Neurobiology of Disease最新文献

{"title":"P2RX7 modulates the function of human microglia-like cells and mediates the association of IL18 with Alzheimer's disease traits","authors":"Kelsey S. Heavener ,&nbsp;Kirstin A. Tamucci ,&nbsp;Annie J. Lee ,&nbsp;Khushbu Kabra ,&nbsp;Zena K. Chatila ,&nbsp;Maedot Yidenk ,&nbsp;David A. Bennett ,&nbsp;Badri N. Vardarajan ,&nbsp;Elizabeth M. Bradshaw","doi":"10.1016/j.nbd.2025.107106","DOIUrl":"10.1016/j.nbd.2025.107106","url":null,"abstract":"<div><div>The immune system plays a dynamic role in neurodegenerative diseases, and purinergic receptors allow immune cells to recognize neuronal signaling, cell injury, or stress. Purinergic Receptor 7 (P2RX7) can modulate inflammatory cascades, and its expression is upregulated in Alzheimer's disease (AD) brain tissue. P2RX7 expression is enriched in microglia, and elevated levels are found in microglia surrounding amyloid-beta (Aβ) plaques in the brain. Despite evidence linking P2RX7 to AD, the mechanisms by which it shapes microglial responses and contributes to AD remain poorly defined. Here, we utilize a human monocyte-derived microglia-like cell model (MDMi) to interrogate P2RX7 activation and downstream consequences on microglial function. Specifically, we measured <em>IL1β</em> and <em>IL18</em> production and Aβ1–42 uptake following ATP-induced P2RX7 activation. Our results show that ATP-stimulation of MDMi triggers upregulation of <em>IL1β</em> and <em>IL18</em> expression, which is blocked with the A740003 P2RX7 antagonist. Elevated extracellular ATP also impaired Aβ1–42 uptake, an effect reversed by P2RX7 inhibition with A740003. In addition, pretreatment of MDMi with IL-1Ra limited ATP-driven <em>IL1β</em> and <em>IL18</em> gene expression upregulation, indicating that ATP immunomodulation of P2RX7 is IL-1R dependent. Critically, analysis of postmortem human brain revealed that <em>P2RX7</em> expression significantly mediated the association between <em>IL18</em>, but not <em>IL1β</em>, and multiple AD traits, including amyloid load, tau tangle density, global AD pathology burden, cortical and neocortical Lewy bodies, cognitive decline, and clinical dementia. Consistent with these findings, in our MDMi model, <em>P2RX7</em> gene expression correlated with <em>IL18</em> but not <em>IL1β</em>. Together, these findings highlight P2RX7 as a critical integrator of extracellular danger signals and microglial immune function, underscoring its potential as a therapeutic target in neurodegeneration.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"216 ","pages":"Article 107106"},"PeriodicalIF":5.6,"publicationDate":"2025-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131641","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":"PKR-driven ISR signaling controls synaptic translation and structural plasticity in an age-dependent manner.","authors":"Nicolás W Martínez, Felipe Gómez, Ariel Tapia-Godoy, Juan Francisco Roa, Yuwei Liu, Claudia Jara, Cheril Tapia-Rojas, Iván Alfaro, Mauro Costa-Mattioli, Soledad Matus","doi":"10.1016/j.nbd.2025.107113","DOIUrl":"https://doi.org/10.1016/j.nbd.2025.107113","url":null,"abstract":"<p><p>The integrated stress response (ISR) modulates protein homeostasis in response to both intracellular and extracellular signals. The four kinases involved in the ISR all phosphorylate the same target, the alpha subunit of eukaryotic initiation factor 2 (eIF2a), to integrate various stress signals, thereby regulating cell fate. The activation of the ISR reprograms the proteome by inhibiting general protein synthesis while increasing the translation of specific mRNAs. In the brain, the ISR regulates the type of synaptic plasticity necessary for forming long-term memory. More importantly, the activation of the ISR has emerged as a causal mechanism underlying cognitive decline associated with a wide range of neurological disorders, prompting several pharmaceutical companies to target the ISR to promote brain health. However, whether the ISR acts at