Brain, Behavior, and Immunity最新文献

{"title":"Long COVID: Current landscape of neurocognitive sequalae and opportunities to improve care management","authors":"Tiffany A. Walker , Jonah Z. Kohler , Michelle M. Haddad","doi":"10.1016/j.bbi.2025.106108","DOIUrl":"10.1016/j.bbi.2025.106108","url":null,"abstract":"","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106108"},"PeriodicalIF":7.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145019124","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":"Decoding NMDAR encephalitis: proteomic markers and computational identification of potential therapeutic pathways","authors":"Shengnan Wang ,&nbsp;Yuhao Yuan ,&nbsp;Xiaoqing Guo ,&nbsp;Mengting Qin ,&nbsp;Jiaojiao Chen ,&nbsp;Dailiang Jiang ,&nbsp;Yuhang Feng ,&nbsp;Ling Mao","doi":"10.1016/j.bbi.2025.106101","DOIUrl":"10.1016/j.bbi.2025.106101","url":null,"abstract":"<div><h3>Background</h3><div>The proteome is a valuable resource for pinpointing therapeutic targets. Therefore, we conducted a proteome-wide Mendelian randomization (MR) study aimed at identifying potential protein markers and therapeutic targets for Anti-N-Methyl-D-Aspartate Receptor Encephalitis (NMDAR-E).</div></div><div><h3>Methods</h3><div>Protein quantitative trait loci (pQTLs) were obtained from seven published genome-wide association studies (GWASs) focusing on the plasma proteome, resulting in summary-level data for 734 circulating protein markers. Genetic associations with NMDAR-E were determined via a large <em>meta</em>-analysis encompassing 323 cases and 1,519 controls. To confirm the causal roles of candidate proteins, we performed sequential colocalization. Subsequently, we experimentally validated prioritized proteins through two complementary approaches: (1) stimulation of HMC3 microglial cells with patient-derived anti-NMDAR-IgG versus control human IgG to assess antibody-induced protein expression dynamics; (2) anti-NMDAR-IgG was stereotactically injected into the lateral ventricle of mice to establish the passive immunization NMDAR-E model, with comparative analysis of lateralized protein expression 7 days post-injection. Additionally, single cell-type expression analysis, protein–protein interaction (PPI) assessments, and evaluations of druggability were conducted to pinpoint enriched cell types and possible therapeutic targets.</div></div><div><h3>Results</h3><div>In total, genetically predicted levels of 37 proteins showed associations with NMDAR-E risk. Elevated levels of three proteins (SIRPA, LGALS3, CASP3) and decreased levels of two proteins (TREM2, IL1RN) were correlated with an increased risk of NMDAR-E. The identified protein-coding genes were predominantly expressed in CD20+ B cells, with comparably elevated expression also observed in mast cells and CD16+ monocytes within the peripheral blood mononuclear cells (PBMCs) of NMDAR-E patients. Anti-NMDAR-IgG induced upregulation of four proteins in human microglial cells and four laterally upregulated proteins in murine brains, with three overlapping responders. Furthermore, proteins TREM2, LGALS3, SIRPA, IL1RN and CASP3, which were initially targeted for drug development in cancer and autoimmune conditions, may also represent therapeutic options for NMDAR-E.</div></div><div><h3>Conclusions</h3><div>This study integrates genetic epidemiology with functional validation, successfully identifying protein biomarkers associated with NMDAR-E risk. The convergence of MR-predicted causal proteins with antibody-driven expression changes in human microglia and mouse models underscores their pathological relevance, providing actionable insights for biomarker screening and therapeutic development.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106101"},"PeriodicalIF":7.