Neurobiology of Disease最新文献

{"title":"Shank3B−/− pathophysiology: Early metformin treatment rescues behavioural deficits and normalises exacerbated mRNA translation","authors":"Laura Marsal-García ,&nbsp;Jung-Hyun Choi ,&nbsp;Eve Peraldi ,&nbsp;Pei You Wu ,&nbsp;Cong Loc Dang ,&nbsp;R. Anne McKinney ,&nbsp;Ilse Gantois ,&nbsp;Nahum Sonenberg","doi":"10.1016/j.nbd.2025.107217","DOIUrl":"10.1016/j.nbd.2025.107217","url":null,"abstract":"<div><div>Phelan-McDermid syndrome (PMS), a rare neurodevelopmental disorder associated with autism spectrum disorder and intellectual disability, is caused by either deletions in human chromosome 22q13 or mutations in the SH3 and multiple ankyrin repeat domains 3 <em>(SHANK3)</em> gene. PMS is highly debilitating, and existing treatments are ineffective. SHANK3 interacts with at least 3 synaptic receptors through synaptic-associated proteins, some of which are upstream of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1) and mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) signalling pathways. Metformin, an inhibitor of the mTORC1 and MAPK/ERK signalling pathways, was shown to correct core phenotypes in a fragile X mouse model, offering therapeutic potential for PMS. Male <em>Shank3B</em>^{<em>−/−</em>}, a PMS mouse model, and wild-type mice were treated from birth with metformin (5 mg/mL) or vehicle. <em>Shank3B</em>^{<em>−/−</em>} mice displayed increased self-grooming, decreased social interaction, reduced duration and frequency of ultrasonic vocalisations, and impaired hippocampal-dependent memory. Upregulated mTORC1 activity was observed in the hippocampus and prefrontal cortex, along with decreased synaptosomal protein expression in the striatum of GluN2B (an <em>N</em>-methyl-<span>d</span>-aspartate receptor (NMDAR) subunit), Homer1 (a synaptic-associated protein) and GluA2 (an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit), all of which interact with Shank3. Metformin treatment from birth corrected core behavioural impairments, exaggerated mRNA translation, and decreased striatal synaptic protein expression. Considering its exceptional safety profile, metformin is a promising therapeutic option for a rapid clinical translation of PMS treatment.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107217"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145695775","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":"Astrocytic α7-nicotinic acetylcholine receptors mediate pain information processing and perception","authors":"Teng Teng ,&nbsp;Shaofan Yang ,&nbsp;Jin Li ,&nbsp;Haoyu Wang ,&nbsp;Fengjuan Wu ,&nbsp;Yong He ,&nbsp;Jihua Fan ,&nbsp;Hongwei Shi ,&nbsp;Mingzhu Huang ,&nbsp;Xiang Zhou ,&nbsp;Ying Liu ,&nbsp;Mingyue Gong ,&nbsp;Chuanyan Yang ,&nbsp;Huiquan Wang ,&nbsp;Zhenlu Cai ,&nbsp;Hongli Li ,&nbsp;Kuan Zhang","doi":"10.1016/j.nbd.2025.107245","DOIUrl":"10.1016/j.nbd.2025.107245","url":null,"abstract":"<div><div>The astrocyte–neuron network in the primary somatosensory cortex (S1) responds dynamically to pain stimuli and plays a pivotal role in pain processing. These stimuli activate astrocytic α7-nicotinic acetylcholine receptors (α7-nAChRs), yet their contribution to pain perception remains largely unclear. This study investigates the role of astrocytic α7-nAChRs in pain information processing and perception. Astrocytic α7-nAChRs were selectively deleted by injecting rAAV5-GfaABC₁D-NLS-Cre-P2A-mCherry into the S1 region of LoxP-Chrna7 transgenic mice or by tamoxifen administration in ALDH1-CreERT2:Chrna7^loxP/loxP mice. Immunohistochemistry was used to assess the expression of α7-nAChR and gliotransmitter <span>d</span>-serine. Astrocytic Ca²⁺ transients were monitored in vivo using two-photon Ca²⁺ imaging following AAV5-GfaABC₁D-cytoGCaMP6f-SV40 labeling. Neuronal Ca²⁺ transients in S1 evoked by plantar electric shock were recorded via fiber photometry in freely moving mice. Nociceptive and sensory behaviors were evaluated using hot plate and von Frey tests. Statistical analyses included Welch's <em>t</em>-tests for normally distributed data, Mann–Whitney <em>U</em> tests