specific localities within neurons, including synapses, remains unclear. Here, we examined the presence, activity, and spatial arrangement of the ISR branch driven by the double-stranded RNA-dependent protein kinase (PKR) (PKR-eIF2a axis) in synapses and assessed the role of PKR in maintaining synaptic proteostasis over time. Our findings demonstrate that both PKR and eIF2a are localized at synapses, where a dynamic PKR-eIF2a axis regulates synaptic size and the abundance of synaptic proteins in an age-dependent manner. Moreover, PKR deficiency leads to an increase in protein synthesis in synapse-enriched fractions. Thus, the PKR branch of the ISR serves as a new regulator of synaptic structural plasticity.</p>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":" ","pages":"107113"},"PeriodicalIF":5.6,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145113862","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":"Projection from the parafascicular nucleus of the thalamus to the insular cortex mediate analgesia and anti-anxiety behaviors in mice","authors":"Fei Li ,&nbsp;Zi-Ang Li ,&nbsp;Jia Li ,&nbsp;Hui-Min Tian ,&nbsp;Dong-Ning Li ,&nbsp;Zhong-Yi Liu ,&nbsp;Jin Cheng ,&nbsp;Tian-Yu Zhao ,&nbsp;Li-Ming Liu ,&nbsp;Yao-Hua Liu ,&nbsp;Sha-Sha Tao ,&nbsp;Fen-Sheng Huang ,&nbsp;Yan-Gang Sun ,&nbsp;Shui-Bing Liu ,&nbsp;Yun-Qing Li","doi":"10.1016/j.nbd.2025.107107","DOIUrl":"10.1016/j.nbd.2025.107107","url":null,"abstract":"<div><div>The parafascicular nucleus of the thalamus (PF), part of the intralaminar nuclei of the thalamus, plays critical roles in both motor and pain regulations. In this study, the projection from the ventral region of the PF to the dorsal area of the insular cortex (IC) were identified using a neuroanatomical approach. Then, chemogenetic inhibition or activation of the PF-IC neural pathway in the normal mice or in the spared nerve injury (SNI) model mice induced hyperalgesia and anxiety-like behaviors or alleviated hypersensitivity and anxiety-like behaviors, respectively. Additionally, a reduction in the intrinsic electrophysiological activity of the PF neurons projecting to the IC was recorded in 2-week SNI mice. Finally, the results of viral tracing and immunofluorescence histochemical staining demonstrated that the fibers and terminals projecting from the PF predominantly terminated on the parvalbumin-positive interneurons. These findings suggest that the activity of the PF-IC neuronal pathway is suppressed under neuropathic pain condition and that the activation of this pathway exhibits analgesic and anxiolytic effects in mice suffering from nerve injury.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"216 ","pages":"Article 107107"},"PeriodicalIF":5.6,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145102961","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 relationship between anaemia, haemoglobin levels, and cognitive function: Evidence in two population-based cohorts from India and the United States","authors":"Laura M. Winchester ,&nbsp;Danielle Newby ,&nbsp;Upamanyu Ghose ,&nbsp;Peifeng Hu ,&nbsp;Hunter Green ,&nbsp;Sandy Chien ,&nbsp;Janice M. Ranson ,&nbsp;Jessica Faul ,&nbsp;David Llewellyn ,&nbsp;Jinkook Lee ,&nbsp;Sarah Bauermeister ,&nbsp;Alejo Nevado-Holgado","doi":"10.1016/j.nbd.2025.107112","DOIUrl":"10.1016/j.nbd.2025.107112","url":null,"abstract":"<div><h3>Background</h3><div>In India, studies of anaemia in older populations are lacking despite the adverse effect on cognitive function and dementia. The Longitudinal Ageing Study in India–Harmonized Diagnostic Assessment of Dementia (LASI-DAD) dataset contains detailed measures to allow better understanding of anaemia as a potential risk factor for dementia.</div></div><div><h3>Method</h3><div>Linear regression was applied in the LASI-DAD cohort (<em>n</em> = 2758) between blood measures (including anaemia and haemoglobin concentration (g/dL)) with 11 cognitive tests. All models were adjusted for age and gender (full model includes rural location, education, smoking, region, BMI and population weights). The USA-based Health and Retirement Study (HRS) cohort (<em>n</em> = 5720) was used to replicate associations between blood and global cognition.