a comprehensive framework encompassing their diverse roles in peripheral-central immune crosstalk remains underdeveloped. This review synthesizes recent advances elucidating how microglia link the CNS to peripheral immune and metabolic signals in PD. We further highlight microglial contributions to α-syn propagation along the gut-brain axis and discuss how their functional states influence disease progression. A deeper understanding of microglial involvement in this complex neuroimmune interface may inform the development of effective and system-level therapeutic strategies for PD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"66"},"PeriodicalIF":15.2,"publicationDate":"2025-12-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12696919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145726305","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":"Meningeal lymphatics as a therapeutic target for neurodegenerative disorders.","authors":"Yijia Feng, Shengya Wang, Huwei Xia, Xinyi Jiang, Mingming Wu, Sipei Pan, Weihong Song","doi":"10.1186/s40035-025-00528-y","DOIUrl":"10.1186/s40035-025-00528-y","url":null,"abstract":"<p><p>Advancements in visualization methods have brought the meningeal lymphatic system (MLS) into the spotlight. The meningeal lymphatic vessels (mLVs) play a vital role in draining cerebrospinal fluid and immune cells, acting as a central hub for immune surveillance in the brain. Age-related morphological and functional declines of mLVs suggest their involvement in the pathogenesis of neurodegenerative disorders (NDDs). In this article, we summarize key discoveries about the MLS over the past decade, highlight the neuro-immune crosstalk in the meninges, and discuss the role of mLVs in both brain homeostasis and neurodegeneration. As a critical regulator of brain function and a potential therapeutic target, the MLS offers a promising avenue for the diagnosis and treatment of NDDs, particularly Alzheimer's Disease.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"65"},"PeriodicalIF":15.2,"publicationDate":"2025-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12687538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145716012","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LRRK2 G2019S mutation contributes to mitochondrial transfer dysfunction in a Drp1-STX17-dependent manner.","authors":"Mei Ding, Fen Wang, Lan-Lan Jiang, Chao Ma, Yu-Wan Qi, Jun-Yi Liu, Juan Li, Mei-Xia Wang, Hong Jin, Jin-Ru Zhang, Cheng-Jie Mao, Xiao-Kang Li, Chun-Feng Liu, Xiao-Yu Cheng","doi":"10.1186/s40035-025-00525-1","DOIUrl":"10.1186/s40035-025-00525-1","url":null,"abstract":"<p><strong>Background: </strong>Previous studies have shown that astrocytes can transfer healthy mitochondria to dopaminergic (DA) neurons, which may serve as an intrinsic neuroprotective mechanism in Parkinson's disease (PD). LRRK2 G2019S is the most common pathogenic mutation associated with PD. In this study, we explored whether mitochondrial transfer is influenced by genetic and environmental factors and whether dysfunction in this process is one of the mechanisms of the pathogenic LRRK2 G2019S mutation.</p><p><strong>Methods: </strong>DA neurons and astrocytes were differentiated from induced pluripotent stem cells generated from the peripheral blood of a healthy individual and a PD patient carrying the LRRK2 G2019S mutation. A coculture system of astrocytes and DA neurons was established to explore the pathogenic mechanisms of LRRK2 G2019S.</p><p><strong>Results: </strong>Exposure to the environmental toxin rotenone impaired mitochondrial transfer from astrocytes to DA neurons. Compared with the co-culture system from the healthy participant, the co-culture system harboring the LRRK2 G2019S mutation experienced more pronounced damage. Specifically, STX17 was colocalized with the mitochondrial outer membrane marker TOM20, and its knockdown caused damage to mitochondrial transfer. Drp1 interacted with STX17. LRRK2 G2019S-mutant astrocytes exhibited markedly increased phosphorylation of Drp1 at Ser616 upon rotenone exposure. Moreover, the degree of colocalization of STX17 with TOM20 decreased. The Drp1 phosphorylation inhibitor DUSP6 restored the colocalization of STX17 and TOM20, as well as the mitochondrial transfer efficiency and neuronal survival.</p><p><strong>Conclusions: </strong>The impairment of mitochondrial transfer is a potential pathogenic mechanism associated with LRRK2 G2019S mutation. The molecular mechanisms of mitochondrial transfer were observed to occur through a Drp1-STX17-dependent pathway. Notably, inhibitors for Drp1 Ser616 phosphorylation may offer neuroprotection through mitigating mitochondrial transfer impairments. This study provides novel insights into the pathogenesis of PD and the development of new therapeutic targets.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"64"},"PeriodicalIF":19.1,"publicationDate":"2025-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12683823/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145701837","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":"Stratification of brain-derived extracellular vesicles of Alzheimer's disease patients indicates a unique proteomic content and a higher seeding capacity of small extracellular vesicles.","authors":"Marie Oosterlynck, Elodie Leroux, Balasubramaniam Namasivayam, Thomas Bouillet, Raphaelle Caillierez, Anne Loyens, Daniele Mazur, Romain Perbet, Christophe Lefebvre, Soulaimane Aboulouard, Claude-Alain Maurage, Bertrand Accart, Luc Buée, Morvane Colin","doi":"10.1186/s40035-025-00519-z","DOIUrl":"10.1186/s40035-025-00519-z","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is the most prominent form of dementia worldwide. It is characterized by tau lesions that spread throughout the brain in a spatio-temporal manner. This has led to the prion-like propagation hypothesis implicating a transfer of pathological tau seeds from cell to cell. Human brain-derived extracellular vesicles (BD-EVs) isolated from the brain-derived fluid of AD patients contain seeds that contribute to this tau pathology spreading. Knowing the rich diversity of EVs, isolation of functional EV sub-populations is required to unravel their implication in the pathophysiology of AD.</p><p><strong>Methods: </strong>Here, enriched-small EVs (eSEVs) and enriched-large EVs (eLEVs) were isolated from frozen tissues after collagenase enzymatic brain dissociation to guarantee the best EVs' integrity. Then proteomic profiling and tau seeding capacity testing were performed in vitro and in vivo.