Xi-Yue Zhang , Hang Xu , Xue-Wei Ren , Qin-Xin Li , Chen Hong , Ye-Fan Chen , Jin Yang , Juan Ji , Ruo-Bing Guo , Xiu-Lan Sun
{"title":"Nuclear localization of platelet activating factor receptor accounts for microglial phagocytosis in ischemic stroke","authors":"Xi-Yue Zhang , Hang Xu , Xue-Wei Ren , Qin-Xin Li , Chen Hong , Ye-Fan Chen , Jin Yang , Juan Ji , Ruo-Bing Guo , Xiu-Lan Sun","doi":"10.1016/j.nbd.2025.107020","DOIUrl":"10.1016/j.nbd.2025.107020","url":null,"abstract":"<div><div>Ischemic stroke (IS) is a leading cause of global morbidity and mortality. A critical strategy for improving the prognosis of IS involves mitigating neuronal loss to enhance neuroplasticity, with microglia playing a vital role in neuronal survival. The platelet activating factor receptor (PTAFR) participates in the pathological processes underlying IS; however, little is known about its mechanism in pathological stress. In this study, we investigated the potential role of PTAFR in regulating the microglia/macrophage phagocytosis of neurons, aiming to identify new therapeutic strategies for IS. The mRNA and protein expression levels of PTAFR were upregulated, peaking on day 5 post-ischemic stroke and gradually returning to baseline levels thereafter. PTAFR was found to mediate interactions between the microglia/macrophage and neurons in IS. Notably, the inhibition of phagocytosis of stressed-but-viable neurons following IS depends on the nuclear localization of PTAFR. Mechanistically, nuclear PTAFR recruited the transcription factor Specificity Protein 1 (SP1) to initiate the transcription of milk fat globule EGF factor 8 (MFGE8). In comparison to the membrane-impermeable antagonist Ginkgolide B, the membrane-permeable PTAFR antagonist Apafant significantly enhances neurological recovery in IS model mice. This effect is achieved by inhibiting PTAFR nuclear translocation, which reduces microglia/macrophage phagocytosis of stressed-but-viable neurons. Our findings provide insight into the mechanism of nuclear PTAFR-mediated microglia/macrophage phagocytosis and have significant implications for the selection of PTAFR antagonists in the treatment of ischemic stroke, particularly those targeting nuclear receptors.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107020"},"PeriodicalIF":5.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584278","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}
Joshua Peter , Kaejaren C.N. Caldwell , Lucas McClain , Jason Tchieu , Ashley E. Ross , Yu Luo
{"title":"Inhibition of PTPRS function does not affect the survival or regeneration of dopaminergic neurons but alters synaptic function in the nigrostriatal pathway","authors":"Joshua Peter , Kaejaren C.N. Caldwell , Lucas McClain , Jason Tchieu , Ashley E. Ross , Yu Luo","doi":"10.1016/j.nbd.2025.107023","DOIUrl":"10.1016/j.nbd.2025.107023","url":null,"abstract":"<div><div>Parkinson's Disease (PD) is characterized by midbrain dopaminergic (mDA) neuron degeneration in the ventral midbrain, contributing to debilitating motor symptoms. This study investigated whether Protein Tyrosine Phosphatase Receptor Sigma (PTPRS), a known inhibitor of axonal growth through chondroitin sulfate proteoglycan (CSPG) interaction, plays a role in mDA neuron survival, function, and regeneration in PD. Our data show that inhibition of PTPRS using intracellular sigma peptide (ISP) enhances human mDA neuron neurite outgrowth in vitro, suggesting an inhibitory role of this receptor in the differentiation of human embryonic stem cell (hESC)-derived mDA neurons in vitro. However, genetic deletion and pharmacological inhibition of PTPRS does not affect mDA neuron survival, axon density, or motor behavior in 6-OHDA unilateral partially lesioned mice. Similarly, mDA-specific deletion of <em>Ptprs</em> does not affect the basal behavioral measurement in cKO mice, including general locomotion and motor learning. Interestingly, however, <em>Ptprs</em> deletion led to a reduced response in the behavior sensitization to repeated methamphetamine (METH) exposure in cKO mice, suggesting a dampened response in synaptic function in cKO mice under these conditions. Ex vivo voltammetry recording in the striatum indeed shows altered parameters of dopamine (DA) release upon stimulation. These findings indicate that the inhibition of PTPRS function in human mDA neuron progenitors might be a promising strategy for enhancing neurite outgrowth or incorporation in host tissues in transplantation therapies. Finally, our data support that inhibition of PTPRS function in mDA neurons in adult mice in vivo could inhibit METH induced plasticity and behavioral sensitization.