</div></div><div><h3>Results</h3><div>In LASI-DAD, we showed an association between anaemia and poor memory (<em>p</em>-value = 0.0054). We found a positive association between haemoglobin concentration and ten cognitive tests (β = 0.041–0.071,<em>p</em>-value&lt;0.05). The strongest association with haemoglobin was identified for memory-based tests (β = 0.061–0.071,<em>p</em>-value&lt;0.005). Positive associations were shown between the general cognitive score and red blood count tests including mean corpuscular haemoglobin concentration (MCHC,β = 0.06,<em>p</em>-value = 0.0001) and red cell distribution width (RDW,β = −0.11,<em>p</em>-value&lt;0.0001). In the HRS, associations were replicated between general cognitive score and other blood count tests (Red Blood Cell, MCHC, RDW, p-value&lt;0.05).</div></div><div><h3>Conclusions</h3><div>We have established in a South Asian population that low haemoglobin and anaemia are associated with low cognitive function, therefore indicating that anaemia could be an important modifiable risk factor for dementia. We have validated this result demonstrating both the variability of this risk factor cross-nationally and its generalizable association with cognitive outcomes.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"216 ","pages":"Article 107112"},"PeriodicalIF":5.6,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091594","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":"Subtype-specific alterations in first- and higher-order thalamic reticular neurons in the Shank3 mutant mouse model of autism","authors":"Carlos Alberto Ortiz-Cruz ,&nbsp;Miroslava Peralta-Ramirez ,&nbsp;Mateo Alberto Herrera-Murillo ,&nbsp;Regina Andrea Mejia-Ortiz ,&nbsp;Marcela Palomero-Rivero ,&nbsp;Baolin Guo ,&nbsp;Uri Nimrod Ramirez-Jarquin ,&nbsp;Violeta Gisselle Lopez-Huerta","doi":"10.1016/j.nbd.2025.107108","DOIUrl":"10.1016/j.nbd.2025.107108","url":null,"abstract":"<div><div>The thalamic reticular nucleus (TRN) is a critical inhibitory structure in the thalamocortical network, playing key roles in sensory processing, attention, cognitive flexibility, and sleep rhythms; importantly these functions are altered in autism spectrum disorder (ASD). The TRN consists mainly of two neuronal subpopulations: first order (FO) neurons, which modulate sensory relay nuclei, and higher-order (HO) neurons, which control associative thalamic circuits. TRN-FO neurons are located in the core region, show a high expression of repetitive burst firing, and are known to contribute to slow-wave oscillations. In contrast, neurons innervating HO thalamic nuclei are in the anterior and peripheral regions of the TRN and have fewer burst firing. These subpopulations provide specialized inhibition to thalamus, but their alterations in ASD have rarely been explored. We evaluated the reticular inhibitory system in thalamic nuclei (FO and HO) in Shank3 KO mice, a well-established monogenic model of ASD. We analyzed electrophysiological properties of targeted TRN neurons, our results show that TRN neurons projecting to FO and HO nuclei exhibit differential changes in Shank3 KO mice, including decreased burst firing in FO projecting neurons, which is crucial for maintaining sleep architecture. Additionally, we examined spontaneous and miniature inhibitory postsynaptic currents (IPSCs), in ventroposteromedial (VPM-FO) and posteromedial (POm-HO) thalamic nuclei. We show a reduction in frequency of spontaneous IPSCs and mIPSCs in VPM and POm. Together, our results show distinct alterations in the inhibitory control of FO and HO thalamic nuclei in Shank3 KO mice, which could contribute to the deficits in sleep and sensory processing observed in ASD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"216 ","pages":"Article 