Neurobiology of Disease最新文献

{"title":"Early α-synuclein aggregation decreases corticostriatal glutamate drive and synapse density","authors":"Charlotte F. Brzozowski ,&nbsp;Harshita Challa ,&nbsp;Nolwazi Z. Gcwensa ,&nbsp;Dominic Hall ,&nbsp;Douglas Nabert ,&nbsp;Nicole Chambers ,&nbsp;Ignacio Gallardo ,&nbsp;Michael Millet ,&nbsp;Laura Volpicelli-Daley ,&nbsp;Mark S. Moehle","doi":"10.1016/j.nbd.2025.106918","DOIUrl":"10.1016/j.nbd.2025.106918","url":null,"abstract":"<div><div>Neuronal inclusions of α-synuclein (α-syn) are pathological hallmarks of Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). α-Syn pathology accumulates in cortical neurons which project to the striatum. To understand how α-syn pathology affects cortico-striatal synapses at early time points before significant dopamine neuron loss, pre-formed α-syn fibrils (PFF) were injected into the striatum to induce endogenous α-syn aggregation in corticostriatal-projecting neurons. Electrophysiological recordings of striatal spiny projection neurons (SPNs) from acute slices found a significant decrease in evoked corticostriatal glutamate release and corticostriatal synaptic release sites in mice with PFF-induced aggregates compared to monomer injected mice. Expansion microscopy, confocal microscopy and Imaris reconstructions were used to identify VGLUT1 positive presynaptic terminals juxtaposed to Homer1 positive postsynaptic densities, termed synaptic loci. Quantitation of synaptic loci density revealed an early loss of corticostriatal synapses. Immunoblots of the striatum showed reductions in expression of pre-synaptic proteins VGLUT1, VAMP2 and Snap25, in mice with α-syn aggregates compared to controls. Paradoxically, a small percentage of remaining VGLUT1+ synaptic loci positive for pS129-α-syn aggregates showed enlarged volumes compared to nearby synapses without α-syn aggregates. Our combined physiology and high-resolution imaging data point to an early loss of corticostriatal synapses in mice harboring α-synuclein inclusions, which may contribute to impaired basal ganglia circuitry in PD and DLB.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"210 ","pages":"Article 106918"},"PeriodicalIF":5.1,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating myeloid-derived suppressor cell load and disease severity are associated to an enhanced oligodendroglial production in a murine model of multiple sclerosis","authors":"Mari Paz Serrano-Regal ,&nbsp;Celia Camacho-Toledano ,&nbsp;Inmaculada Alonso-García ,&nbsp;María Cristina Ortega ,&nbsp;Isabel Machín-Díaz ,&nbsp;Rafael Lebrón-Galán ,&nbsp;Jénnifer García-Arocha ,&nbsp;Leticia Calahorra ,&nbsp;Manuel Nieto-Díaz ,&nbsp;Diego Clemente","doi":"10.1016/j.nbd.2025.106919","DOIUrl":"10.1016/j.nbd.2025.106919","url":null,"abstract":"<div><div>Multiple sclerosis (MS) is a highly heterogeneous immune-mediated demyelinating disease. Myelin restoration is essential to prevent disability progression in MS patients. However, remyelinating therapies are failing in clinical trials, in part, due to the lack of biomarkers that classify the differing endogenous regenerative capacities of enrolled patients. In the experimental autoimmune encephalomyelitis (EAE) MS model, circulating monocytic myeloid-derived suppressor cells (M-MDSCs) are associated to milder disease courses, better recovery and less degree of tissue damage. Here, we show that disease severity affects the gradient of oligodendrocyte precursor cells (OPCs) present in mixed active-inactive lesions of MS patients, along with a positive correlation between M-MDSC density and OPC abundance. EAE disease severity negatively influences the density of total and newly generated OPCs found associated to the demyelinated lesions. In addition, disease severity also impacts the abundance of newly generated oligodendrocytes throughout the EAE disease course. Interestingly, circulating M-MDSCs at EAE onset and peak of the disease are directly associated to a higher density of newly generated oligodendrocytes in the demyelinated lesions. Our results set the basis for further studies on M-MDSCs as a promising new biomarker that identify a CNS prone to new oligodendrocyte generation in response to an inflammatory insult.