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145019123","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":"Impaired social fear extinction in chronically stressed mice: Impact on inflammatory brain markers and the contribution of oxytocin","authors":"Katharina Gryksa ,&nbsp;Anna K. Schmidtner ,&nbsp;Theresa Schäfer ,&nbsp;Stefan O. Reber ,&nbsp;Inga D. Neumann","doi":"10.1016/j.bbi.2025.106104","DOIUrl":"10.1016/j.bbi.2025.106104","url":null,"abstract":"<div><div>Chronic psychosocial stress is a frequent burden in modern societies and risk factor for numerous somatic and affective disorders, including social anxiety disorder (SAD). Traumatic experiences after prolonged periods of stress exposure often trigger these diseases. Although human and animal studies support the hypothesis of an over-reactive immune system being critically involved in the pathogenesis of psychopathologies, the underlying mechanisms are not fully understood. Accordingly, immune-focused treatment options are lacking.</div><div>The current study was performed in male C57BL/6 and CD1 mice using a combination of chronic subordinate colony housing (CSC), a mouse model for chronic psychosocial stress, and social fear conditioning (SFC), a mouse model for SAD. We can show that CSC prior to SFC exposure facilitates the manifestation of trauma-induced social avoidance and impairs its extinction, while increasing the release of inflammatory factors in the brain, especially in the amygdala. The neuropeptide oxytocin (OXT) with its profound pro-social, stress-buffering and anti-inflammatory effects has been suggested as a promising therapeutic option for stress-related diseases including SAD. Here, we can show that central OXT infusion protected against the observed behavioral phenotype, whereas the inflammatory parameters in the amygdala remained unchanged.</div><div>Although further mechanistic studies are warranted, our findings indicate that chronic psychosocial stress aggravates the development of SAD-like symptoms caused by a traumatic social event and impairs its recovery. In addition, our data provide further evidence for stress- and trauma-protective effects of OXT but did not confirm its anti-inflammatory properties.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106104"},"PeriodicalIF":7.6,"publicationDate":"2025-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032785","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":"Comparing two anti-inflammatory reflexes: Splanchnic and hypothalamic–pituitary–adrenal","authors":"Michael McKinley ,&nbsp;Song T Yao ,&nbsp;Davide Martelli ,&nbsp;Robin McAllen","doi":"10.1016/j.bbi.2025.106099","DOIUrl":"10.1016/j.bbi.2025.106099","url":null,"abstract":"<div><div>Both the autonomic nervous system and the hypothalamic–pituitary–adrenal axis respond to systemic immune challenge by initiating anti-inflammatory reflexes. Here we compare those two homeostatic responses <em>in vivo.</em> We first confirmed in male urethane-anaesthetized rats that disabling the autonomic reflex by bilateral section of the splanchnic sympathetic nerves increased plasma tumor necrosis factor α (TNF) responses to systemic lipopolysaccharide (LPS, 60 µg/kg i.v.) while reducing levels of the key anti-inflammatory cytokine, interleukin 10 (IL-10). Bilateral adrenalectomy, removing both adrenal catecholamines and glucocorticoids, increased TNF responses to LPS by a factor similar to splanchnic nerve section, but unlike splanchnic nerve section, did not reduce IL-10 responses. Both the splanchnic anti-inflammatory reflex and the adrenal glucocorticoid response independently suppress TNF production. When either pathway was disabled individually, TNF responses to LPS increased. When both were disabled simultaneously, by combining adrenalectomy with splanchnic nerve section, TNF levels rose further, in an approximately additive manner. In contrast, IL-10 responses reflected the balance between catecholamine-driven enhancement and glucocorticoid-mediated suppression. When compared to adrenal nerve section, which prevents adrenal catecholamine release, bilateral adrenalectomy (removing both adrenaline and glucocorticoids) actually increased IL-10 responses to LPS. This indicates that circulating glucocorticoids actively suppress IL-10 as well as TNF. That inference was confirmed by restoring plasma corticosterone levels in adrenalectomized rats. We conclude that systemic immune challenge initiates two early, powerful anti-inflammatory reflexes that suppress TNF with similar potency. These reflexes act through independent mechanisms and exert opposing control over IL-10, highlighting their broader regulatory role in cytokine balance.