Neurobiology of Disease最新文献

{"title":"Multi-omics characterization of oncosis in spinal cord injury","authors":"Zhipeng Jiang ,&nbsp;Youwei Guo ,&nbsp;Zihan Wang ,&nbsp;Jinhao Ouyang ,&nbsp;Hailong Huang ,&nbsp;Haoxuan Huang ,&nbsp;Tianqian Shen ,&nbsp;Lei Wang ,&nbsp;Wen Yin ,&nbsp;Xingjun Jiang ,&nbsp;Caiping Ren","doi":"10.1016/j.nbd.2025.106982","DOIUrl":"10.1016/j.nbd.2025.106982","url":null,"abstract":"<div><div>Spinal cord injury (SCI) initiates a cascade of complex secondary damage processes, prominently involving programmed cell death (PCD). Although apoptosis and necroptosis have been extensively characterized, the role of oncosis in SCI remains inadequately understood. In this study, we examined the expression dynamics and cellular localization of oncosis-related genes (ORGs) following SCI. We conducted an analysis of bulk RNA-seq data to identify differentially expressed ORGs at five distinct time points post-injury. Six candidate genes (Trp53, Casp3, Jun, Tmem123, Chmp6, Map2) were identified based on their temporal expression patterns. Single-cell RNA sequencing and spatial transcriptomics revealed specific cell-type specificity and lesion-centered spatial enrichment of these genes. Trp53 and Casp3 were found to be rapidly upregulated in neurons and microglia, whereas Tmem123 exhibited a progressive downregulation. Jun emonstrated biphasic activation in astrocytes and oligodendrocytes. In vitro experiments using LPS-treated PC12 cells corroborated key expression trends, with transmission electron microscopy (TEM) confirming the morphological characteristics of oncosis. In vivo, quantitative reverse transcription PCR (qRT-PCR) qRT-PCR and immunofluorescence analyses in a rat SCI model further validated the altered expression of these genes. Significantly, a reduction in Map2 and an elevation in Chmp6 were associated with cytoskeletal collapse and plasma membrane rupture, respectively. Together, our findings provide the first spatiotemporal mapping of oncotic gene regulation following SCI and identify potential targets for therapeutic intervention.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106982"},"PeriodicalIF":5.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205297","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":"Choroid plexus area and choroid plexus /lateral ventricle area index are potential imaging markers for freezing of gait in Parkinson's disease","authors":"Xi Yin ,&nbsp;Miao Wang ,&nbsp;Fenqiang Zhao ,&nbsp;Fengzhu Li ,&nbsp;Yuxing Tang ,&nbsp;Xiaoyu Wang ,&nbsp;Caohui Duan ,&nbsp;Song Wang ,&nbsp;Yongqin Xiong ,&nbsp;Jiarui Yao ,&nbsp;Tong Chen ,&nbsp;Zhenfu Wang ,&nbsp;Yifan Li ,&nbsp;Xin Lou ,&nbsp;Zhongbao Gao","doi":"10.1016/j.nbd.2025.106984","DOIUrl":"10.1016/j.nbd.2025.106984","url":null,"abstract":"<div><h3>Background</h3><div>The choroid plexus (CP), an important structure involved in cerebrospinal fluid (CSF) circulation, plays a key role in clearing harmful metabolites from the brain. However, the relationship between CP and the development of Parkinson's disease (PD) remains unclear, especially in those with freezing of gait (FOG). We aim to investigate the association between the CP area and CP/lateral ventricle area (CP/Ven) index with clinical symptoms of PD and the development of FOG.</div></div><div><h3>Methods</h3><div>Seventy-three patients with PD (17 with FOG and 56 without FOG) and 49 healthy controls (HCs) underwent 7 T magnetic resonance imaging and neurological assessments. The CP area and CP/Ven index were calculated, and the differences across groups were compared. Spearman's rank correlation was used to evaluate associations between these indices and clinical scales. Binary logistic regression was used to explore the impact of the CP area and CP/Ven index on FOG occurrence in PD.