Translational Neurodegeneration最新文献

{"title":"Brain region-resolved pharmacodynamics of an antisense oligonucleotide targeting human SNCA 3'UTR in BAC-hSNCA rats.","authors":"Marianna Naki, Fedon-Giasin Kattan, Marina Pantazopoulou, Sissy Skea, Dimitrios Zisis, Eleftherios Pilalis, Maria Fouka, Effrosyni Koronaiou, Christos Fotis, Olaf Riess, Aristotelis Chatziioannou, Leonidas G Alexopoulos, Leonidas Stefanis, Epaminondas Doxakis","doi":"10.1186/s40035-026-00577-x","DOIUrl":"10.1186/s40035-026-00577-x","url":null,"abstract":"<p><strong>Background: </strong>Alpha-synuclein accumulation contributes to Parkinson's disease (PD), and lowering α-synuclein expression is a candidate disease-modifying approach. The brain-wide pharmacodynamic profile of human-targeting antisense oligonucleotides (ASOs) remains incompletely defined in humanized models that preserve the regulatory architecture of the human SNCA locus.</p><p><strong>Methods: </strong>BAC-hSNCA rats were treated at an early stage, when human α-synuclein is elevated, but striatal dopamine content remains largely preserved. A single intracerebroventricular dose of an ASO targeting human SNCA 3'UTR (SNCA ASO3.0) was administered, and outcomes were assessed 45 days later by isoform-specific RT-qPCR, immunoblotting of soluble and detergent-insoluble α-synuclein species, bulk RNA-seq across selected regions, multiplex cytokine profiling, phospho-kinase assays, neurotransmitter quantification, and behavioral testing.</p><p><strong>Results: </strong>SNCA ASO3.0 reduced human SNCA mRNA and multiple α-synuclein protein species in a regionally graded manner, with the strongest effects in the olfactory bulb and striatum. Bulk RNA-seq identified anatomically distinct transcriptional responses, including synaptic and metabolic pathway shifts in the olfactory bulbs and immune-related enrichment within glial signatures in the striatum and midbrain, without detectable changes in protein levels of glial fibrillary acidic protein or ionized calcium-binding adapter molecule 1. Cytokine profiling showed selective modulation of a subset of analytes, and phospho-kinase assays indicated reduced AKT1S1/PRAS40 phosphorylation. Striatal dopamine levels were unchanged, whereas the striatal tyrosine hydroxylase level was increased. SNCA ASO3.0 increased locomotor activity and improved exploratory behavior and selected measures of olfactory discrimination.</p><p><strong>Conclusions: </strong>Partial suppression of human α-synuclein in a humanized rat model yields region-specific molecular adaptations accompanied by early behavioral changes at a stage preceding overt dopamine depletion. These data provide a framework for evaluating region-resolved consequences of α-synuclein-lowering interventions in synucleinopathies.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579807/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148983708","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":"Human amniotic mesenchymal stromal cell-derived extracellular vesicles reprogram microglia and prevent neurodegeneration in experimental models of Alzheimer's disease.","authors":"Andrea Papait, Francesca Natale, Antonietta Rosa Silini, Ida Nifo Sarrapochiello, Elisa Orecchini, Raimondo Sollazzo, Marco Rinaudo, Serafina Farigu, Nicoletta Garofalo, Giulia Mantini, Guido Maria Giuffrè, Pietro Romele, Elvira Ragozzino, Alice Dellaria, Luciano Giacò, Camillo Marra, Cristian Ripoli, Claudio Grassi, Ornella Parolini, Salvatore Fusco","doi":"10.1186/s40035-026-00581-1","DOIUrl":"10.1186/s40035-026-00581-1","url":null,"abstract":"<p><strong>Background: </strong>Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder and disproportionately affects women, with neuroinflammation emerging as a key driver of disease onset and progression. Beyond amyloid-β (Aβ) and hyperphosphorylated tau protein accumulation, chronic activation of microglia and astrocytes amplifies synaptic dysfunction and neuronal loss. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) represent a promising translational strategy due to their capacity to modulate inflammation and promote neuroprotection. Here, we investigated whether intranasal administration of extracellular vesicles derived from human amniotic membrane MSCs (hAMSC-EVs) could counteract cognitive decline, neuroinflammation, and synaptic alterations in experimental and human cellular models of AD.