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"210 ","pages":"Article 106919"},"PeriodicalIF":5.1,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864400","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Manifold functions of Mediator complex in neurodevelopmental disorders","authors":"Yi-Wei Li ,&nbsp;Si-Xin Tu ,&nbsp;Ze-Xuan Li ,&nbsp;Yu-Qiang Ding ,&nbsp;Ling Hu","doi":"10.1016/j.nbd.2025.106913","DOIUrl":"10.1016/j.nbd.2025.106913","url":null,"abstract":"<div><div>Neurodevelopmental disorders (NDDs) encompass a diverse range of impairments affecting brain development and functions, often presenting as deficits in motor skills, cognitive abilities, language development and neuropsychiatric health. The emergence of next-generation sequencing has unveiled numerous genetic variants linked to NDDs, implicating molecular pathways involved in essential neuronal processes such as synaptic plasticity, neuronal architecture and proteostasis. Central to these processes is the Mediator complex, a highly conserved multi-subunit assembly crucial for RNA polymerase II (Pol II)-dependent transcription. The Mediator functions as a key regulator of gene expression, playing a pivotal role in coordinating cellular processes essential for neuronal differentiation and developmental signaling cascades. Increasingly evidence has shown that its dysfunction is highly associated with the pathogenesis of NDDs. This review aims to comprehensively examine the structural and functional characteristics of individual mediator subunits. We will focus on clinical case reports and recent preclinical studies that highlight the connection between genetic abnormalities in the Mediator complex and specific neurodevelopmental phenotypes, ultimately guiding the development of enhanced diagnostic tools and therapeutic interventions. Furthermore, this review will advance our understanding of the general role transcriptional regulation plays in the etiology of NDDs.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"210 ","pages":"Article 106913"},"PeriodicalIF":5.1,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143860426","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cortical thickness and structural covariance network alterations in cerebral amyloid angiopathy: A graph theoretical analysis","authors":"Yijun Lin ,&nbsp;Bin Gao ,&nbsp;Yang Du ,&nbsp;Mengyao Li ,&nbsp;Yanfang Liu ,&nbsp;Xingquan Zhao","doi":"10.1016/j.nbd.2025.106911","DOIUrl":"10.1016/j.nbd.2025.106911","url":null,"abstract":"<div><h3>Aims</h3><div>This study investigates large-scale brain network alterations in cerebral amyloid angiopathy (CAA) using structural covariance network (SCN) analysis and graph theory based on 7 T MRI.</div></div><div><h3>Methods</h3><div>We employed structural covariance network (SCN) analysis based on cortical thickness data from ultra-high field 7 T MRI to investigate network alterations in CAA patients. Graph theoretical analysis was applied to quantify topological properties, including small-worldness, nodal centrality, and network efficiency. Between-group differences were assessed using permutation tests and false discovery rate (FDR) correction.</div></div><div><h3>Results</h3><div>CAA patients exhibited significant alterations in small-world properties, with decreased Gamma (<em>p</em> = 0.002) and Sigma (<em>p</em> &lt; 0.001), suggesting a shift toward a less optimal network configuration. Local efficiency was significantly different between groups (<em>p</em> = 0.045), while global efficiency remained unchanged (<em>p</em> = 0.127), indicating regionally disrupted rather than globally impaired network efficiency. At the nodal level, the right superior frontal gyrus exhibited increased betweenness centrality (<em>p</em> = 0.013), whereas the right banks of the superior temporal sulcus, left postcentral gyrus, and left superior temporal gyrus showed significantly reduced centrality (all <em>p</em> &lt; 0.05). Additionally, nodal degree and efficiency were altered in key memory-related and association regions, including the entorhinal cortex, fusiform gyrus, and temporal pole.