107108"},"PeriodicalIF":5.6,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145086598","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":"Corrigendum to “The mediation effects of white matter microstructural abnormalities on the associations between cerebral small vessel disease burden and cognitive impairment” [Neurobiology of Disease Volume 214, October 2025, 107025].","authors":"Chaofan Sui ,&nbsp;Changhu Liang ,&nbsp;Yian Gao ,&nbsp;Na Wang ,&nbsp;Xinyue Zhang ,&nbsp;Yuanyuan Wang ,&nbsp;Nan Zhang ,&nbsp;Yena Che ,&nbsp;Mengmeng Feng ,&nbsp;Haotian Xin ,&nbsp;Jing Li ,&nbsp;Lingfei Guo ,&nbsp;Hongwei Wen","doi":"10.1016/j.nbd.2025.107100","DOIUrl":"10.1016/j.nbd.2025.107100","url":null,"abstract":"","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"215 ","pages":"Article 107100"},"PeriodicalIF":5.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075718","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 mechanisms by which mitochondrial dysfunction drives neuromuscular junction degeneration in amyotrophic lateral sclerosis","authors":"Xie Yipeng ,&nbsp;Wang Guiqian ,&nbsp;Zhu Qiaochu ,&nbsp;He Tengjie ,&nbsp;Zhao Yan ,&nbsp;Huang Hai ,&nbsp;Zhou Jing","doi":"10.1016/j.nbd.2025.107103","DOIUrl":"10.1016/j.nbd.2025.107103","url":null,"abstract":"<div><h3>Background</h3><div>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder marked by progressive degeneration of motor neurons and early deterioration of neuromuscular junctions (NMJs). Increasing evidence indicates that mitochondrial dysfunction plays a pivotal role in driving NMJ degeneration in ALS.</div></div><div><h3>Objective</h3><div>This review aims to comprehensively summarize the molecular mechanisms by which mitochondrial defects contribute to NMJ instability, with a particular focus on bioenergetics, calcium homeostasis, oxidative stress, and impaired mitochondrial biogenesis.</div></div><div><h3>Conclusion</h3><div>Mitochondrial dysfunction is a core driver of NMJ degeneration in ALS. Targeting mitochondrial biogenesis and metabolism—particularly through the PGC-1α pathway—represents a promising strategy to preserve NMJ integrity and slow disease progression.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"216 ","pages":"Article 107103"},"PeriodicalIF":5.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081344","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":"Comparison of the ApoE allelic variants in the formation of intracerebral Aβ deposits","authors":"Guilian Xu ,&nbsp;Conner Angelle ,&nbsp;Divya Huilgol ,&nbsp;Patricia Sacilotto ,&nbsp;Karen N. McFarland ,&nbsp;Susan Fromholt ,&nbsp;Amanda Lopez ,&nbsp;Quan Vo ,&nbsp;Andrea Rivasplata ,&nbsp;Selma Brkic ,&nbsp;Carmelina Gorski ,&nbsp;Parul Bali ,&nbsp;Qing Lu ,&nbsp;David R. Borchelt ,&nbsp;Paramita Chakrabarty","doi":"10.1016/j.nbd.2025.107105","DOIUrl":"10.1016/j.nbd.2025.107105","url":null,"abstract":"<div><div>The Apolipoprotein E (APOE) isoforms <em>APOE</em>2, <em>APOE</em>3 and <em>APOE</em>4 differentially modulate risk of Alzheimer's disease (AD). Despite established evidence for <em>APOE</em>'s impact on Aβ deposition, the differential effects of <em>APOE</em> genotypes on distinct forms of amyloid pathology remain poorly understood. The three primary types of amyloid pathology in the brain are dense-cored fibrillar plaques, diffuse Aβ deposits, and vascular deposits in the form of cerebral amyloid angiopathy (CAA) and their relative distribution is thought to be important in determining the phenotypic outcomes in AD and related dementias. Here, we used different mouse models of AD-amyloidosis to ask two main questions: (1) does human APOE4 promote the deposition of all these subtypes of types of amyloid pathology, and (2) does presence of APOE4 influence the morphological transformation of diffuse Aβ deposits into dense-core neuritic plaques? In the SAA-APP knock-in model of dense-cored Aβ deposits resulting from accumulation of protofibrillar-favoring Aβ42, we observed that crossing in human <em>APOE</em> reduced amyloid burden. Among