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107023"},"PeriodicalIF":5.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144581284","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}
Tao Feng , Yanfeng Yang , Yihe Wang , Xiaotong Fan , Tianren Wang , Sichang Chen , Penghu Wei , Yongzhi Shan , Guoguang Zhao
{"title":"Mapping grey matter and network abnormalities in seizure-onset patterns via stereotactic EEG","authors":"Tao Feng , Yanfeng Yang , Yihe Wang , Xiaotong Fan , Tianren Wang , Sichang Chen , Penghu Wei , Yongzhi Shan , Guoguang Zhao","doi":"10.1016/j.nbd.2025.107021","DOIUrl":"10.1016/j.nbd.2025.107021","url":null,"abstract":"<div><h3>Background</h3><div>Mesial temporal lobe epilepsy (MTLE) is the most common medically refractory focal epilepsy, classified into seizure-onset patterns (SOPs) such as hypersynchronous (HYP) and low-voltage fast (LVF) rhythms. However, the morphological and network differences underlying these SOPs and their prognostic implications remain unclear.</div></div><div><h3>Methods</h3><div>Using voxel-based morphometry (VBM) and individualized structural covariance networks (IDSCNs), we analyzed 55 MTLE patients and 37 healthy controls with high-resolution MRI and stereotactic EEG recordings. VBM identified grey matter volume (GMV) abnormalities, and IDSCNs evaluated patient-specific network disruptions. Hierarchical clustering explored network subtypes, and ROC analysis assessed the predictive value of VBM and IDSCN measures for surgical outcomes.</div></div><div><h3>Results</h3><div>HYP-onset patients exhibited ipsilateral mesial temporal atrophy and widespread bilateral network disruptions centered on the hippocampus and supramarginal gyrus, along with significant interhemispheric connectivity abnormalities. LVF-onset patients showed subcortical abnormalities and hemispheric network disruptions centered on the fusiform gyrus, with limited interhemispheric propagation. Both SOPs displayed basal ganglia abnormalities. Hierarchical clustering revealed SOP-specific network subtypes. IDSCN outperformed VBM in predicting surgical outcomes.</div></div><div><h3>Conclusion</h3><div>This study identifies distinct SOP-related morphological and network abnormalities in MTLE and suggests that IDSCN may offer valuable insights into personalized treatment planning and prognostic evaluation, supporting further exploration of network-based biomarkers.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107021"},"PeriodicalIF":5.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144584377","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}
Hong-Li Guo , Xi-Li Sun , Yang-Yang Xu , Yuan-Yuan Zhang , Jie Wang , Lin Fan , Ya-Hui Hu , Fang Sun , Heng Tang , Xiao-Peng Lu , Jin Xu , Feng Chen
{"title":"An elusive causal link between epilepsy and vitamin D in children: More questions than answers? A narrative review","authors":"Hong-Li Guo , Xi-Li Sun , Yang-Yang Xu , Yuan-Yuan Zhang , Jie Wang , Lin Fan , Ya-Hui Hu , Fang Sun , Heng Tang , Xiao-Peng Lu , Jin Xu , Feng Chen","doi":"10.1016/j.nbd.2025.107022","DOIUrl":"10.1016/j.nbd.2025.107022","url":null,"abstract":"<div><div>When discussing childhood epilepsy and children's serum vitamin D status together, the matter becomes complex and intriguing. A long-standing question has been whether there is a causal link between epilepsy itself and the serum vitamin D status: does vitamin D deficiency lead to seizures, or do seizures occur alongside or result in vitamin D deficiency, or is the