</div></div><div><h3>Conclusion</h3><div>SCN analysis combined with graph theory offers a valuable approach for understanding disease-related connectivity disruptions and may contribute to the development of network-based biomarkers for CAA.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"210 ","pages":"Article 106911"},"PeriodicalIF":5.1,"publicationDate":"2025-04-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842542","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Imaging of human stem cell-derived dopamine grafts correlates with behavioural recovery and reveals microstructural brain changes","authors":"Stephen J. Paisey ,&nbsp;Lucy R. Jones ,&nbsp;David J. Harrison ,&nbsp;Nicola J. Drummond ,&nbsp;Olivia Z. Edwards ,&nbsp;Maurice A. Canham ,&nbsp;Victoria H. Roberton ,&nbsp;Christopher Marshall ,&nbsp;Greg Parker ,&nbsp;Rachel Hills ,&nbsp;Anne E. Rosser ,&nbsp;Emma L. Lane ,&nbsp;Stephen B. Dunnett ,&nbsp;Tilo Kunath ,&nbsp;Yaniv Assaf ,&nbsp;Mariah J. Lelos","doi":"10.1016/j.nbd.2025.106910","DOIUrl":"10.1016/j.nbd.2025.106910","url":null,"abstract":"<div><div>Cell therapy is a promising therapeutic intervention for Parkinson's disease (PD) and is currently undergoing safety and efficacy testing in clinical trials worldwide. The goals of this project were (1) to determine whether [¹⁸F]Fluorodopa or [¹⁸F]Fallypride imaging correlates robustly with functional recovery; and (2) to explore whether diffusion-weighted MR imaging (DWI) could detect graft-induced cytoarchitectural changes in the host brain. hfVM and hESC-derived dopamine precursor cells were transplanted into the 6-OHDA lesioned rat striatum. Tests of motor function and PET and MR imaging were conducted up to 6 months post-transplantation. Our data demonstrate that [¹⁸F]Fluorodopa imaging identified presynaptic DA synthesis from hfVM and hESC-derived dopaminergic grafts and [¹⁸F]Fallypride imaging confirmed occupancy and normalisation of D₂/D₃ receptor expression in the grafted hemisphere. In hfVM grafted rats, [¹⁸F]Fluorodopa binding correlated robustly with motor recovery on a range of drug-induced and drug-free behavioural tasks. In hESC-DA grafted rats, improvements in [¹⁸F]Fluorodopa PET imaging signals preceded recovery of naturalistic motor behaviours. DWI revealed widespread graft-mediated microstructural changes in the rodent brain, which did not identify graft placement, but instead may reflect remodelling of neuroglia. These data further our understanding of the impact of dopaminergic grafts on brain cytoarchitecture and the potential of these radioligands to predict graft efficacy may aid in the translation of therapeutics from preclinical to clinical settings.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"209 ","pages":"Article 106910"},"PeriodicalIF":5.1,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143828270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Disrupted synaptic gene expression in Fabry disease: Findings from RNA sequencing","authors":"Laura López-Valverde ,&nbsp;María E. Vázquez-Mosquera ,&nbsp;Cristóbal Colón-Mejeras ,&nbsp;J. Víctor Álvarez ,&nbsp;Beatriz Martín López-Pardo ,&nbsp;Lluis Lis López ,&nbsp;Rosario Sánchez-Martínez ,&nbsp;Manuel López-Mendoza ,&nbsp;Mónica López-Rodríguez ,&nbsp;Eduardo Villacorta-Argüelles ,&nbsp;María A. Goicoechea-Diezhandino ,&nbsp;Francisco J. Guerrero-Márquez ,&nbsp;Saida Ortolano ,&nbsp;Elisa Leao-Teles ,&nbsp;Álvaro Hermida-Ameijeiras ,&nbsp;María L. Couce","doi":"10.1016/j.nbd.2025.106908","DOIUrl":"10.1016/j.nbd.2025.106908","url":null,"abstract":"<div><div>Fabry disease (FD) is a rare X-linked lysosomal storage disorder caused by a deficiency in the enzyme α-galactosidase A. This defect leads to the progressive accumulation of glycosphingolipids, resulting in kidney, heart, and nervous system damage, which contributes to significant morbidity and mortality. Early diagnosis is essential to prevent irreversible damage and optimize