Molecular Neurodegeneration最新文献

{"title":"ApoE lipoproteins in the central nervous system under homeostasis and role in Alzheimer's disease and related disorders.","authors":"Michael R Strickland,David M Holtzman","doi":"10.1186/s13024-026-00970-0","DOIUrl":"https://doi.org/10.1186/s13024-026-00970-0","url":null,"abstract":"Apolipoprotein E (ApoE) is highly expressed in the central nervous system (CNS) where it plays a critical role in lipid homeostasis and in the etiology of Alzheimer's disease (AD) and related diseases. ApoE associates with lipids to form discoidal and spherical lipoproteins that carry lipid and protein cargo throughout the brain. In this review, we focus on the significance of ApoE as a lipoprotein and how this impacts the function of ApoE in homeostasis and disease. In the CNS, ApoE is primarily secreted by astrocytes, though other cells, including microglia, secrete ApoE under certain conditions. ApoE lipoproteins (LpE) secreted by different cell types carry unique lipids and proteins which alter its function. The lipidation state of ApoE alters its conformation and binding to different receptors and, consequently, its ultimate impact on AD pathology. Most dramatically, nonlipidated ApoE has minimal binding to the low density lipoprotein receptor (LDLR), while lipidation of ApoE restores high affinity binding to LDLR. Furthermore, the degree of ApoE lipidation also impacts ApoE receptor binding through changes in protein conformation and stoichiometry of ApoE molecules per lipoprotein. The lipidation state of ApoE also alters its interaction with amyloid-β and tau, the proteins involved in forming amyloid plaques and neurofibrillary tangles, the pathological hallmarks of AD. LpE also carry lipids and proteins that alter the function of ApoE. Understanding how the lipid and protein content of LpE interacts with the conformational changes that occur with lipidation and maturation are essential to mechanistically understanding the role of ApoE in homeostasis and disease pathogenesis. In this review, we highlight the current understanding of LpE biology in the CNS and delineate important areas of future research.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"368 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148400793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TDP-43 dysfunction facilitates the pathological conversion of tau.","authors":"Meghraj S Baghel,Grace D Burns,Margarita Tsapatsis,Aswathy Peethambaran Mallika,Anna Lourdes F Cruz,Tianyu Cao,Xiaoke K Chen,Isabel De La Rosa,Shaelyn R Marx,Yingzhi Ye,Shuying Sun,Tong Li,Jonathan P Ling,Philip C Wong","doi":"10.1186/s13024-026-00968-8","DOIUrl":"https://doi.org/10.1186/s13024-026-00968-8","url":null,"abstract":"TDP-43 proteinopathy coexists with tauopathy in a variety of neurodegenerative disorders, including Alzheimer's Disease (AD) and AD related dementia (ADRD). While such co-pathology of TDP-43 is strongly associated with worsened neurodegeneration, the pathogenic mechanism underlying the exacerbated neuron loss remains elusive. Loss of TDP-43 splicing repression occurring during the early stage of neurodegenerative disease suggests that such loss could facilitate the pathological conversion of tau. Here, we report that TDP-43 loss-of-function (LOF) in forebrain neurons (Tau4R; CaMKII-CreER; Tardbpf/f mice) exacerbates tauopathy-dependent brain atrophy is associated with vulnerable neurons sensitive to caspase 3-dependent cleavage of endogenous tau. We demonstrate that TDP-43 LOF in human iPSC-derived cortical neurons promotes TDP-43 dependent cryptic splicing which precedes caspase 3-mediated endoproteolysis of tau. Using a genetic approach to seed tauopathy in CaMKII-CreER; Tardbpf/f mice by expressing a four-repeat microtubule binding domain of human tau, we show that the amount of tau seed correlates with caspase 3-dependent tau cleavage, accelerated tauopathy and the loss of vulnerable neurons deficient in TDP-43. Together, these results strongly support the view that TDP-43 dysfunction exacerbates tauopathy-dependent brain atrophy by promoting caspase 3-dependent endoproteolysis of tau, disclosing novel mechanistic insights and therapeutic targets for human tauopathies harboring the co-pathology of TDP-43.