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106099"},"PeriodicalIF":7.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996588","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":"Human microglia reduce alpha-synuclein aggregation and are neuroprotective in adult mouse brain","authors":"Katrina Albert ,&nbsp;Sanni Peltonen ,&nbsp;Anni Vanne ,&nbsp;Sara Kälvälä ,&nbsp;Valtteri Syvänen ,&nbsp;Jari Koistinaho ,&nbsp;Kelvin C. Luk ,&nbsp;Šárka Lehtonen","doi":"10.1016/j.bbi.2025.106097","DOIUrl":"10.1016/j.bbi.2025.106097","url":null,"abstract":"<div><div>Microglia, brain-resident immune cells, are involved in pathophysiology of several neurodegenerative diseases, including Parkinson’s disease. Given significant species-specific differences in microglia gene expression, particularly in disease-risk genes, as well as the highly reactive nature of these cells, studying human microglia in a whole brain environment is essential. Here, we established a humanized mouse model by transplanting human induced pluripotent stem cell-derived hematopoietic progenitor cells into the striatum of immunodeficient adult mice and injected human alpha-synuclein preformed fibrils to model Parkinson’s disease pathology. Transplanted human cells engraft, mature into microglia and maintain their phenotype for at least three months post-transplantation. These human microglia interact with alpha-synuclein, significantly limiting its propagation from the striatum to the substantia nigra and further reducing local small aggregates; they also mildly protect tyrosine hydroxylase neurons there. Transcriptomic profiling reveals 56 differentially expressed genes in human microglia in response to alpha-synuclein preformed fibrils, while host mouse cells show 202 gene expression changes, including an upregulation of gene Hcrt (fold change = 7.77, p = 0.0015). Immunohistochemistry analysis further confirms the preservation of hypocretin-positive neurons in the hypothalamus of the transplanted mice (p = 0.0079). The findings highlight the neuroprotective role of human microglia and establish a more disease-relevant <em>in vivo</em> model for investigating alpha-synuclein aggregation and therapeutic interventions in Parkinson’s disease.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106097"},"PeriodicalIF":7.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144996587","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 human microglia responsome: a resource for microglia states in health and disease","authors":"Gijsje J.L.J. Snijders ,&nbsp;Katia de Paiva Lopes ,&nbsp;Marjolein A.M. Sneeboer ,&nbsp;Benjamin Z. Muller ,&nbsp;Frederieke A.J. Gigase ,&nbsp;Dante D’Urso ,&nbsp;Ricardo A. Vialle ,&nbsp;Roy Missall ,&nbsp;Raphael Kubler ,&nbsp;Towfique Raj ,&nbsp;Jack Humphrey ,&nbsp;Lot D. de Witte","doi":"10.1016/j.bbi.2025.106095","DOIUrl":"10.1016/j.bbi.2025.106095","url":null,"abstract":"<div><div>Microglia, the immune cells of the brain, are increasingly implicated in neurodegenerative disorders through genetic studies. However, how genetic risk factors for these diseases are related to microglial gene expression, microglial function, and ultimately disease, is still largely unknown. Microglia change rapidly in response to alterations in their cellular environment, which is regulated through changes in transcriptional programs, which are yet poorly understood. Here, we compared the effects of a set of inflammatory and restorative stimuli (lipopolysaccharide, interferon-gamma, resiquimod, tumor necrosis factor-alpha, adenosine triphosphate, dexamethasone, and interleukin-4) on human enriched microglial cells from 67 different donors (N = 398 samples, primarily aged &gt;60 years) at the gene and transcript level. We show that enriched microglia from different anatomical brain regions show distinct responses to inflammatory stimuli. We define specific enriched microglial signatures across conditions which are highly relevant for a wide range of biological functions and complex human diseases. Finally, we used our stimulation signatures to interpret associations from Alzheimer’s disease (AD) (genetic) studies and enriched microglia. Together, we provide a comprehensive transcriptomic resource of the human microglia responsome.