treatment strategies. Recent research aims to provide a better understanding of FD pathophysiology to improve management approaches. This study is an international, multicenter, cross-sectional analysis that used RNA sequencing (RNA-seq) to compare blood samples from 50 FD patients and 50 age- and sex-matched healthy controls. The objective was to identify gene expression patterns and investigate secondary cellular pathways affected by lysosomal dysfunction. Among the more than 400 differentially expressed genes detected, 207 were protein-coding genes, most of which were overexpressed in the FD cohort. Functional enrichment analysis highlighted processes related to synaptic function, specifically concerning chemical synaptic transmission and membrane potential regulation. Identified genes included those related to voltage-gated ion channels, neurotransmitter receptors, cell adhesion molecules, scaffold proteins, and proteins associated with synaptic vesicles and neurotrophic signaling, all linked to lipid rafts. Notable identified genes included those encoding voltage-gated potassium channel genes (<em>KCNQ2</em>, <em>KCNQ3</em>, <em>KCNMA1</em>) and ionotropic receptor genes involved in glutamatergic (<em>GRIN2A</em>, <em>GRIN2B</em>) and GABAergic systems (<em>GABRA4</em>, <em>GABRB1</em>, <em>GABRG2</em>, <em>GABRQ</em>). These findings suggest that lysosomal dysfunction contributes to synaptic defects in FD, paving the way for further research into the role of synaptic pathology and lipid rafts in the underlying pathogenesis and clinical outcomes in FD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"209 ","pages":"Article 106908"},"PeriodicalIF":5.1,"publicationDate":"2025-04-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143834890","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conservation of strain properties of bank vole-adapted chronic wasting disease in the absence of glycosylation and membrane anchoring","authors":"Enric Vidal ,&nbsp;Hasier Eraña ,&nbsp;Jorge M. Charco ,&nbsp;Nuria L. Lorenzo ,&nbsp;Samanta Giler ,&nbsp;Montserrat Ordóñez ,&nbsp;Eva Fernández-Muñoz ,&nbsp;Maitena San-Juan-Ansoleaga ,&nbsp;Glenn C. Telling ,&nbsp;Manuel A. Sánchez-Martín ,&nbsp;Mariví Geijo ,&nbsp;Jesús R. Requena ,&nbsp;Joaquín Castilla","doi":"10.1016/j.nbd.2025.106894","DOIUrl":"10.1016/j.nbd.2025.106894","url":null,"abstract":"<div><div>Prion disease phenotypes (prion strains) are primarily determined by the specific misfolded conformation of the cellular prion protein (PrP^C). However, post-translational modifications, including glycosyl phosphatidyl inositol (GPI) membrane anchoring and glycosylation, may influence strain characteristics. We investigated whether these modifications are essential for maintaining the unique properties of bank vole-adapted Chronic Wasting Disease (CWD-vole), the fastest known prion strain. Using a novel transgenic mouse model expressing I109 bank vole PrP^C lacking the GPI anchor and largely devoid of glycans, we performed serial passages of CWD-vole prions. Despite elongated initial incubation periods, the strain maintained 100 % attack rate through three passages. Although the pathological phenotype showed characteristic GPI-less features, including abundant extracellular plaque formation, three subsequent serial passages in fully glycosylated and GPI-anchored bank vole I109 PrP^C expressing transgenic mice TgVole (1×) demonstrated that the strain's distinctive rapid propagation properties were preserved. These findings suggest that neither GPI anchoring nor glycosylation are essential for maintaining CWD-vole strain properties, supporting the concept that strain characteristics are primarily encoded in the protein's misfolded structure.