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"448 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148385691","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Early binding of anti-amyloid antibodies to CAA drives complement activation, inflammation and ARIA in mice.","authors":"Praveen Bathini, Stephan Schilling, Jens-Ulrich Rahfeld, David M Holtzman, Takaomi C Saido, Cynthia A Lemere","doi":"10.1186/s13024-026-00965-x","DOIUrl":"10.1186/s13024-026-00965-x","url":null,"abstract":"<p><p>Anti-amyloid antibody treatment for Alzheimer's disease is linked to Amyloid-Related Imaging Abnormalities (ARIA), including vasogenic edema (ARIA-E) and microhemorrhages (ARIA-H), especially in ApoE ε4/4 carriers. To investigate mechanisms underlying ARIA, we examined the binding and temporal vascular effects of immunization with 3D6, the precursor to the anti-amyloid antibody bapineuzumab, in two aged Alzheimer's disease amyloid mouse models. Acutely, 3D6 bound to cerebral amyloid angiopathy (CAA), resulting in C1q binding and classical complement activation. Weekly short-term immunization over 7 weeks resulted in elevated CAA- and plaque-associated complement deposition, red blood cell extravasation and microhemorrhages, and was accompanied by significant transcriptomic changes in genes related to complement, inflammation, vascular dysfunction, and endothelial lipid responses. Longer-term dosing over 13-15 weeks further increased complement deposition and was associated with blood-brain barrier disruption, MMP-9 upregulation, and microhemorrhages, accompanied by reduced amyloid burden and modest CAA clearance. C3 levels correlated with microhemorrhage severity. Perivascular macrophages co-localized with complement-decorated CAA in 3D6-treated mice. These findings implicate complement activation as an early key driver of ARIA and suggest that therapeutic targeting of complement may reduce ARIA risk.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13579800/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148339305","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":"Standardized protocol to detect phosphorylated α-synuclein in skin biopsies: recommendations from an expert panel.","authors":"V Donadio,C Gibbons,C Delprete,K Doppler,A Furia,A Incensi,M Ingelsson,J Yang,M Liu,G Melli,M Nolano,V Provitera,G Rizzo,K Tsukita,R Freeman,R Liguori","doi":"10.1186/s13024-026-00966-w","DOIUrl":"https://doi.org/10.1186/s13024-026-00966-w","url":null,"abstract":"BACKGROUNDSkin biopsy is a promising diagnostic tool for the in vivo identification of Parkinson's disease and other α-synucleinopathies. However, despite increasing adoption, methodological variability exists among different laboratories applying this technique. To move toward a formal standardized protocol, leading experts in the field convened for a meeting focused on discussing and harmonizing the main methodological differences. The outcome of this meeting was a consensus-based skin biopsy protocol, which is here presented.RESULTSA formal expert opinion conference was held on November 15-16, 2024, at the IRCCS Institute of Neurological Sciences of Bologna (Italy). The consensus was reached by using a Question & Answer format following the PICO (Population, Intervention, Comparison, Outcome) methodology. An online Delphi survey was then performed based on the contrasting issues raised during the meeting. Unanimous consensus was reached on key elements, including the skin biopsy technique, choice of fixative, use of a cryostat, staining method for phosphorylated α-synuclein (p-α-syn), use of high-power fluorescence microscope, co-localization of p-α-syn with neuronal or glial markers, and high-magnification analysis. Additional agreement, achieved through the Delphi method, concerned specific procedural parameters such as the number of samples and section thickness, punch diameter, preferred biopsy sites in cases of asymmetric motor involvement, quantitative methods for assessing p-α-syn load, and use of p-α-syn as the optimal marker for identifying misfolded α-synuclein in the skin. Conclusions We have developed a consensus-based protocol for the detection of p-α-syn in skin samples from patients with suspected α-synucleinopathies, with the aim of promoting standardization, a broader adoption of the method, and its translation into clinical practice.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"34 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148322751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A reappraisal of APOE genetic effects on Alzheimer's disease risk in the Japanese population: a meta-analysis.","authors":"Akinori Miyashita,Norikazu Hara,Ai Obinata,Tamao Tsukie,Mai Hasegawa,Takanobu Ishiguro,Kensaku Kasuga,Masataka Kikuchi,Tadafumi Hashimoto,Takahisa Kanekiyo,Takeshi Ikeuchi","doi":"10.1186/s13024-026-00963-z","DOIUrl":"https://doi.org/10.1186/s13024-026-00963-z","url":null,"abstract":"Our meta-analysis demonstrates that the risk effect of APOE-e4*4 relative to APOE-e3*3 for Alzheimer's disease in the Japanese population is approximately 12-15-fold, comparable to that reported in Caucasian populations, rather than greater than 20-fold as previously reported.