deficiency caused by anti-seizure medication therapy? Clarifying these questions would significantly enhance our understanding of the relationship between them and improve the treatment and management for childhood epilepsy. This narrative review summarized existing literature on vitamin D and pediatric epilepsy and collected those clinical and non-clinical researches in this field to see if sufficient evidence has accumulated to address these questions. Current evidence revealed that children with epilepsy experienced higher rates of vitamin D deficiency, but whether this stems from the condition itself or its treatment remains uncertain. Both clinical and non-clinical studies suggested vitamin D may help control seizures, but its effective dosing and treatment duration need rigorous clinical validation. This clinical situation indicates that continued attention is needed on this important clinical issue concerning children's health, as well as more efforts and attempts to ultimately clarify these matters.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107022"},"PeriodicalIF":5.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144581283","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":"The complex phenotype and function of spinal cord microglia during ALS progression and the impact of metabotropic glutamate receptor type 5 down-regulation in SOD1G93A mice","authors":"Matilde Balbi , Carola Torazza , Tiziana Altosole , Silvia Ravera , Emanuele Farinini , Sara Tessitore , Francesca Bacchetti , Francesca Rosso , Ilaria Musante , Silvana Alfei , Maria Cerminara , Aldamaria Puliti , Gilberto Filaci , Daniela Fenoglio , Riccardo Leardi , Ernesto Fedele , Giambattista Bonanno , Marco Milanese , Tiziana Bonifacino","doi":"10.1016/j.nbd.2025.107017","DOIUrl":"10.1016/j.nbd.2025.107017","url":null,"abstract":"<div><div>Over the last few decades, scientists' attention has shifted from neuronal to non-neuronal cells to explain the mechanisms at the basis of neurodegenerative disorders, including amyotrophic lateral sclerosis (ALS). ALS is a multifactorial and multicellular disease in which microglia have a central role, during disease progression. We previously demonstrated that metabotropic glutamate receptor 5 (mGluR5) is dysfunctional in the spinal cord of the SOD1<sup>G93A</sup> ALS mice, and its in-vivo genetic or pharmacological dampening ameliorates disease outcome and astrocyte and microglia reactivity. Here, we studied the expression of typical phenotype-related markers during the disease progression in spinal cord microglia cells acutely isolated from early asymptomatic and late symptomatic SOD1<sup>G93A</sup> ALS mice. Moreover, we investigated whether reducing mGluR5 affected the microglia phenotype and function. In contrast to what we previously observed in astrocytes, mGluR5 expression decreased during disease progression in microglia acutely isolated from adult SOD1<sup>G93A</sup> mice. In-vivo genetic mGluR5 downregulation did not affect microglia phenotype-relevant markers, which evidenced a unique expression distribution. Conversely, mGluR5 reduction ameliorated redox balance and bioenergetics of adult microglia. Microglia cultured from the spinal cord of SOD1<sup>G93A</sup> pups showed that in-vitro mGluR5 pharmacological manipulation by the negative allosteric modulator CTEP partially modified their bioenergetic and oxidative status. Overall, our results suggest that mGluR5 manipulation ameliorates microglia phenotype and function in ALS by both direct and indirect mechanisms. Consequently, we hypothesised that the improvement of microglia reactive status by in-vivo mGluR5 downregulation or CTEP pharmacological modulation is supported by ameliorated bioenergetic metabolism, and the indirect astrocyte's phenotype change that promotes an improvement of the surrounding environment.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107017"},"PeriodicalIF":5.