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106095"},"PeriodicalIF":7.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144991158","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":"Microglia-derived exosomes modulate myelin regeneration via activating Nrf2 signaling pathway in oligodendrocyte precursor cells in MS","authors":"Jia-Yi He ,&nbsp;Xiao-Yu Ji ,&nbsp;Bo Huang ,&nbsp;Qing-Qing Sun ,&nbsp;Yao Zhang ,&nbsp;Rui Gao ,&nbsp;Zi-Han Fang ,&nbsp;Li-Bin Wang ,&nbsp;Yan-Hua Li ,&nbsp;Yuan Zhang ,&nbsp;Xing Li","doi":"10.1016/j.bbi.2025.106092","DOIUrl":"10.1016/j.bbi.2025.106092","url":null,"abstract":"<div><div>Demyelination is a prominent feature of multiple sclerosis (MS), where the ability of damaged areas to regenerate myelin is limited. Oligodendrocyte precursor cells (OPCs) accumulate in these areas but struggle to mature into oligodendrocytes (OLGs). Microglia also gather at the lesion site, but their impact on OPCs differentiation is not well understood. Here, we found that miR-155-5p was significantly elevated in the expression profile of exosomes extracted from activated microglia. This miRNA binds to the 3′ UTR of the transcription factor Nrf2 in OPCs, inhibiting their differentiation. In a mouse model of demyelination induced by cuprizone, inhibiting miR-155-5p in microglia led to improved motor function recovery, increased the number of mature oligodendrocytes and promoted remyelination. In this study, we highlight a potential new target for treating demyelinating diseases.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106092"},"PeriodicalIF":7.6,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144990884","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":"Killer cell immunoglobulin-like receptor (KIR) alleles suggested to be associated with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)","authors":"Donia Jamal Ramadan ,&nbsp;Katherine M. Kichula ,&nbsp;Sudan Tao ,&nbsp;Timothy Porfilio ,&nbsp;Asgeir Lande ,&nbsp;Øystein Fluge ,&nbsp;Olav Mella ,&nbsp;Elin Bolle Strand ,&nbsp;Ola Didrik Saugstad ,&nbsp;Paul J. Norman ,&nbsp;Benedicte A. Lie ,&nbsp;Marte K. Viken","doi":"10.1016/j.bbi.2025.106098","DOIUrl":"10.1016/j.bbi.2025.106098","url":null,"abstract":"<div><div>Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic and debilitating disease with unknown cause. Involvement of infection and immune dysregulation has been suggested, including changes in immune cell subsets and abnormal functions of natural killer (NK) cells. The regulatory NK cell receptors, killer cell immunoglobulin-like receptors (KIR) have previously been investigated in small cohorts of ME/CFS patients with conflicting results regarding gene content. Here, we studied <em>KIR</em> genes also at the allelic level using high-resolution sequencing, in 418 ME/CFS patients and 473 healthy controls. Human leukocyte antigen (HLA) class I genotype data were included for KIR ligand annotation. Our healthy control data represent <em>KIR</em> frequencies for a Norwegian population, which have not previously been reported. We found no association between ME/CFS and <em>KIR</em> gene content or copy number variations. However, our data suggested that specific <em>KIR</em> alleles at loci encoding inhibitory receptors were associated with ME/CFS, which was further supported by allelic haplotype analyses. Three alleles were more frequent in patients, i.e. <em>KIR3DL3*002</em> (OR = 1.43, 95 % CI (1.09–1.86), p = 0.009), <em>KIR3DL1*020</em> (OR = 2.20, 95 % CI (1.19–4.06), p = 0.01) and <em>KIR3DL2*009</em> (OR = 1.56, 95 % CI (1.09–2.23), p = 0.01), while two alleles had a reduced patient frequency, i.e. <em>KIR3DL3*013</em> (OR = 0.60, 95 % CI (0.42–0.86), p = 0.005) and <em>KIR3DL2*</em>010 (OR = 0.46, 95 % CI (0.30–0.71), p = 0.0005). Our data support an involvement of NK cells in ME/CFS.