</p><p><strong>Results: </strong>BD-EVs were stratified according to their size (eSEVs and eLEVs) and characterized to define new markers specific to EVs in AD. Both AD-derived eSEVs and eLEVs show the presence of GWAS-associated proteins and indicate a specific AD pathophysiological signature. Notably, AD eSEVs contain more proteins relative to the integrin-mediated synaptic signaling, while AD eLEVs proteins were more related to respiratory electron transport and brain immunity. Injection of these vesicles in transgenic mouse brain revealed that the AD-derived eSEVs are more prone than eLEVs to participate in the prion-like propagation and hence represent an interesting therapeutic target.</p><p><strong>Conclusion: </strong>This study highlights the significant contribution of AD-derived EVs to tau propagation and provides new insights into different roles of EV sub-populations in AD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"63"},"PeriodicalIF":15.2,"publicationDate":"2025-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12679798/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678867","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 glucose imaging reveals functional brain reconfiguration by subthalamic deep brain stimulation in Parkinsonian rats.","authors":"Jiazhi Chen, Ningfei Li, Muthuraman Muthuraman, Nengxing Liang, Jens Volkmann, Takahiro Higuchi, Chi Wang Ip","doi":"10.1186/s40035-025-00523-3","DOIUrl":"10.1186/s40035-025-00523-3","url":null,"abstract":"<p><strong>Background: </strong>In order to elucidate the neuromodulatory mechanisms underlying therapeutic subthalamic deep brain stimulation (DBS), we here reverse-translate a methodological pipeline that integrates neurostimulation effect parameterization and molecular imaging.</p><p><strong>Methods: </strong>¹⁸F-fluorodeoxyglucose positron emission tomography was performed in a human-mimicking A53T alpha-synuclein Parkinson's disease rat model and in control rats under both stimulation ON and OFF conditions, with additional CT scans acquired for each rat. Patient-derived approaches-including electrode modeling, electric field estimation, and volume of tissue activated measurement-were applied to assess stimulation effects at the stimulation spot.</p><p><strong>Results: </strong>We revealed consistent hypometabolism in the ipsilateral subthalamic nucleus, substantia nigra, zona incerta, cerebellum, and entopeduncular nucleus, alongside hypermetabolism in the ipsilateral lateral caudate putamen and globus pallidus externus in A53T rats at the OFF condition. Subthalamic DBS improved motor dysfunction and induced specific metabolic responses that differentiated from controls, including increased metabolism in the ipsilateral subthalamic nucleus, substantia nigra, and zona incerta, and decreased metabolism in the bilateral primary motor and somatosensory area, lateral caudate putamen, and contralateral secondary motor area.</p><p><strong>Conclusions: </strong>Therapeutic subthalamic DBS activates the target region and modulates global brain function by restoring OFF-state hypometabolism in the ipsilateral subthalamic-substantia nigra loop and by reducing metabolic activity in the bilateral cortico-striatal circuitry. A reverse-translational pipeline is established to study stimulation-induced modulation of brain function, integrating a novel positron emission tomography template aligned with the Waxholm space of Sprague-Dawley rats.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"62"},"PeriodicalIF":15.2,"publicationDate":"2025-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12670866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145655711","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":"Exploring the skin as an open window onto neurodegenerative diseases.","authors":"Francesca Lozzi, Emanuela Camera, Giorgia Cardinali, Anna Di Nardo","doi":"10.1186/s40035-025-00522-4","DOIUrl":"https://doi.org/10.1186/s40035-025-00522-4","url":null,"abstract":"<p><p>Neurodegenerative diseases (NDDs), including Parkinson's disease and Alzheimer's disease, are major age-related disorders characterized by progressive neuronal degeneration and a decline in cognitive and motor functions. Managing NDDs poses an increasing healthcare challenge as the global population ages. The onset of NDDs is linked to protein misfolding, oxidative stress, dysfunction of mitochondria and lysosomes, and neuroinflammation. Clinical manifestations of NDDs only appear after substantial neuronal damage has already occurred. This underscores the urgent need for accessible tissue biomarkers to enable early diagnosis, disease monitoring and assessment of therapeutic efficacy. The skin has emerged as a valuable peripheral indicator of neurodegeneration, sharing embryological origin, gene expression profiles, protein alterations and cellular dysfunctions with the brain. Notably, pathological protein deposits, which are hallmarks of NDDs, such as beta-amyloid, tau proteins, and oligomeric alpha-synuclein, have been observed in the skin. Increasing evidence links NDDs with various pathological skin conditions, including melanoma and inflammatory diseases. This review aims to explore the potential of the skin as a window into neurodegenerative processes at an early stage, before clinical signs arise. The main advantages of using skin as a source of NDD biomarkers are its accessibility and the minimally invasive sampling methods such as stratum corneum collection, sebum and volatile compounds analysis, and biopsies. Immunohistochemistry and omics approaches applied to skin samples provide valuable insights into NDD pathophysiology and facilitate biomarker discovery for early diagnosis and disease monitoring. NDDs are multisystemic disorders and new findings in skin research highlight the value of peripheral tissues for investigating central nervous system alterations enabling earlier neuroprotective interventions.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"14 1","pages":"61"},"PeriodicalIF":15.2,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12659071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145640354","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":"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}