for non-normal data, and two-way ANOVA. Results showed that conditional deletion of α7-nAChRs in astrocytes markedly reduced <span>d</span>-serine levels within astrocytic territories. Two-photon Ca²⁺ imaging and fiber photometry revealed that α7-nAChR deletion attenuated both astrocytic Ca²⁺ transients and footshock-evoked neuronal Ca²⁺ activity in S1. Behaviorally, thermal pain responses were significantly impaired, whereas tactile thresholds and open-field behaviors were unaffected. These findings identify astrocytic α7-nAChRs in S1 facilitate <span>d</span>-serine levels and enhance astrocytic activity. Their physiological function is essential for pain-related information processing within astrocyte–neuron networks and plays a critical role in regulating pain perception.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107245"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844000","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 conditional knock-in mouse model for APOE4-to-APOE3 switching","authors":"Ruoyi Ishikawa ,&nbsp;Yu Yamazaki ,&nbsp;Nayuta Nakazawa ,&nbsp;Xin Li ,&nbsp;Taku Tazuma ,&nbsp;Yoshiko Takebayashi ,&nbsp;Masahiro Nakamori ,&nbsp;Yusuke Sotomaru ,&nbsp;Hirofumi Maruyama","doi":"10.1016/j.nbd.2025.107244","DOIUrl":"10.1016/j.nbd.2025.107244","url":null,"abstract":"<div><div><em>APOE</em> polymorphisms are major genetic risk factors of Alzheimer's disease (AD). Compared with <em>APOE3/</em>E3, the <em>APOE4/E4</em> genotype is associated with a &gt; 14-fold increased risk. Therefore, we hypothesized that conversion of <em>APOE4</em> to <em>APOE3</em> would ameliorate AD-related pathologies. Accordingly, we generated a knock-in mouse model harboring an APOE4-FLEx (Flip-Excision) 4-to-3 construct enabling postnatal Cre-mediated APOE4-to-APOE3 switching. This construct comprised an <em>APOE3</em> exon inserted in a reverse orientation downstream of the <em>APOE4</em> exon, flanked by alternating loxP and mutant loxP sites, allowing Cre-mediated FLEx switching from APOE4-to-APOE3. For <em>in vitro</em> validation, HEK293T cells were transfected with APOE4-FLEx 4-to-3 plasmid, followed by AAV8-mediated iCre delivery. For <em>in vivo</em> studies, endogenous <em>Apoe</em> was replaced with the APOE4-FLEx 4-to-3 construct to generate APOE4-FLEx 4-to-3 knock-in mice, which were crossed with tamoxifen-inducible Rosa26-CreERT2 mice to yield Cre: APOE4-FLEx 4-to-3 double-knock-in mice. Tamoxifen was administered to induce <em>APOE</em> switching. Cre expression successfully induced APOE4-to-APOE3 switching <em>in vitro</em>. Tamoxifen administration in Cre: APOE4-FLEx 4-to-3 mice triggered APOE4-to-APOE3 switching in the liver, demonstrating the feasibility of postnatal isoform switching. However, brain APOE protein levels were below the detection limit. Investigation of the underlying cause involving transcript analysis revealed aberrant retention of intron 3 (APOE-I3). This abnormal splicing probably contributed to the decreased expression of fully spliced, translation-competent (mature) APOE mRNA, driving the subsequent protein reduction. Although APOE expression across organs in APOE4-FLEx 4-to-3 mice requires further optimization, our findings demonstrate that Cre-mediated FLEx switching can serve as a potential strategy to induce <em>APOE</em> genotype switching <em>in vivo</em>.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107244"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145844018","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":"Reduced cortico-muscular output is associated with intrinsic hypoexcitability and reduced persistent inward currents in motor cortex neurons of TDP-43Q331K ALS mice","authors":"Jose A. Viteri ,&nbsp;Nathan R. Kerr ,&nbsp;Charles D. Brennan ,&nbsp;Priyanka Paradkar ,&nbsp;Leena A. Suleiman ,&nbsp;Charles D. Wendt ,&nbsp;Chunhui Xu ,&nbsp;Hong An ,&nbsp;Meifang Wang ,&nbsp;Hiroshi Nishimune ,&nbsp;Joseph M. Santin ,&nbsp;W. David Arnold","doi":"10.1016/j.nbd.2025.107247","DOIUrl":"10.1016/j.nbd.2025.107247","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by spinal and cortical motor neuron loss and progressive neuromuscular decline. When ALS pathology involves the primary motor cortex (PMC), cortical excitability is often disrupted, yet how these alterations map onto motor deficits during symptomatic ALS remains unclear.