</div></div><div><h3>Results</h3><div>Patients with FOG (PD-FOG) exhibited significantly higher CP area and CP/Ven index than those without FOG (PD-nFOG). Both the CP area and CP/Ven index were positively correlated with the PD motor scale scores, especially postural instability/gait disturbance. Receiver operating characteristic curve analysis showed that the CP area and CP/Ven index effectively distinguished PD-FOG from PD-nFOG, with area under curve of 0.887 and 0.854, respectively. Logistic regression analysis confirmed that both indices independently increased the risk of FOG in PD.</div></div><div><h3>Conclusion</h3><div>Elevated CP area and CP/Ven index are novel, noninvasive neuroimaging markers of FOG in PD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106984"},"PeriodicalIF":5.1,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144205296","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":"APOE4 reshapes the lipid droplet proteome and modulates microglial inflammatory responses","authors":"Cassi M. Friday ,&nbsp;Isaiah O. Stephens ,&nbsp;Cathryn T. Smith ,&nbsp;Sangderk Lee ,&nbsp;Diksha Satish ,&nbsp;Nicholas A. Devanney ,&nbsp;Sarah Cohen ,&nbsp;Josh M. Morganti ,&nbsp;Scott M. Gordon ,&nbsp;Lance A. Johnson","doi":"10.1016/j.nbd.2025.106983","DOIUrl":"10.1016/j.nbd.2025.106983","url":null,"abstract":"<div><div>Excess lipid droplet (LD) accumulation is implicated in various diseases, including Alzheimer's disease (AD), yet the mechanisms underlying this accumulation remain unclear. Apolipoprotein E (ApoE) is a droplet-associated protein, and its E4 variant confers the greatest genetic risk for late-onset AD while also being linked to increased neuroinflammation and LD accumulation. In this study, we compared the lipid and protein composition of hepatic LDs in targeted replacement mice expressing human E3 (neutral) or E4 (risk variant), under both baseline conditions and following lipopolysaccharide (LPS) administration. Lipidomic analysis revealed that E4 LDs exhibit a shift in glycerophospholipid distribution, with an increase in phosphatidylcholine species, such that their baseline profile resembles that of LPS-treated LDs. Quantitative proteomics indicated that E4 LDs are enriched in proteins related to vesicle transport but show decreased levels of proteins involved in fatty acid β-oxidation. Notably, many LD-associated proteins overlapped with those identified in AD postmortem and microglial ‘omics studies, suggesting a role for LDs in AD pathogenesis. To further explore these findings, primary microglia from E3 and E4 mice were exposed to exogenous lipids, LPS, and necroptotic N2A cells. Under most conditions, E4 microglia accumulated more LDs and secreted higher levels of proinflammatory cytokines (TNF, IL-1β, IL-10) compared to E3 microglia, although their LPS response was blunted. These data suggest that altered LD dynamics in E4 microglia may contribute to the increased AD risk associated with APOE4.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106983"},"PeriodicalIF":5.1,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199672","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":"Targeting MMP-9 activation after early-life seizures reduces seizure susceptibility and memory deficits in a larval zebrafish model","authors":"Christopher Stegmuller ,&nbsp;Alfonsina Ramón ,&nbsp;Kasulul Melissa Bhuiyan,&nbsp;Nat Berk,&nbsp;Rebecca Han,&nbsp;Faisha Salami,&nbsp;Marina D'Angelo,&nbsp;Jocelyn J. Lippman-Bell","doi":"10.1016/j.nbd.2025.106978","DOIUrl":"10.1016/j.nbd.2025.106978","url":null,"abstract":"<div><div>One in 26 Americans experience seizures, with a high incidence occurring in the first years of life. Chronic consequences of prolonged early-life seizures (ELS) in humans and rodent models vary, but can include the development of epilepsy (spontaneous, recurrent seizures) and cognitive impairment. Because it is not clear how seizures might lead to these consequences, no therapeutic strategy exists to prevent or predict them. Here, we optimized a larval zebrafish ELS model to assess a therapeutic approach targeting post-ELS sequelae. Using increased