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575874","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":"A novel stable transgenic zebrafish line expressing mCherry-tagged human alpha-synuclein in the nervous system and exhibiting all the key features of Lewy body disorders at larval stage","authors":"Silvia Zini , Alessia Muscò , Francesca Longhena , Gaia Faustini , Chiara Tobia , Giuseppe Borsani , Maria Grazia Spillantini , Daniela Zizioli , Arianna Bellucci","doi":"10.1016/j.nbd.2025.107018","DOIUrl":"10.1016/j.nbd.2025.107018","url":null,"abstract":"<div><div>Lewy Bodies, proteinaceous inclusions containing α-Synuclein fibrillary aggregates, are defining neuropathological hallmarks of Parkinson's disease and Dementia with Lewy Bodies. Recently, zebrafish arose as a valuable model to study neurodegenerative diseases, but despite attempts to generate stable human α-Synuclein transgenic zebrafish lines recapitulating the main phenotypic characteristics of Lewy Body disorders, <em>i.e.</em>, α-Synuclein fibrillary aggregate deposition, neurodegeneration and behavioral deficits, none of the models produced so far could develop all these features. Here, we describe the generation of a novel transgenic zebrafish line stably expressing human α-Synuclein in the nervous system and developing all the key Parkinson's Disease phenotypic traits during larval stage, named Tg(<em>elavl3</em>:mCherry-<em>hsa.SNCA</em>). By behavioral studies, molecular biology analysis, confocal and light-sheet fluorescence microscopy we found that Tg(<em>elavl3</em>:mCherry-<em>hsa.SNCA</em>) larvae developed basal motility deficits and anxiety traits as well as a significant increase of brain apoptotic cells in parallel with marked reduction of tyrosine hydroxylase-immunopositivity in forebrain regions at 5 days post fertilization. The Tg(<em>elavl3</em>:mCherry-<em>hsa.SNCA</em>) larvae accumulated Thioflavin-S-positive and high molecular weight serine-129-phosphorylated α-Synuclein. Furthermore, they displayed other typical pathologic alterations associated with Parkinson's Disease and Dementia with Lewy Bodies, such as accumulation of synapsins and changes in key autophagy markers. These findings, coupled with the suitability of larval zebrafish for high-throughput screening, support that the novel Tg(<em>elavl3</em>:mCherry-<em>hsa.SNCA</em>) line constitutes the first stable zebrafish experimental model for rapid and reliable studies addressing both the molecular basis of Lewy body disorders and the efficacy of new therapeutic approaches.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107018"},"PeriodicalIF":5.1,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575856","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}
Li Zhang , Alireza Pouya , Janina Kopetzky , Sara Bitar , Christina Wolf , Federica Dal Bello , David Gomez-Zepeda , Stefan Tenzer , Axel Methner
{"title":"Increased BNIP3-mediated mitophagy attenuates GDAP1 loss of function - implications for Charcot-Marie-Tooth disease 4A","authors":"Li Zhang , Alireza Pouya , Janina Kopetzky , Sara Bitar , Christina Wolf , Federica Dal Bello , David Gomez-Zepeda , Stefan Tenzer , Axel Methner","doi":"10.1016/j.nbd.2025.107019","DOIUrl":"10.1016/j.nbd.2025.107019","url":null,"abstract":"<div><div>Charcot-Marie-Tooth disease type 4 A ((CMT4A), an autosomal recessive neuropathy, is caused by mutations in ganglioside-induced differentiation-associated protein 1 (<em>GDAP1</em>). GDAP1 resides in the outer mitochondrial membrane facing the cytosol and is involved in mitochondrial dynamics and function. Its perturbation affects mitochondrial shape, contact sites, redox homeostasis and cellular metabolism. In response to <em>GDAP1</em> knockdown in a human neuronal cell line, we found increased mitochondrial turnover, biogenesis and mitophagy. This was associated with more lysosomal proteins in mitochondrial fractions including BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3) and its homolog BNIP3-like (BNIP3L) – proteins involved in the recruitment of autophagy machinery via direct interaction. Flies with neural <em>Gdap1</em> knockdown also exhibited upregulated levels of the sole BNIP3 ortholog. Neural expression of human BNIP3 reduced the detrimental effects of <em>Gdap1</em> knockdown on eclosion and climbing ability in adult flies, while simultaneous knockdown of both genes was detrimental. These findings suggest that increased BNIP3-driven mitophagy may act as a protective mechanism, partially counteracting the cellular dysfunction caused by <em>GDAP1</em> loss of function, and highlight the potential of targeting mitophagy pathways as a therapeutic strategy for CMT4A.