</div><div>To investigate this, we examined the neuromuscular function, cortico-muscular output, and neuronal excitability of symptomatic 4-month-old TDP-43^Q331K mice. TDP-43 mice exhibited reduced neuromuscular excitability and impaired strength compared to WT mice. Cranial motor evoked potentials were significantly reduced in TDP-43 mice, indicating decreased cortical output to muscle. Compared to WT mice, whole-cell patch-clamp recordings from TDP-43 PMC layer V pyramidal neurons revealed intrinsic hypoexcitability, diminished persistent inward currents (PICs), and decreased excitatory synaptic activity. Corroborating PIC findings, immunohistochemical analysis showed that PMC layer V neurons exhibited reduced signal intensity of the PIC-associated proteins Nav1.6 and 5-HT2C.</div><div>Bulk RNA-seq of the cortex showed distinct transcriptional profiles in TDP-43 mice, with enrichment analysis indicating altered pathways relating to ion transport, synaptic signaling, and neuronal excitability. These results suggest that cortex-wide transcriptional changes may reflect broader and additional molecular mechanisms underlying cortical hypoexcitability in ALS.</div><div>Together, our results demonstrate that symptomatic TDP-43^Q331K mice exhibit a reduction in cortico-muscular output and PMC neuron excitability, accompanied by reduced PICs and PIC-associated proteins within these neurons. These findings identify cortical hypoexcitability as a defining feature of the TDP-43^Q331k ALS mouse model and establish multi-level associations between cortical cellular-level dysfunction and impaired motor systems output.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107247"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145843979","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":"microRNA-17-5p modulates ventral hippocampal transcriptome and synaptic proteome: Implications for emotional regulation in adult male rats.","authors":"F.A. Olave ,&nbsp;W.A. Corrales ,&nbsp;T.A. Guarnieri ,&nbsp;J.P. Silva ,&nbsp;F.I. Aguayo ,&nbsp;M. Alarcón-Mardones ,&nbsp;L. Román-Albasini ,&nbsp;J.C. Catalán ,&nbsp;P.I. González-Mori ,&nbsp;N. Palacios-Avendaño ,&nbsp;V. Mora-González ,&nbsp;C. Álvarez-Navarro ,&nbsp;E. Aliaga ,&nbsp;J.A. Cidlowski ,&nbsp;P. Zamorano ,&nbsp;J.L. Fiedler","doi":"10.1016/j.nbd.2025.107198","DOIUrl":"10.1016/j.nbd.2025.107198","url":null,"abstract":"<div><div>The hippocampus plays a crucial role in memory and emotional regulation, with its dorsal pole supporting cognitive functions and the ventral hippocampus modulating anxiety and affective processing via limbic interactions. Chronic restraint stress induces anxious- and depressive-like behaviors in rodents, alongside transcriptomic changes in the ventral hippocampus. Emerging evidence highlights microRNAs as modulators of synaptic architecture and gene expression. Notably, <em>miR-17-5p</em>—part of the <em>miR-17-92</em> cluster— shows increased cortical expression in individuals with mood disorders, and its levels in neural extracellular vesicles correlate directly with depressive symptom severity in male patients, suggesting translational relevance. In rodent models, chronic stress exposure produces divergent hippocampal expression patterns of <em>miR-17-5p</em>. Whether <em>miR-17-5p</em> acts as a passive biomarker of mood disorder or actively contributes to stress adaptation remains unclear.