seizure susceptibility as a readout of the epileptogenic process and a novel object recognition task to assess memory, we found that two weeks after a three-day ELS induction paradigm, zebrafish were significantly more susceptible to seizures and showed a significant memory deficit. Therefore, we next used this model to identify and target underlying mechanisms. After observing an acute post-ELS increase in <em>mmp9</em> gene expression, we pharmacologically inhibited the conversion of pro-MMP-9 to active MMP-9 after ELS using JNJ0966, and tested subsequent seizure susceptibility and memory two weeks later. Preventing formation of active MMP-9 for the first hour post-ELS was sufficient to return memory and seizure susceptibility readouts to that of clutch mate controls. This study provides novel insight into the development of ELS sequelae and presents a promising model for moving ELS research forward, demonstrating seizure susceptibility, memory assessment, therapeutic targeting, and pharmacological testing in a simplified model.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106978"},"PeriodicalIF":5.1,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170765","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":"Striatal cell-type–specific molecular signatures reveal potential therapeutic targets in a model of dystonia","authors":"Kaitlyn M. Roman ,&nbsp;Ashok R. Dinasarapu ,&nbsp;Suraj Cherian ,&nbsp;Xueliang Fan ,&nbsp;Yuping Donsante ,&nbsp;Nivetha Aravind ,&nbsp;C. Savio Chan ,&nbsp;H.A. Jinnah ,&nbsp;Ellen J. Hess","doi":"10.1016/j.nbd.2025.106981","DOIUrl":"10.1016/j.nbd.2025.106981","url":null,"abstract":"<div><div>Abnormal dopamine neurotransmission and striatal dysfunction is implicated in many forms of dystonia, yet the underlying molecular processes remain unknown. Here, we identified thousands of dysregulated genes within striatal spiny projection neuron (SPN) subtypes in a genetic mouse model of DOPA-responsive dystonia (DRD), which is caused by gene defects that reduce dopamine neurotransmission. Although changes in mRNA expression were unique to each SPN subtype, abnormal glutamatergic signaling was implicated in each SPN subtype. Indeed, both AMPA and NMDA receptor-mediated currents were enhanced in direct SPNs but diminished in indirect SPNs in DRD mice. The pattern of mRNA dysregulation was distinct from parkinsonism where the dopamine deficit occurs in adults, suggesting that the phenotypic outcome is dependent on both the timing of the dopaminergic deficit and the SPN-specific adaptions. By leveraging these disease-specific molecular signatures, we identified LRRK2 inhibition, among other mechanisms, as a novel therapeutic target for dystonia.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106981"},"PeriodicalIF":5.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144185633","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":"Cogwheel rigidity in Parkinson's disease: Clinical, biomechanical and neurophysiological features","authors":"Marco Falletti ,&nbsp;Francesco Asci ,&nbsp;Alessandro Zampogna ,&nbsp;Martina Patera ,&nbsp;Antonio Suppa","doi":"10.1016/j.nbd.2025.106980","DOIUrl":"10.1016/j.nbd.2025.106980","url":null,"abstract":"<div><h3>Objectives</h3><div>Cogwheel rigidity in Parkinson's disease has been poorly investigated so far, thus leaving the scientific interpretation of this phenomenon substantially unsolved. A detailed clinical, biomechanical and neurophysiological investigation would clarify the pathophysiological underpinning of cogwheel rigidity.</div></div><div><h3>Methods</h3><div>Patients underwent robot-assisted wrist extensions at various angular velocities, when OFF and ON therapies. For each value of angular velocity, several biomechanical (i.e. elastic, viscous and neural components) and neurophysiological measures (i.e. long-latency stretch reflex) were synchronously assessed and correlated with the clinical score of rigidity (i.e. Movement Disorder Society Unified Parkinson's Disease Rating Scale—part III, subitems for the upper limb).