</p><p><strong>Methods: </strong>hAMSC-EVs were isolated and characterized for size, markers, and biodistribution. Female 3 × Tg-AD mice received chronic intranasal hAMSC-EV administration from 3 to 9 months of age. Cognitive performance was assessed using novel object recognition, object place recognition, and Y-maze tests. Hippocampal Aβ levels, tau phosphorylation, glial density, microglial morphology, cytokine profiles, and synaptic protein expression were analyzed by immunoblotting, ELISA, immunofluorescence, and morphometric analyses. Bioinformatic analyses were performed to investigate the miRNA cargoes of hAMSC-EVs. Translational relevance of the hAMSC-EV effects was assessed in glutamatergic neurons differentiated from induced pluripotent stem cells derived from sporadic AD patients.</p><p><strong>Results: </strong>The hAMSC-EVs delivered intranasally reached the hippocampus and were internalized by neurons and microglia. hAMSC-EV treatment significantly improved cognitive performance of female 3 × Tg-AD mice and reduced hippocampal Aβ levels without affecting tau phosphorylation. The hAMSC-EVs attenuated neuroinflammation by reducing microglial and astrocytic density, inducing microglial structural remodeling, and downregulating TMEM119 and TREM2 expression. We also detected a shift toward an anti-inflammatory cytokine profile and increased expression of neuroplasticity-related proteins, including BDNF, GluA1, and ARC in the hippocampus of 3 × Tg-AD mice. Bioinformatic analyses identified EV miRNA cargoes enriched in immunomodulatory and neuroprotective pathways. In human AD neurons, hAMSC-EVs prevented neurite atrophy and rescued synaptic protein expression without affecting the cell viability.</p><p><strong>Conclusions: </strong>hAMSC-EVs exert robust anti-inflammatory and neuroprotective effects in both murine and human AD models, improving cognition, modulating glial activation, and restoring synaptic integrity. These findings highlight the translational potential of intranasal hAMSC-EVs as an adjuvant therapeutic strategy targeting neuroinflammation and neurodegeneration in AD.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13556012/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148913455","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":"The gut neuroepithelial unit as a neurodegeneration-relevant interface in the gut-brain axis.","authors":"Siqi Guo, Rui Guo, Qingyu Zhang, Liyuan Fu, Huaxu Zhu, Qichun Zhang","doi":"10.1186/s40035-026-00582-0","DOIUrl":"10.1186/s40035-026-00582-0","url":null,"abstract":"<p><p>Neurodegenerative diseases are increasingly linked to abnormalities in the gut-brain axis, yet the local intestinal interface at which luminal and mucosal perturbations are related with the central nervous system remains poorly defined. The gut neuroepithelial unit (GNU) is proposed as a localized mucosal signalling interface composed of sensory epithelial cells, enteric neurons, glia and adjacent immune-stromal elements that detect, encode and route intestinal information into neural, endocrine and immune outputs. This framework shifts the intestine from being a diffuse upstream modifier of brain pathology to a mesoscopic unit through which microbial products, barrier dysfunction, inflammatory cues and metabolic signals are transformed into disease-relevant gut-to-brain communication. Particularly, in Parkinson's disease and Alzheimer's disease, the GNU may function as a conditional interface that amplifies, filters or biases peripheral signals before they engage central circuits. The GNU therefore provides a tractable framework for mechanistic dissection, translational stratification and peripheral therapeutic targeting in neurodegeneration.