</div><div>In the present study, chronic stress exposure increased <em>miR-17-5p</em> expression specifically in the ventral hippocampus of male rats, with no changes detected in females. To assess its functional relevance, we reproduced this alteration in the ventral hippocampus of naïve male to evaluate behavioral outcomes and characterize both global and synaptic transcriptomic and proteomic profiles. Behaviorally, <em>miR-17-5p</em> mimic administration increased the sucrose preference, revealing an antidepressant-like effect. On the other hand, the open field test did not reveal anxiety-related differences, whereas the novelty-suppressed feeding test indicated a decrease in anxious-like behavior following <em>miR-17-5p</em> administration. Molecular analyses in ventral hippocampus homogenates and synaptic-enriched fractions revealed modulation of ribosomal protein composition and translational regulation—likely through mTOR pathway activation—favoring GABAergic adaptation and synaptic remodeling. These findings suggest a region-specific role of <em>miR-17-5p</em> in the ventral hippocampus that may contribute to its anxiolytic and antidepressant-like effects.</div><div>These results provide novel insights into <em>miR-17-5p</em>-mediated mood regulation, highlighting its potential as a therapeutic target for anxiety and depressive disorders.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107198"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145588352","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":"Free-water imaging reveals cholinergic pathway damage in multiple system atrophy","authors":"Yao Wang ,&nbsp;Han Zhang ,&nbsp;Shan Ren ,&nbsp;Xinning Zhang ,&nbsp;Sushi Wang ,&nbsp;Weizheng Ran ,&nbsp;Wenyang Tian ,&nbsp;Ying Zhou ,&nbsp;Zhigang Chen","doi":"10.1016/j.nbd.2025.107213","DOIUrl":"10.1016/j.nbd.2025.107213","url":null,"abstract":"<div><h3>Background</h3><div>Dysfunction of the cholinergic system is implicated in the pathophysiology of Multiple System Atrophy (MSA). However, in vivo assessment of cholinergic pathways originating from the nucleus basalis of Meynert (NBM) and pedunculopontine nucleus (PPN), and their clinical relevance remains inadequately characterized.</div></div><div><h3>Objectives</h3><div>To utilize diffusion MRI and free-water (FW) image model to characterize cholinergic system degeneration in MSA and examine its association with clinical features.</div></div><div><h3>Methods</h3><div>We included 103 MSA patients and 44 healthy controls who underwent diffusion MRI. Probabilistic tractography reconstructed three major cholinergic pathways: a medial NBM projection via cingulum, a lateral NBM projection via external capsule, and PPN-thalamus pathway. FW imaging quantified microstructural integrity using FW fraction (FWf) and corrected axial diffusivity (cAxD). These DWI-based metric were analyzed to (1) differentiate patients from controls and (2) examine the associations with clinical features in MSA.</div></div><div><h3>Results</h3><div>Compared to controls, MSA patients showed higher FWf values in both the lateral NBM and PPN-thalamus pathways. Receiver operating characteristic analysis showed that the FWf-based model best differentiated MSA from controls (AUC = 0.89 [0.76–1.00]), with PPN-thalamus FWf being the most discriminative feature. Across all three cholinergic pathways, higher FWf values were associated with longer disease duration, and PPN-thalamus FWf values specifically correlated with total Unified Multiple System Atrophy Rating Scale scores.</div></div><div><h3>Conclusion</h3><div>Cholinergic pathway damage is a prominent pathological feature of MSA, with PPN-thalamus pathway showing particular vulnerability (as indicated by increased FWf) and strong clinical relevance. This FWf elevation likely related to neuronal degeneration or neuroinflammatory changes driven by α-synuclein pathology.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107213"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145678220","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":"MAPK family members differentially regulate pThr175 tau-mediated pathogenicity","authors":"Neil Donison ,&nbsp;Matthew A. Hintermayer ,&nbsp;Jacqueline Palik ,&nbsp;Jessica Fisher ,&nbsp;Kathryn Volkening ,&nbsp;Michael J. Strong","doi":"10.1016/j.nbd.2025.107223","DOIUrl":"10.1016/j.nbd.2025.107223","url":null,"abstract":"<div><div>The phosphorylation of tau is a critical determinant of both its physiological function and the induction