</div></div><div><h3>Results</h3><div>A total of 18 PD patients participated. Patients were divided into two groups according to the presence of cogwheel rigidity at the clinical examination (CWR and No-CWR, respectively). CWR patients had a longer disease duration, greater motor severity and disability scores compared to those who did not. Biomechanical (NC and TF) and neurophysiological data (LLRs amplitude and AUC) also disclosed a more pronounced impairment in patients with cogwheel rigidity. L-DOPA comparably improved rigidity measures in patients with and without cogwheel rigidity.</div></div><div><h3>Discussion</h3><div>Cogwheel rigidity may be associated with prominent impairment in clinical, biomechanical, and neurophysiological features of rigidity in patients with PD. Future studies in larger cohorts are needed to achieve more firm conclusions.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106980"},"PeriodicalIF":5.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170768","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":"Dopamine D2 receptor-mediated epidermal growth factor receptor signaling regulates neurogenesis in the subventricular zone of adult brain","authors":"Yea Jue Kim ,&nbsp;Byeong Jun Kang ,&nbsp;Jihee Seo ,&nbsp;Sion Kim ,&nbsp;Eun-chang Lee ,&nbsp;Ha-yeon Cho ,&nbsp;Donghoon Kim ,&nbsp;Im Joo Rhyu ,&nbsp;Ja-Hyun Baik","doi":"10.1016/j.nbd.2025.106979","DOIUrl":"10.1016/j.nbd.2025.106979","url":null,"abstract":"<div><div>Mechanisms underlying selective dopaminergic neuronal degeneration in Parkinson's disease (PD) remain unclear. Impaired adult neurogenesis has been implicated in PD pathology, but its molecular regulation is not fully understood. We previously reported that dopamine D2 receptor (D2R)-mediated epidermal growth factor receptor (EGFR) signaling is critical for dopaminergic neuron development. To analyze how alterations in the dopamine system, especially D2R signaling in association with EGFR, contribute to dopamine-related dysfunction in vivo, we established a D2R cell-specific EGFR-deleted animal model, Drd2-Cre; EGFR^f/f mice. These mice displayed a significant reduction in motor coordination ability and a decrease in the number of dopaminergic neurons in the midbrain, which resembles the characteristics of PD. We observed a reduction in the number of newly generated cells in the subventricular zone (SVZ) of aged Drd2-Cre; EGFR^f/f mice, suggesting that the absence of EGFR in D2R-expressing cells could induce altered adult neurogenesis in the SVZ. Furthermore, when we compared the effect of <strong><span>l</span></strong>-3,4-dihydroxyphenylalanine (<strong><span>l</span></strong>-DOPA) on SVZ proliferation in 6-OHDA-lesioned control EGFR^f/f and Drd2-Cre; EGFR^f/f mice, the Drd2-Cre; EGFR^f/f mice exhibited hindered L-DOPA-induced SVZ proliferation, indicating that D2R–EGFR signaling is necessary for the dopaminergic regulation of SVZ neurogenesis. These findings suggest that D2R–EGFR signaling is essential for maintaining midbrain dopaminergic neuron integrity and supporting adult neurogenesis, highlighting this pathway as a potential therapeutic target for promoting endogenous regenerative responses in PD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106979"},"PeriodicalIF":5.1,"publicationDate":"2025-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144177900","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":"Microstructural integrity of autonomic central nervous tracts is linked to cardiovascular health","authors":"Janis M. Nolde ,&nbsp;Alexander Rau ,&nbsp;Elias Kellner ,&nbsp;Horst Urbach ,&nbsp;Cornelius Weiller ,&nbsp;Fabian Bamberg ,&nbsp;Jakob Weiss ,&nbsp;Marco Reisert ,&nbsp;Jonas A. Hosp","doi":"10.1016/j.nbd.2025.106972","DOIUrl":"10.1016/j.nbd.2025.106972","url":null,"abstract":"<div><h3>Introduction</h3><div>The central autonomic network (CAN), which controls sympathetic and parasympathetic activity, plays a central role in the pathogenesis of cardiovascular disease and serves as a target for therapeutic approaches. This study investigates the association of microstructural integrity of white matter fibres representing the CAN with cardiovascular damage, risk and outcomes using a large population-based cohort study.