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"7 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148305060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perspective of retinal Chlamydia pneumoniae infection in Alzheimer's disease pathogenesis.","authors":"He Baixu,Wang Qing,Xie Chunming","doi":"10.1186/s13024-026-00964-y","DOIUrl":"https://doi.org/10.1186/s13024-026-00964-y","url":null,"abstract":"","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"19 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148313273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A 'Tangled Web' in the CNS: unraveling neutrophil extracellular traps in neurological disorders.","authors":"Haixia Wang,Ruiming Wen,Emily Parker,Luodan Yang","doi":"10.1186/s13024-026-00967-9","DOIUrl":"https://doi.org/10.1186/s13024-026-00967-9","url":null,"abstract":"Neutrophil Extracellular Traps (NETs) are web-like structures composed of DNA, histones, and antimicrobial proteins released by activated neutrophils, which play a critical role in modulating neutrophil-mediated immune responses. Initially recognized for their role in host defense, NETs function as \"molecular traps\" that rapidly ensnare pathogens. They then achieve efficient clearance by directly degrading virulence factors through the action of associated antimicrobial proteins. However, the functions of NETs extend beyond immune defense. Dysregulation of NETs in pathological conditions can lead to detrimental effects. Recent studies have highlighted the importance of aberrant NET formation and impaired clearance in the pathogenesis of central nervous system (CNS) diseases, making them a field hotspot. In view of this, we discuss NETs, the structural characteristics and diverse generation patterns of NETs, and clarify how neutrophils cross the blood-brain barrier (BBB) to enter the CNS. We also explore triggers of NETosis within the brain, such as oxidative stress and inflammatory mediators. Furthermore, we analyze the pathological contributions of NETs to a range of CNS disorders, including stroke, traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), Alzheimer's disease (AD), multiple sclerosis (MS), etc. Finally, we summarize emerging neuroprotective strategies that target NETs, highlighting advances in interventions designed to inhibit NET formation or promote their degradation. By synthesizing current evidence, this review aims to uncover the mysterious veil of NETs in neurological diseases and to offer new insights for understanding disease mechanisms and developing targeted therapeutic approaches.","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":"31 1","pages":""},"PeriodicalIF":15.1,"publicationDate":"2026-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148313326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Riboregulation: a non-canonical tau function.","authors":"Katherine R LeBlanc, Randall J Eck, Sarah J Benbow, Brian C Kraemer","doi":"10.1186/s13024-026-00949-x","DOIUrl":"10.1186/s13024-026-00949-x","url":null,"abstract":"<p><p>Almost since its discovery, tau protein has perplexed scientists and clinicians with its varied roles in physiology as well as its appearance as phosphorylated protein aggregates of various structures in many neurodegenerative diseases. Tau plays a role in microtubule stabilization, but from the earliest of studies, tau has also been observed to bind to RNA, with recent research suggesting tau has a higher affinity for some RNA species compared to microtubules. In the context of disease, tau dysfunction potentiates disruptions to RNA metabolism, including the perturbation of mRNA splicing, impairment of translation, de-repression of transposable elements, and alteration of RNA export and degradation. Tau aggregates directly sequester diverse RNA species and RNA binding proteins. Emerging evidence reinforces the characterization of tau as an RNA binding protein, highlighting questions about both the physiological and disease-related functions of this direct RNA binding. The disparate structure of tau in normal and various disease states makes teasing apart the various impacts on RNA and regulation a more difficult puzzle requiring future study. In this review, we summarize the evidence for tau's role in RNA biology, including as an RNA binding protein.