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"210 ","pages":"Article 106894"},"PeriodicalIF":5.1,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ATXN2L primarily interacts with NUFIP2, the absence of ATXN2L results in NUFIP2 depletion, and the ATXN2-polyQ expansion triggers NUFIP2 accumulation","authors":"Jana Key ,&nbsp;Luis-Enrique Almaguer-Mederos ,&nbsp;Arvind Reddy Kandi ,&nbsp;Nesli-Ece Sen ,&nbsp;Suzana Gispert ,&nbsp;Gabriele Köpf ,&nbsp;David Meierhofer ,&nbsp;Georg Auburger","doi":"10.1016/j.nbd.2025.106903","DOIUrl":"10.1016/j.nbd.2025.106903","url":null,"abstract":"<div><div>The cytoplasmic Ataxin-2 (ATXN2) protein associates with TDP-43 in stress granules (SG) where RNA quality control occurs. Mutations in this pathway underlie Spinocerebellar Ataxia type 2 (SCA2) and Amyotrophic Lateral Sclerosis. In contrast, Ataxin-2-like (ATXN2L) is predominantly perinuclear, more abundant, and essential for embryonic life. Its sequestration into ATXN2 aggregates may contribute to disease. In this study, we utilized two approaches to clarify the roles of ATXN2L. First, we identified interactors through co-immunoprecipitation in both wild-type and ATXN2L-null murine embryonic fibroblasts. Second, we assessed the proteome profile effects using mass spectrometry in these cells. Additionally, we examined the accumulation of ATXN2L interactors in the SCA2 mouse model, <em>Atxn2</em>-CAG100-KnockIn (KIN). We observed that RNA-binding proteins, including PABPN1, NUFIP2, MCRIP2, RBMS1, LARP1, PTBP1, FMR1, RPS20, FUBP3, MBNL2, ZMAT3, SFPQ, CSDE1, HNRNPK, and HNRNPDL, exhibit a stronger association with ATXN2L compared to established interactors like ATXN2, PABPC1, LSM12, and G3BP2. Additionally, ATXN2L interacted with components of the actin complex, such as SYNE2, LMOD1, ACTA2, FYB, and GOLGA3. We noted that oxidative stress increased HNRNPK but decreased SYNE2 association, which likely reflects the relocalization of SG. Proteome profiling revealed that NUFIP2 and SYNE2 are depleted in ATXN2L-null fibroblasts. Furthermore, NUFIP2 homodimers and SYNE1 accumulate during the ATXN2 aggregation process in KIN 14-month-old spinal cord tissues. The functions of ATXN2L and its interactors are therefore critical in RNA granule trafficking and surveillance, particularly for the maintenance of differentiated neurons.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"209 ","pages":"Article 106903"},"PeriodicalIF":5.1,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143821063","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanism of PANoptosis and programmed cell death in neurological diseases","authors":"Ketian Hou ,&nbsp;Wenhan Pan ,&nbsp;Lianhui Liu ,&nbsp;Qianqian Yu ,&nbsp;Jiahao Ou ,&nbsp;Yueqi Li ,&nbsp;Xi Yang ,&nbsp;Zhenlang Lin ,&nbsp;Jun Hui Yuan ,&nbsp;Mingchu Fang","doi":"10.1016/j.nbd.2025.106907","DOIUrl":"10.1016/j.nbd.2025.106907","url":null,"abstract":"<div><div>PANoptosis represents a highly coordinated inflammatory programmed cell death governed by the assembly and activation of PANoptosome, which strategically integrate core molecular elements from pyroptosis, apoptosis, and necroptosis. The triple-component cell death pathways set themselves apart from alternative regulated cell death mechanisms through their unique capacity to concurrently integrate and process molecular signals derived from multiple death-signaling modalities, thereby coordinating a multifaceted cellular defense system against diverse pathological insults. Pathogen-associated molecular patterns synergistically interact with cytokine storms, and oncogenic stress to active PANoptosis, establishing this programmed cell death pathway as a critical nexus in inflammatory pathogenesis and tumor immunomodulation. This molecular crosstalk highlights PANoptosis as a promising therapeutic target for managing immune-related disorders and malignant transformation. Emerging evidence links PANoptosis to neuroinflammatory disorders through dysregulated crosstalk between programmed death pathways (apoptosis, necroptosis, pyroptosis) and accidental necrosis, driving neuronal loss and neural damage. Single-cell transcriptomics reveals spatially resolved PANoptosis signatures in Alzheimer's hippocampal microenvironments and multiple sclerosis demyelinating plaques, with distinct molecular clusters correlating to quantifiable neuroinflammatory metrics. Emerging PANoptosis-targeted therapies show preclinical promise in alleviating