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148876009","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":"Central nervous system lymphatic network: from the maintenance of brain homeostasis to emerging therapeutic perspectives in neurodegenerative diseases.","authors":"Shixin Ding, Jiguang Yang, Ze Wang, Ruiliang Bai, Kuiying Yin, Lei Jin, Maximilian Kueckelhaus, Sven G Meuth, Ming Xiao, Gang Hu","doi":"10.1186/s40035-026-00579-9","DOIUrl":"10.1186/s40035-026-00579-9","url":null,"abstract":"<p><p>The brain was long been regarded as an immune-privileged organ with a lack of lymphatic drainage, partly because of the absence of parenchymal lymphatic vessels. This long-held doctrine has been challenged by recent advancements in central lymphatic vascular biology. The central drainage network, which consists of the glymphatic system, meningeal lymphatic vessels, and cranial perineural drainage pathways, plays a crucial role in the clearance of metabolic brain waste and the maintenance of brain homeostasis. Furthermore, the meninges and brain perivascular spaces are rich in immune cells that regulate neuronal activities and diverse behaviors through secretion of cytokines. Dysfunction of the central lymphatic network is widely observed in natural aging and neurodegenerative disorders, which is characterized by mislocalization of aquaporin-4 on astrocytic endfeet, impairment of lymphatic valvular integrity, and alterations in the proportion and phenotype of meningeal immune cells. In this review, we provide a comprehensive overview of the anatomical foundations, molecular regulatory mechanisms, and physiological functions of this system. We summarize the pathological roles of the central lymphatic network across neurodegenerative conditions and discuss emerging clinical assessment frameworks based on multimodal imaging and liquid biomarkers. We also highlight promising therapeutic strategies, such as restoring meningeal lymphatic function, targeting glymphatic drainage, and modulating the meningeal immune microenvironment. Elucidating the dynamics of the central lymphatic network will reshape our understanding of brain homeostasis, paving the way for novel diagnostic and therapeutic strategies for neurodegenerative diseases. Future research should focus on translating fundamental findings into clinical applications, thereby accelerating the transition from basic research to clinical practice.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13536567/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875955","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":"Phase separation in neurodegenerative disorders: a metabolic perspective on protein aggregation and therapeutic targeting.","authors":"Shujun Peng, Hui Chen, Guowei Yin, Alexei Verkhratsky, Chenju Yi","doi":"10.1186/s40035-026-00575-z","DOIUrl":"10.1186/s40035-026-00575-z","url":null,"abstract":"<p><p>Biomolecular condensates formed via liquid-liquid phase separation (LLPS) are increasingly recognised as dynamic organisers of intracellular biochemistry, particularly in neurons where spatially restricted signalling, RNA metabolism, and proteostasis are essential. Aberrant phase transitions of disease-associated proteins, including TDP-43, FUS, tau, and α-synuclein, contribute to protein aggregation and neurodegenerative pathology. Beyond protein-intrinsic sequence features, metabolic state has emerged as an important contextual regulator of condensate assembly, material properties, and liquid-to-solid maturation. Metabolic cues, including ATP availability, NAD⁺/NADH balance, redox state, lipid composition, enzyme-mediated post-translational modifications, and cellular stress responses, can influence the phase behaviour across biochemical, cellular, and disease-model systems. However, direct causal evidence in neurons, animal models, and human neurodegenerative diseases remains uneven and protein-specific. Here, we review LLPS in neurodegenerative disorders from the metabolic perspective, distinguishing established mechanisms from plausible but incompletely validated links. We discuss how pathological condensates may impair RNA metabolism, synaptic function, proteostasis, and cognition, and critically evaluate emerging therapeutic strategies that aim to modulate aberrant phase behaviour. This review therefore provides a cautious framework in which metabolic dysregulation is considered a potential upstream contributor to pathological phase transitions rather than an established master regulator.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13528016/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148866594","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":"HSPA8 orchestrates SNARE complex assembly to drive extracellular vesicle-mediated spread of p-tau217 in Alzheimer's disease.","authors":"Bin Xu, Zhen Guo, Jun Chen, Yazhou Xie, Pan Wang, Xiao Xiong, Jiayi Yu, Zhi Xu, Yuan Fu, Zhuoqing Lan, Guoping Peng, Jing Zhang","doi":"10.1186/s40035-026-00570-4","DOIUrl":"10.1186/s40035-026-00570-4","url":null,"abstract":"<p><strong>Background: </strong>Dysregulation of multivesicular bodies (MVBs) in Alzheimer's disease (AD) contributes to aberrant tau secretion via extracellular vesicles (EVs). This may potentially explain our previous paradoxical observation of elevated free-form p-tau217 alongside reduced p-tau217⁺ EVs in plasma. This study aimed to investigate the mechanisms underlying the reduction of p-tau217⁺ EVs to uncover AD therapeutic targets.