</div></div><div><h3>Methods</h3><div>The microstructural integrity of the CAN was evaluated using magnetic resonance imaging (MRI) of the brain from the population-based UK Biobank study applying previously developed diffusion imaging data-processing techniques. Subsequently, measures of cardiac and vascular organ damage (i.e. left ventricular (LV) myocardial mass, LV wall myocardial thickness and arterial stiffness index) were correlated with the integrity of CAN fibres and other brain regions. Furthermore, the patterns of regional CAN associations with cardiovascular organ damage and major adverse cardiovascular events (MACE) following imaging were analysed. Both cortical and subcortical components of the CAN were examined separately.</div></div><div><h3>Results</h3><div>A total of 43,994 individuals were included in the analysis (mean age: 55.0 ± 7.5 years, 53 % females). The microstructural integrity of the CAN demonstrated stronger associations with cardiac and vascular organ damage parameters than with brain regions outside the CAN. In cortical CAN tracts, measures of cardiac and vascular damage were positively associated with the free water compartment, whereas a negative association existed for intra-axonal volume (all <em>p</em> &lt; 0.001). Also, the proportion of free water in CAN fibres interconnecting the cingulum and the insular cortex was a strong predictor of MACE. A 10 % increase in the free-water compartment of these brain tracts was associated with a hazard ratio for MACE after imaging of 3.8 (95 % CI: 2.1–6.9; <em>p</em> &lt; 0.001) and 4.2 (95 % CI: 2,1–8.4; p &lt; 0.001), for left and right side respectively). Subcortical CAN components showed modest associations, particularly between increased intra-axonal volume and cardiac parameters.</div></div><div><h3>Conclusion</h3><div>Our findings indicate a distinct association between the integrity of brain networks regulating autonomic activity and cardiovascular health. Particularly, connections between the rostral-anterior cingulum and the insular cortex may be associated with higher risk for future MACE. Differential patterns were observed in cortical versus subcortical CAN structures, suggesting distinct pathophysiological roles within the heart-brain axis.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106972"},"PeriodicalIF":5.1,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144170764","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":"Global Grin2a loss causes divergent impairments to PV+ and SST+ interneurons and alters gamma oscillations in prefrontal cortex","authors":"Hassan Hosseini ,&nbsp;Sky Evans-Martin ,&nbsp;Kevin S. Jones","doi":"10.1016/j.nbd.2025.106977","DOIUrl":"10.1016/j.nbd.2025.106977","url":null,"abstract":"<div><h3>Background</h3><div>Loss-of-function mutations in the <em>Grin2a</em> gene, encoding the GluN2A subunit of NMDA receptors, confer elevated schizophrenia (SCZ) risk. Although GluN2A is expressed in multiple interneuron subtypes, its role in inhibitory circuit function remains incompletely understood. Recent genetic and transcriptomic studies implicate somatostatin-positive (SST⁺) interneurons in SCZ pathophysiology, raising the question of whether <em>Grin2a</em> deletion differentially affects SST⁺ and parvalbumin-positive (PV⁺) cells.</div></div><div><h3>Methods</h3><div>We utilized global <em>Grin2a</em> knockout (KO) and heterozygous (HET) mice to investigate how GluN2A deficiency affects inhibitory dynamics in the prelimbic (PrL) medial prefrontal cortex (mPFC). Immunohistochemistry quantified interneuron density, while slice electrophysiology and optogenetics assessed inhibitory postsynaptic current (IPSC) amplitude and kinetics, quantal GABA release, and PV⁺- and SST-driven gamma-band oscillations (GBOs).