neurovascular dysfunction while preserving physiological microglial surveillance functions. Accumulating evidence linking dysregulated cell death pathways (particularly PANoptosis) to neurological disorders underscores the urgency of deciphering its molecular mechanisms and developing precision modulators as next-generation therapies. This review systematically deciphers PANoptosome assembly mechanisms and associated cell death cascades, evaluates their pathological roles in neurological disorders through multiscale regulatory networks, and proposes PANoptosis-targeted therapeutic frameworks to advance precision neurology.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"209 ","pages":"Article 106907"},"PeriodicalIF":5.1,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143829797","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differences in transcriptome characteristics and drug repositioning of Alzheimer's disease according to sex","authors":"Jingqi Shi ,&nbsp;Minghua Zhang ,&nbsp;Yazhuo Hu ,&nbsp;Jing Liu ,&nbsp;Ke Li ,&nbsp;Xuan Sun ,&nbsp;Siyu Chen ,&nbsp;Jianwei Liu ,&nbsp;Ling Ye ,&nbsp;Jiao Fan ,&nbsp;Jianjun Jia","doi":"10.1016/j.nbd.2025.106909","DOIUrl":"10.1016/j.nbd.2025.106909","url":null,"abstract":"<div><h3>Background</h3><div>Previous studies have shown significant sex differences in AD with regarding its epidemiology, pathophysiology, clinical presentation, and treatment response. However, the transcriptome variances associated with sex in AD remain unclear.</div></div><div><h3>Methods</h3><div>RNA sequencing (RNA-seq) and transcriptomic analyses were performed on peripheral blood samples from total of 54 patients, including male AD patients (<em>n</em> = 15), female AD patients (<em>n</em> = 10), male MCI patients (<em>n</em> = 7), female MCI patients (<em>n</em> = 11), male healthy controls (<em>n</em> = 6), female healthy controls (<em>n</em> = 5). The snRNA-seq dataset (GSE167494, GSE157827) of prefrontal cortex tissues was obtained from the Gene Expression Omnibus (GEO). We conducted an investigation into differentially expressed genes and pathways in the peripheral blood cells as well as prefrontal cortex tissues of both male and female AD patients with consideration to sex-related factors. Additionally, we analyzed the distribution and characteristics of cells in the cerebral cortex as well as the interaction and communication between cells of male and female AD patients. Connectivity Map (CMap) was utilized for predicting and screening potential sex-specific drugs for AD.</div></div><div><h3>Results</h3><div>The transcriptome profile and associated biological processes in the peripheral blood of male and female AD and MCI patients exhibit discernible differences, including upregulation of BASP1 in AD male patients and arousing TNS1 in AD female patients. The distribution of various cell types in the prefrontal cortex tissues differs between male and female AD patients, like neuron and oligodendrocyte decreased and endothelial cell and astrocyte increased in female compared with male, while a multitude of genes exhibit significant differential expression. The results of cell communication analysis, such as collagen signaling pathway, suggest that sex disparities impact intercellular interactions within prefrontal cortex tissues among individuals with AD. By drug repositioning, several drugs, including torin-2 and YM-298198, might have the potential to therapeutic value of MCI or AD, while drugs like homoharringtonine and teniposide have potential opposite effects in different sexes.</div></div><div><h3>Conclusion</h3><div>The characteristics of the transcriptome in peripheral blood and single-cell transcriptome in the prefrontal cortex exhibit significant differences between male and female patients with AD, which providing a basis for future sex stratified treatment of AD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"210 ","pages":"Article 106909"},"PeriodicalIF":5.1,"publicationDate":"2025-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143842541","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}