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107019"},"PeriodicalIF":5.1,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144575873","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}
Sara Naya-Forcano , Ángel Gaudioso , Beatriz Soto-Huelin , Celia García-Vilela , César Venero , Edward H. Schuchman , José A. Esteban , María Dolores Ledesma
{"title":"Sphingomyelin-induced glucocorticoid receptor alterations lead to impaired presynaptic plasticity in acid sphingomyelinase deficient neurons","authors":"Sara Naya-Forcano , Ángel Gaudioso , Beatriz Soto-Huelin , Celia García-Vilela , César Venero , Edward H. Schuchman , José A. Esteban , María Dolores Ledesma","doi":"10.1016/j.nbd.2025.107016","DOIUrl":"10.1016/j.nbd.2025.107016","url":null,"abstract":"<div><div>Acid sphingomyelinase deficiency (ASMD) is a rare disease caused by mutations in the gene encoding ASM, an enzyme that degrades sphingomyelin (SM). In addition to SM accumulation, neuroinflammation and cognitive impairment are pathological hallmarks of neurovisceral ASMD. Since the glucocorticoid system may influence these features, we have characterized it in ASM knockout (ASMko) mice that mimic this form of the disease. While plasma corticosterone levels are not altered in these mice, brain levels of the α, but not the β, isoform of glucocorticoid receptors (GR) are reduced. The reduction is evident in neurons and is due to the accumulation of SM. As a consequence, the expression of the protein, synapsin I, is low in ASMko neurons, leading to the disorganization of synaptic vesicles and to impaired presynaptic plasticity. Treatment with the glucocorticoid hydrocortisone diminished SM levels, increased synapsin I expression, and improved presynaptic function in neuronal cultures and hippocampal slices of ASMko mice. These findings establish, for the first time, a link between the glucocorticoid system and brain pathology in ASMD, highlighting the GR as a potential therapeutic target for this devastating disease.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107016"},"PeriodicalIF":5.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144535385","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}
Virginia Pelagotti , Domenico Plantone , Francesca D’Amico , Stefano Raffa , Pietro Mattioli , Beatrice Orso , Mattia Losa , Carlo Manco , Delia Righi , Dario Arnaldi , Antonio Uccelli , Andrea Chincarini , Gianmario Sambuceti , Silvia Morbelli , Nicola De Stefano , Federico Massa , Matteo Pardini
{"title":"[18F]FDG PET metabolic correlates of cerebrospinal fluid TAR DNA-binding protein 43 in prodromal Alzheimer's disease","authors":"Virginia Pelagotti , Domenico Plantone , Francesca D’Amico , Stefano Raffa , Pietro Mattioli , Beatrice Orso , Mattia Losa , Carlo Manco , Delia Righi , Dario Arnaldi , Antonio Uccelli , Andrea Chincarini , Gianmario Sambuceti , Silvia Morbelli , Nicola De Stefano , Federico Massa , Matteo Pardini","doi":"10.1016/j.nbd.2025.107014","DOIUrl":"10.1016/j.nbd.2025.107014","url":null,"abstract":"<div><h3>Introduction</h3><div>Limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC) are characterized by phosphorylated TDP-43 aggregates in limbic regions, often co-occurring with Alzheimer's disease (AD) pathology, amplifying clinical and neuroimaging alterations. <em>In vivo</em> biomarkers for LATE-NC are lacking, but changes in CSF TDP-43 levels may reflect LATE-NC in AD patients. This study explored the correlation between CSF TDP-43 and [<sup>18</sup>F]FDG PET metrics in prodromal AD, providing insights into the impact of LATE-NC on AD brain metabolism.