</div></div><div><h3>Results</h3><div><em>Grin2a</em> KO and HET mice exhibited increased PV⁺ and SST⁺ interneuron density and a shift in excitatory–inhibitory (E/I) balance favoring inhibition. PV⁺ interneurons displayed functional impairments characterized by prolonged IPSC decay, elevated asynchronous GABA release, and enhanced PV-driven gamma-band oscillations (GBOs), consistent with impaired presynaptic calcium handling. In contrast, SST⁺ interneurons exhibited increased IPSC amplitudes without alterations in short-term plasticity or oscillatory drive, suggesting modulation of inhibitory tone without affecting network synchrony.</div></div><div><h3>Conclusion</h3><div>GluN2A loss appears to disrupt inhibitory networks through distinct cell-type-specific mechanisms—presynaptic dysfunction in PV⁺ cells and postsynaptic enhancement from SST⁺ cells. PV⁺ dysfunction aligns with gamma synchrony impairments linked to SCZ cognitive flexibility, while SST⁺ alterations may contribute to impaired feedback inhibition and sensory deficits. These findings clarify GluN2A's role in interneuron subtype function and network stability in SCZ.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106977"},"PeriodicalIF":5.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144174083","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 chaperones HSP90AA1, HSP90AB1 and BAG3 are specifically distributed among human hippocampal subfields during different Alzheimer's disease stages","authors":"Carmen Soriano-Herrador ,&nbsp;Isabel Ubeda-Banon ,&nbsp;Patricia Villanueva-Anguita ,&nbsp;Daniel Saiz-Sanchez ,&nbsp;Veronica Astillero-Lopez ,&nbsp;Alino Martinez-Marcos ,&nbsp;Alicia Flores-Cuadrado","doi":"10.1016/j.nbd.2025.106971","DOIUrl":"10.1016/j.nbd.2025.106971","url":null,"abstract":"<div><div>Alzheimer's disease (AD) includes amyloid-β plaques and tau tangles as associated proteinopathies. Tau aggregates appear in a sequential and predictable manner, defined by six stages (Braak stages I–VI) of neuropathological diagnosis, with the hippocampus, particularly the CA1 subfield, being involved in the early stages. Chaperones play a key role in amyloid-β and tau misfolding. Chaperones constitute a vast family of proteins, but proteomic assays have indicated that HSP90AA1, HSP90AB1 and BAG3 are differentially expressed in the hippocampus of human AD patients. However, it is unknown whether the distribution of these proteins changes across different hippocampal subfields and/or in different neuropathological stages. Therefore, the distributions of the HSP90AA1, HSP90AB1 and BAG3 chaperones across hippocampal subfields (CA1, CA2, CA3 and DG) and across neuropathological stages (non-AD, 0; initial-AD, I-I; intermediate-AD, III–IV; and advanced-AD, V–VI) were stereologically quantified using the Area Fraction Fractionator probe. The area fraction of HSP90AA1 was lower in CA1 in advanced stages, whereas that of HSP90AB1 was greater in CA2 in advanced stages. In contrast, the area fraction of BAG3 was greater in CA1, CA3 and the DG between the non-AD and initial-AD stages but was lower in the DG in the intermediate-AD stage. This finding suggests that chaperone dysregulation could be responsible for the altered clearance and increased pathological misfolding that is observed in AD, leading to differential subfield vulnerability. Indeed, these chaperones could be useful as predictive biomarkers or therapeutic targets for AD because of their differential distribution across subfields and stages, which may increase the sensitivity and specificity of these proteins for use in these ways.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"212 ","pages":"Article 106971"},"PeriodicalIF":5.1,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144154913","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}