</p><p><strong>Methods: </strong>By integrating hippocampal spatial transcriptomics of human brain with EV proteomics of cerebrospinal fluid, we identified key regulators of p-tau217⁺ EV release. Subsequently, we investigated the mechanisms underlying the synthesis and secretion of p-tau217⁺ EVs. The regulatory roles of these candidate proteins were systematically evaluated through shRNA knockdown and interference with a synthetic peptide in both Aβ₄₂-treated cells and AD model mice.</p><p><strong>Results: </strong>Heat shock protein family A member 8 (HSPA8) was identified as a crucial regulator of EV biogenesis and release, mediating the Aβ-SNAP29 interaction to disrupt SNARE complex assembly and impair p-tau217⁺ EV secretion. In AD models, HSPA8 inhibition with shRNA rescued p-tau217⁺ EVs and improved cognitive function. Additionally, blocking the Aβ-SNAP29 interaction with a selective peptide inhibitor for HSPA8 reversed the decline in p-tau217⁺ EV and cognitive deficits.</p><p><strong>Conclusions: </strong>These findings reveal a role of HSPA8 in regulating the MVB-mediated EV release and tau propagation, and highlight HSPA8 as a promising therapeutic target for modifying AD progression.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13520189/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148841075","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":"Correction: 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/s40035-026-00574-0","DOIUrl":"10.1186/s40035-026-00574-0","url":null,"abstract":"","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13508188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148819665","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":"Bridging the gap: neuroinflammation and the dawn of precision medicine in amyotrophic lateral sclerosis.","authors":"Lu Tang, Dongsheng Fan","doi":"10.1186/s40035-026-00572-2","DOIUrl":"10.1186/s40035-026-00572-2","url":null,"abstract":"<p><p>Neuroinflammation is no longer a secondary feature of amyotrophic lateral sclerosis (ALS), but rather a disease-modifying process that actively shapes the motor neuron vulnerability from the earliest stages of pathology. Central and peripheral immune cells, including microglia, astrocytes, and infiltrating T lymphocytes, adopt context-dependent states that can be neuroprotective or neurotoxic depending on disease stage and genetic background. These states are driven by discrete molecular programs, such as cGAS-STING-mediated innate immune sensing, NLRP3 inflammasome activation, and RIPK1-dependent necroptotic signaling, which represent tractable therapeutic targets. The repeated failure of broad-spectrum immunosuppressive trials reflects a fundamental mismatch between the non-selective interventions and the mechanistically distinct immune states of diseases. Converging transcriptomic, genetic, and immunophenotypic evidence supports the existence of putative neuroimmune endotypes in ALS, though this framework remains a working hypothesis pending prospective validation in biomarker-stratified cohorts. Advances in the following three domains are needed for realizing precision immunotherapy: standardized biomarker panels (including cerebrospinal fluid chitinases and TSPO-PET) to stratify patients by inflammatory subtype; pharmacodynamic readouts to confirm target engagement before interpreting clinical outcomes; and adaptive platform trial designs capable of evaluating mechanism-matching interventions in defined subgroups. This review integrates ALS-associated neuroinflammation with emerging precision medicine strategies, arguing that the central translational question is no longer whether or not to target neuroinflammation, but how, when, and in whom neuroinflammation should be targeted.