the three human <em>APOE</em> alleles, <em>APOE</em>4 produced the highest plaque burden and size, relative to <em>APOE</em>3 and <em>APOE</em>2 in the SAA-APP mice. Though all three human <em>APOE</em> isoforms showed comparable levels of colocalization with individual plaques, focused genomic analysis at early stages of pathology revealed that neural connectivity pathways were affected in mice with human <em>APOE</em>4 compared to human <em>APOE</em>3, implicating mechanisms of early neuronal dysfunction. In the slowly-developing APPsi model, characterized by predominantly diffuse Aβ deposits and cerebral amyloid angiopathy (CAA) emerging at older ages, we also found that mouse <em>Apoe</em> showed the greatest amyloid burden, followed by human <em>APOE</em>4 and <em>APOE</em>3. CAA deposition was noted in aged APPsi mice with mouse <em>Apoe</em> or human <em>APOE</em>4 mice but rarely in APPsi mice with human <em>APOE</em>3. Finally, neonatal Aβ seeding in APPsi mice revealed that <em>APOE</em>4 accelerated parenchymal Aβ deposition compared to <em>APOE</em>3 mice, though seeding in the presence of <em>APOE</em>4 did not alter the inherent diffuse morphology of the Aβ deposits. Collectively, these results demonstrate that APOE genotype influences the deposition of all types of amyloid pathology, including dense-cored, diffuse and vascular pathology. Notably, only the amount of amyloid was modified by <em>APOE</em> variants, while the type of amyloid pathology inherent in each model was not altered. Together these findings implicate a key role for apoE as a modifier of all types of Aβ deposition with limited potential to modify plaque compaction or morphology.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"216 ","pages":"Article 107105"},"PeriodicalIF":5.6,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145081333","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 polymorphism of tau aggregates in Pick's disease","authors":"Jiliang Liu ,&nbsp;Theresa Connors Stewart ,&nbsp;Derek H. Oakley ,&nbsp;Bradley T. Hyman ,&nbsp;Manfred Burghammer ,&nbsp;Marine Cotte ,&nbsp;Lee Makowski","doi":"10.1016/j.nbd.2025.107104","DOIUrl":"10.1016/j.nbd.2025.107104","url":null,"abstract":"<div><h3>Background</h3><div>Tau protein is central to progressive neuropathological changes in many neurodegenerative diseases. Although the trajectory by which tau pathology spreads through neural networks has been studied, the molecular processes that drive disease are unknown. Characterizing these processes requires imaging tools that supplement neuropathological examination with information about the molecular organization of lesions while preserving details of their anatomical location. High-resolution cryo-electron microscope studies require isolation of material which destroys information on variation of lesion structure with location. Immunohistochemistry identifies principal constituents of lesions but provides little information about molecular organization. To bridge this knowledge gap, we have developed advanced biophysical imaging tools to probe, <em>in situ</em>, the molecular organization and composition of individual lesions within diseased brain tissue. Here we describe their use to assess the fibrillar organization and variation of elemental composition in tau-containing lesions within the brain of a 66-year-old male with dementia.</div></div><div><h3>Methods</h3><div>We used <em>in situ</em> micro X-ray diffraction (μXRD) to determine the aggregation state of tau in individual lesions and micro-X-ray fluorescence (μXRF) to determine the elemental content of these lesions. The information thus generated was combined with immunohistochemistry of serial sections that confirmed the principal molecular constituents of lesions and placed the results in a broader anatomical context.