</div></div><div><h3>Methods</h3><div>We measured CSF TDP-43 levels using an ultrasensitive immunoassay in 27 MCI-AD patients. To analyze brain metabolism, we employed both a volume of interest (VOI)-based approach and a voxel-based analysis (VBA) of [<sup>18</sup>F]FDG PET scans. The VOI-based approach focused on metabolic values from regions associated with LATE-NC, such as the inferior (IT) and medial temporal (MT) regions, in previous studies. Through VBA, we explored the CSF TDP-43-related brain regions and their spatial association with relative hypometabolism compared with 40 healthy controls (HC), adjusting for relevant covariates.</div></div><div><h3>Results</h3><div>CSF TDP-43 levels directly correlated with metabolism in the temporo-parietal cortex, particularly the bilateral precuneus, and showed spatial independence from relative hypometabolic areas. The VOI analysis revealed no significant correlations between TDP-43 and the MT-VOI, IT-VOI, or their ratio.</div></div><div><h3>Conclusions</h3><div>TDP-43 pathology in prodromal AD, as indicated by elevated CSF TDP-43 levels, contributes to metabolic disruptions in posterior parietal regions, particularly the precuneus. These changes diverge from typical amyloid- and tau-related alterations, offering indirect <em>in vivo</em> insights into TDP-43 co-pathology in prodromal AD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107014"},"PeriodicalIF":5.1,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144560602","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}
Katelynn E. Krick , Erica M. Weekman , Sherika N. Johnson , Tiffany L. Sudduth , Colin B. Rogers , Emma J. Nicolayson , Maureen T. Kleinhenz , Donna M. Wilcock
{"title":"Age-related cerebral amyloid angiopathy accumulation in the APPSw mouse model is associated with perivascular inflammation and brain-wide vascular and inflammatory gene and protein changes","authors":"Katelynn E. Krick , Erica M. Weekman , Sherika N. Johnson , Tiffany L. Sudduth , Colin B. Rogers , Emma J. Nicolayson , Maureen T. Kleinhenz , Donna M. Wilcock","doi":"10.1016/j.nbd.2025.107013","DOIUrl":"10.1016/j.nbd.2025.107013","url":null,"abstract":"<div><div>Cerebral amyloid angiopathy (CAA) is an extremely common pathology of Alzheimer's disease (AD) included under vascular contributions to cognitive impairment and dementia (VCID). CAA has been reported in 78–98 % of AD cases and has clinical significance when considering side effects that arise when using amyloid targeting immunotherapies. Despite its prevalence, studies addressing CAA mechanisms have been scarce and there are clear gaps in our understanding of how CAA progresses. This study uses Tg2576 mice, who develop CAA over time, to establish a time course of CAA progression at 8-, 14-, and 20-months of age. We identify changes in transcriptomic signatures of glial cells using NanoString nCounter and targeted protein changes using NanoString Digital Spatial Profiling. Meso Scale Discovery and immunohistochemistry are used to establish disease progression. In this study, we saw many changes primarily associated with inflammatory response, with some changes being transient (<em>Tnf, Lsr;</em> VEGF<em>)</em> and others remaining chronically altered (<em>Osmr, Ccl3;</em> CTSD). Overarchingly, many of these changes relate to the perpetuation of inflammation or recruiting additional immune support, which we see across our timepoints. Further, we identified differences in abundance of proteins (CD45, GFAP, CD31) based on presence of CAA positive vessels within a brain region. We also identified sex-specific differences in CAA burden, as well as how glial reactivity and vessel density change during disease progression. This data represents a comprehensive analysis of CAA progression and differential responses to parenchymal and vascular amyloid that could inform future basic and clinical studies.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"213 ","pages":"Article 107013"},"PeriodicalIF":5.1,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144535386","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}