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13501664/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148814045","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":"PCSK9 inhibitors in neurodegenerative disorders: mechanisms, therapeutic potential, and clinical implications.","authors":"Jia Dong James Wang, Andrea York Tiang Teo, Bin Xiao, Yinxia Chao, Zhi Dong Zhou, Brendan Jen-Wei Tan, Ling-Ling Chan, Elvira Rosalie, Eng-King Tan","doi":"10.1186/s40035-026-00568-y","DOIUrl":"https://doi.org/10.1186/s40035-026-00568-y","url":null,"abstract":"<p><p>Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in hepatic cholesterol metabolism via low density lipoprotein receptor degradation. PCSK9 inhibitors have revolutionized lipid-lowering therapy, providing robust reduction of cardiovascular risk. Large-scale randomized controlled trials and long-term extensions (e.g., FOURIER and EBBINGHAUS trials) have shown no significant adverse effects of PCSK9 inhibitors on neuropsychological testing or patient-reported cognitive outcomes, even with prolonged and intensive lowering of low-density lipoproteins. Pre-clinical studies also suggest PCSK9 as a key regulator of neurobiological processes, including synaptic plasticity, amyloid-beta clearance, neuroinflammation, and blood-brain barrier integrity. Human genetic studies revealed complex, sometimes conflicting associations between PCSK9 variants and risk of Alzheimer's disease, Parkinson's disease, vascular dementia, and amyotrophic lateral sclerosis. In this review, we highlight the pathophysiologic mechanisms, emerging experimental therapeutics and clinical implications of PCSK9 inhibition in neurodegenerative disorders. Long-term adequately powered trials with robust neuropsychological, biomarker, and imaging endpoints, as well as mechanistic studies in human-derived models are needed to establish the cardiovascular and neurocognitive implications of PCSK9 inhibition and guide precision medicine strategies for those at elevated risk of neurodegeneration.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13483731/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798211","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":"The mitophagy-inflammasome axis: a shared pathological hub in Alzheimer's and Parkinson's diseases.","authors":"Wei Long, Mengqin Yuan, Sirui Wang, Xinyue Tan, Li-Chen Gao","doi":"10.1186/s40035-026-00578-w","DOIUrl":"https://doi.org/10.1186/s40035-026-00578-w","url":null,"abstract":"<p><p>Alzheimer's disease (AD) and Parkinson's disease (PD) represent the most prevalent chronic neurodegenerative disorders, characterized by progressive loss of neurons as a core pathological feature. Despite discrepancies in their clinical phenotypes and signature pathological proteins, accumulating evidence has validated a common molecular pathogenic mechanism: dysfunctional bidirectional crosstalk between mitophagy and inflammasomes. As the central hub of neuronal energy metabolism, mitochondrial impairment triggers the release of damage-associated molecular patterns such as reactive oxygen species and mitochondrial DNA, which in turn activate inflammasomes (e.g., NLRP3) to elicit chronic neuroinflammation. Conversely, excessive inflammasome activation suppresses mitophagy, exacerbating the accumulation of damaged mitochondria and pathological protein aggregates, and forming a pathological mitochondrial damage-inflammatory activation-autophagy inhibition cycle. Microglia and astrocytes, key immunocompetent cells of the central nervous system, act as a hub within this regulatory network. Therapeutic strategies targeting the mitophagy-inflammasome axis have achieved remarkable advancements, including mitophagy agonists, inflammasome inhibitors, and dual-target modulators. This review summarizes recent findings regarding the pathogenic roles of β-amyloid and α-synuclein in AD and PD, as well as the protective effects offered by regulating mitophagy and inflammasome activity. Furthermore, the major directions and potential hurdles in the development of targeted therapeutics are discussed, in the aim of providing insights into the novel therapeutic avenues for the treatment of both disorders.</p>","PeriodicalId":23269,"journal":{"name":"Translational Neurodegeneration","volume":"15 1","pages":""},"PeriodicalIF":19.1,"publicationDate":"2026-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13479707/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148798192","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}