</div></div><div><h3>Results</h3><div>Neuropathological examination revealed classical forms of tau inclusions in the hippocampal formation including extensive Pick bodies in the dentate gyrus. μXRD data indicate that Pick bodies of the granular layer are relatively low in fibril content, whereas, surprisingly, the microscopically diffuse tau in the neuropil in adjacent CA4 and hilus regions exhibit far greater density of fibrillar signal. μXRF data show elevated levels of zinc, calcium and phosphorous relative to surrounding tissue in essentially all tau-containing lesions. Sulfur deposition appeared greater in areas exhibiting high fibrillar content. A second case of Pick's disease showed analogous results.</div></div><div><h3>Conclusions</h3><div>These observations demonstrate a correlation of lesion morphology with anatomical localization, degree of tau fibrillation and differential accumulation of metals and suggest that lesions containing different levels of tau fibrils harbor biochemically distinct microenvironments.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"216 ","pages":"Article 107104"},"PeriodicalIF":5.6,"publicationDate":"2025-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145075844","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":"Interictal activity fluctuations follow rather than precede seizures on multiple time scales in a mouse model of focal cortical dysplasia","authors":"Jan Kudlacek ,&nbsp;Jan Chvojka ,&nbsp;Michaela Kralikova ,&nbsp;Salome Kylarova ,&nbsp;Tejasvi Ravi ,&nbsp;Ondrej Novak ,&nbsp;Jakub Otahal ,&nbsp;Martin Balastik ,&nbsp;Premysl Jiruska","doi":"10.1016/j.nbd.2025.107102","DOIUrl":"10.1016/j.nbd.2025.107102","url":null,"abstract":"<div><div>The unpredictability of seizure occurrence is a major debilitating factor for people with epilepsy. A seizure forecasting system would greatly improve their quality of life. Successful seizure forecasting necessitates a comprehensive understanding of the factors influencing seizure timing at multiple temporal scales. In this study, we investigated multiscale properties of interictal epileptiform discharges (IEDs) and seizure parameters in a highly realistic mouse model of focal cortical dysplasia-related epilepsy. We analyzed the properties' evolution at four timescales, ranging from epilepsy progression and seizure clusters to circadian and peri-ictal changes. We discovered that the FCD-related epilepsy syndrome was progressive in terms of interictal activity rate and seizure characteristics. Sixty percent of seizures occurred in clusters. During the clusters, the seizure duration, seizure power, and IED rate were increasing. Circadian rhythm influenced seizure occurrence with the peak seizure probability at 4 p.m. under a standard 12/12 light dark cycle with lights-on at 6 a.m. Peri-ictal analysis revealed no significant change in IED rate preceding individual seizures; however, a consistent two-peak pattern of IED elevation was observed following seizures. Specifically, an initial peak in IED rate emerged 5–10 minutes post-seizure, returning to baseline within two hours, followed by a secondary peak 4–12 hours later, which again subsided to baseline levels in 24–48 hours. This pattern could be fitted with a sum of three exponentials. Using the three-exponential pattern, we simulated IED rate fluctuations in each animal. The smoothed simulated IED rates showed good agreement with the smoothed real recorded IED rates, suggesting that the cumulative effect of post-ictal IED patterns can account for long-term fluctuations in IED rate. Our results indicate that, in our model of FCD-related epilepsy, consistent IED rate fluctuations follow rather than precede individual seizures. Therefore, fluctuations in IED rate can be viewed as a reflection of cyclic seizure occurrence. This implies that either IED rate fluctuations or accurate seizure records may be equally valuable for seizure risk forecasting.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"216 ","pages":"Article 107102"},"PeriodicalIF":5.6,"publicationDate":"2025-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070089","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}