of pathological misfolding and aggregation. We have previously provided evidence that tau phosphorylation at Thr175 results in the exposure of the N-terminal phosphatase-activating domain (PAD) leading to the subsequent phosphorylation of Thr231, and formation of tau oligomers. A number of tauopathies, including chronic traumatic encephalopathy (CTE), amyotrophic lateral sclerosis with cognitive impairment (ALSci), and experimental traumatic brain injury (TBI) have been proposed to be associated with this cascade of events. However, the cellular mechanism by which Thr175 tau is phosphorylated remains unclear. In this study we identified ERK2, JNK1, and p38 as candidate kinases through molecular and histological analyses in a rodent model of TBI, where increased kinase activity and protein interaction were associated with pThr175 tau. We confirmed that both ERK2 and JNK1 are capable of phosphorylating Thr175 tau <em>in vitro</em>, but only ERK2-mediated phosphorylation of Thr175 tau induced the pathological cascade characterized by PAD exposure and the generation of oligomeric, truncated and neurofibrillary tau. Thr175 phosphorylation was also associated with an altered interaction between tau and the molecular chaperone protein DnaJC7, which regulates tau misfolding. Additionally, we observed that pThr175 and pThr231 tau were increased by oxidative stress, which was associated with the activation of the MAPK signaling pathways. These findings further clarify the mechanisms leading to Thr175 tau phosphorylation and its role in pathological tau formation by identifying ERK1 and JNK2 as important cellular mediators.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107223"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145757099","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":"Glymphatic activity is linked to the synaptic vesicle cycle pathway in frontotemporal dementia: A metabolomics study","authors":"Min Chu,&nbsp;Ailing Yue,&nbsp;Haitian Nan,&nbsp;Hong Ye,&nbsp;Miao Qu,&nbsp;Liyong Wu","doi":"10.1016/j.nbd.2025.107135","DOIUrl":"10.1016/j.nbd.2025.107135","url":null,"abstract":"<div><h3>Background</h3><div>Emerging evidence implicating glymphatic dysfunction contributes to the pathogenesis of frontotemporal dementia (FTD). However, the pathway correlated to glymphatic function in FTD remains poorly understood. We aimed to explore potential underlying metabolic pathways associated with glymphatic dysfunction in FTD.</div></div><div><h3>Methods</h3><div>We enrolled 37 behavior FTD (bvFTD) patients and 40 healthy controls. Glymphatic activity was assessed using diffusion tensor imaging data. Plasma metabolomic profiling was performed to identify glymphatic-associated metabolites, followed by pathway enrichment analysis. Additionally, the plasma biomarker was tested in a subset of 25 patients to validate the metabolite findings.</div></div><div><h3>Results</h3><div>Patients with bvFTD exhibited significantly altered metabolite profiles compared to controls. The glymphatic-associated metabolites were predominantly enriched in the synaptic vesicle cycle pathway (FDR <em>p</em> &lt; 0.05). Furthermore, plasma neuropentraxin-2 (NPTX2) levels positively correlated with anterior glymphatic indices (<em>r</em> = 0.46, <em>p</em> = 0.027).</div></div><div><h3>Conclusion</h3><div>Our findings demonstrate the association between the glymphatic system and synaptic function in bvFTD.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107135"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145252261","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":"Non-cell autonomous autophagy in amyotrophic lateral sclerosis: A new promising target?","authors":"Francesca Rosso ,&nbsp;Rocio Magdalena ,&nbsp;Carola Torazza ,&nbsp;Francesca Bacchetti ,&nbsp;Marco Milanese ,&nbsp;Angelo Poletti ,&nbsp;Giambattista Bonanno ,&nbsp;Riccardo Cristofani ,&nbsp;Tiziana Bonifacino","doi":"10.1016/j.nbd.2025.107203","DOIUrl":"10.1016/j.nbd.2025.107203","url":null,"abstract":"<div><div>Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative non-cell-autonomous