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13548662/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148283782","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 lymphatic dysfunction in Alzheimer's disease: molecular mechanisms, clinical implications, and future perspectives.","authors":"Lian Liu, Jiang-Hui Li, Yu-Di Bai, Yan-Jiang Wang, Xian-Le Bu","doi":"10.1186/s13024-026-00962-0","DOIUrl":"10.1186/s13024-026-00962-0","url":null,"abstract":"<p><p>The meningeal lymphatic system has recently emerged as a critical regulator of brain homeostasis, facilitating cerebrospinal fluid drainage, metabolic waste clearance, and immune cell trafficking. Accumulating evidence now implicates meningeal lymphatic dysfunction as a pivotal contributor to the pathogenesis of Alzheimer's disease (AD). This review critically evaluates current neuroimaging techniques for assessing meningeal lymphatic function in humans, highlighting their technical limitations in capturing dynamic pathological changes specific to AD. We summarize recent advances demonstrating that meningeal lymphatic impairment exacerbates key AD hallmarks-including amyloid-β (Aβ) and tau deposition, neuroimmune dysregulation, and myelin degradation-collectively accelerating disease progression. Building on these insights, we systematically analyse emerging therapeutic strategies aimed at enhancing meningeal lymphatic function, such as pharmacological approaches (e.g., vascular endothelial growth factor C (VEGF-C)-mediated lymphangiogenesis), physical interventions (e.g., transcranial photobiomodulation), and surgical techniques (e.g., cervical lymphaticovenous anastomosis). However, significant challenges remain, including the scarcity of direct human evidence linking meningeal lymphatic dysfunction to AD and the lack of standardized, noninvasive assessment tools. To address these gaps, we propose future fundamental and clinical research directions for meningeal lymphatic vessels and AD. By bridging mechanistic insights with translational applications, this review highlights the role of the meningeal lymphatic system as a promising yet underexplored target for AD modification.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13479427/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148226730","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":"Longitudinal multiphoton imaging of cerebral amyloid angiopathy in response to anti-ApoE4 immunotherapy in mice.","authors":"Orla Bonnar, Fareeha Saadi, Maria V Sanchez-Mico, Lee H Hanlin, Kali A Vom Eigen, Nicole Mumbi, Brian J Bacskai, Steven M Greenberg, David M Holtzman, Susanne J van Veluw","doi":"10.1186/s13024-026-00957-x","DOIUrl":"10.1186/s13024-026-00957-x","url":null,"abstract":"<p><strong>Background: </strong>There are no available treatments to halt or slow the progression of cerebral amyloid angiopathy (CAA), a disease neuropathologically characterized by the deposition of amyloid-β (Aβ) within the walls of the cerebrovasculature. Recently a novel therapeutic strategy has been described, targeting non-lipidated ApoE4 that co-deposits with Aβ, resulting in lower levels of Aβ across the brain. To understand the therapeutic potential for patients with CAA, we sought to determine if this global reduction in Aβ deposits corresponds to the active removal of existing aggregates in the vasculature and if so, whether this may improve vascular function over time.</p><p><strong>Methods: </strong>Cranial windows were implanted in 9-10-month-old 5xFAD mice expressing human APOE4 to facilitate chronic, unanesthetized imaging using in vivo multiphoton microscopy. Mice were treated weekly with anti-ApoE4 immunotherapy (HAE-4) or control IgG (50 mg/kg). Parenchymal and vascular Aβ burden as well as vascular function were measured in vivo before and during treatment. Post-mortem brains were assessed for CAA, parenchymal Aβ plaques and iron deposits. In a separate study, 5xFAD mice were treated with weekly HAE-4 or control IgG with the same doses of antibodies from 8 to 10 months of age in the absence of cranial windows.</p><p><strong>Results: </strong>Treatment with HAE-4 resulted in reduction of total Aβ plaque area post-mortem in mice and shrinkage of existing smaller plaques imaged with in vivo multiphoton microscopy. Vascular fibrillar Aβ under the cranial window conversely increased over time either with or without HAE-4 treatment and there was no treatment-associated improvement in vascular function in cortical arterioles in the areas measured in vivo. There was no evidence of hemorrhagic events linked to treatment, however there was significant immune cell activation. In 5xFAD mice treated without a cranial window, there was a reduction in plaques and CAA as previously described in HAE-4 vs. control treated mice.</p><p><strong>Conclusions: </strong>Anti-ApoE4 immunotherapy, as shown previously, decreased the overall amount of Aβ. It also appeared to remove some existing plaque Aβ without measurable effects on vascular fibrillar Aβ deposits or vascular function in areas measured in vivo under a cranial window. The absence of treatment-associated hemorrhagic events may offer a comparative advantage relative to anti-Aβ immunotherapy.</p>","PeriodicalId":18800,"journal":{"name":"Molecular Neurodegeneration","volume":" ","pages":""},"PeriodicalIF":19.6,"publicationDate":"2026-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13488262/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148226728","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}