disease with no cure, thus research is intensely focused on identifying pharmacological targets. Several studies aimed to clarify the pathogenic mechanisms and involvement in various cell types. A crucial factor in ALS is autophagy, which plays a key role in degrading intracellular protein aggregates. The connection between ALS and autophagy is reinforced by the fact that several genes mutated in ALS are linked to fundamental aspects of autophagy. The blockage of the autophagic flux was observed in ALS motor neurons, where it occurs earlier than in glia. However, the inconsistent effects of autophagy modulators in preclinical and clinical studies indicate the need for a deeper understanding of the role of autophagy in other cell types, such as astrocytes, microglia, and oligodendrocytes. Astrocytes and microglia are significantly impacted by autophagy dysregulation, contributing to neurodegeneration in both mouse and human-derived models. Autophagy is overactivated early in the disease, even before symptoms appear. This overactivation is influenced by the timing and specific tissue involved. It can alter cells' immunophenotype, favouring proinflammatory responses and affecting the cellular environment and autophagy in the surrounding cells. In contrast, oligodendrocytes show mild autophagic alterations. Additionally, sex hormones may affect proper autophagy function and ALS progression. The lack of information on how sex influences autophagy in glia highlights the need for more nuanced investigation into this mechanism. Future research should focus on these aspects, paving the way for personalised pharmacological approaches that consider the roles of cell types, time of intervention, and sex.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107203"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145661496","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":"Chemogenetic activation of oxytocinergic neurons rescues neural correlates of encephalopathy of prematurity in mice","authors":"Marit Knoop ,&nbsp;Marie-Laure Possovre ,&nbsp;Ece Trak ,&nbsp;Jean-Luc Pitetti ,&nbsp;Yohan van de Looij ,&nbsp;Eduardo Sanches ,&nbsp;Stergios Tsartsalis ,&nbsp;Julien Pansiot ,&nbsp;Gabriel Schirmbeck ,&nbsp;Olivier Baud","doi":"10.1016/j.nbd.2025.107250","DOIUrl":"10.1016/j.nbd.2025.107250","url":null,"abstract":"<div><div>Every year, 15 million babies are born preterm, putting them at increased risk of encephalopathy of prematurity (EoP). EoP is characterized by microglia-induced neuroinflammation, which can aggravate injury mechanisms leading to neuronal disorders, myelination delay, and subsequent functional consequences. While effective neuroprotective strategies in the preterm brain remain elusive, interventions such as skin-to-skin, developmental care, and music therapy have a positive impact on newborn brain development, potentially related to the oxytocinergic system. Endogenous oxytocin is recognized as a regulator of maternal-child social bonding, but its neuroprotective effect in the injured brain remains to be elucidated. Here, we investigated the effects of chemogenetic activation of oxytocinergic neurons on the neural correlates of EoP. Using a well-established mouse model of systemic interleukin-1β to induce EoP, we showed that neonatal chemogenetic activation of oxytocinergic neurons has anti-inflammatory effects in microglia, improving microstructural development of the corpus callosum and motor cortex, and rescuing typical social behavior. These neuroprotective effects were more pronounced in females, who showed a greater reduction in microgliosis and improved social behavior compared to males. This study provides a biological explanation for how developmental care and early interventions, linked to the oxytocinergic system, may induce neuroprotection in the developing brain.</div></div>","PeriodicalId":19097,"journal":{"name":"Neurobiology of Disease","volume":"218 ","pages":"Article 107250"},"PeriodicalIF":5.6,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145850454","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}