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106098"},"PeriodicalIF":7.6,"publicationDate":"2025-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932160","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":"Active coping mitigates the effects of stress on glucocorticoid levels in the prefrontal cortex","authors":"Matthew G. Frank ,&nbsp;Emily S. Levy ,&nbsp;Gianni N. Bonnici ,&nbsp;Steven F. Maier ,&nbsp;Michael V. Baratta","doi":"10.1016/j.bbi.2025.106096","DOIUrl":"10.1016/j.bbi.2025.106096","url":null,"abstract":"<div><div>Exposure to stressors elevates glucocorticoid (GC) levels in the periphery and brain, directly impacting neurogenesis, neuronal morphology and function, as well as neuroinflammatory processes. The ability to exert behavioral control over an adverse event prevents many of the sequelae of stressor exposure; however, extensive evidence indicates that this protection occurs without concomitant reductions in hypothalamic–pituitary–adrenal (HPA) axis activity. Given that brain GC levels can be regulated independently of changes in HPA output, we investigated whether controllability might alter corticosterone (CORT) levels and CORT-sensitive gene expression in rat brain, even though it does not modulate peripheral CORT. We found that behavioral control (escapable shock, ES) selectively attenuated stress-induced CORT and modulated CORT-sensitive genes (<em>Nr3c1, Ilb</em>, <em>Nlrp3</em>, and <em>Cd200r1</em>), as well as IL-1β protein in the medial prefrontal cortex (PFC) relative to uncontrollable stress (inescapable shock, IS). Stress-induced expression of PFC 11β-hydroxysteroid dehydrogenase type 1<em>,</em> an enzyme that regulates local concentrations of CORT, was increased (mRNA) and decreased (protein) in ES relative to IS. These controllability effects were absent in other brain structures previously implicated in the differential behavioral outcomes of ES and IS. Together, the findings provide initial evidence that active coping with a stressor is a key determinant for regulating GC action, potentially shaping cognitive and neuroimmune responses to adverse events at a local tissue level.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106096"},"PeriodicalIF":7.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932158","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":"Ketone monoester alleviates cognitive impairment in a transgenic mouse model of Alzheimer’s disease through innate immunological IFITM3 pathway","authors":"Tianying Zhang ,&nbsp;Jingjing Ruan ,&nbsp;Zihan Liu ,&nbsp;Yameng Yu ,&nbsp;Yirui Lu ,&nbsp;Xin Zhang ,&nbsp;Chen Hou ,&nbsp;Xiyu Liu ,&nbsp;Yuan Yuan ,&nbsp;Xiaojuan Han","doi":"10.1016/j.bbi.2025.106094","DOIUrl":"10.1016/j.bbi.2025.106094","url":null,"abstract":"<div><div>Alzheimer’s disease (AD), a progressive neurodegenerative disorder characterized by irreversible cognitive decline and cerebral dysfunction, remains a major global health challenge due to elusive pathogenesis and the lack of disease-modifying therapies. Growing evidence underscores the neuroprotective potential of ketone bodies, particularly β-hydroxybutyrate (β-HB), owing to their diverse biological roles in mitigating AD-related pathology. Recent advances also implicate innate immunity in AD progression, identifying interferon-induced transmembrane protein 3 (IFITM3) as a pivotal regulator of amyloid-β (Aβ) formation. In this study, BD-AcAc2 was administered to induce exogenous ketosis in APP/PS1 transgenic mice, and Aβ-stimulated astrocytes were employed to explore the mechanistic role of β-HB as a nutritional intervention. Our findings demonstrate that β-HB significantly enhanced cognitive performance and reduced hippocampal amyloid plaque burden in APP/PS1 mice, likely through modulation of the IFITM3 pathway. Furthermore, β-HB attenuated Aβ-induced IFITM3 activation, decreased reactive oxygen species (ROS) levels, and downregulated pro-inflammatory cytokine expression in astrocytes. Collectively, these results establish β-HB as a neuroprotective agent that acts through IFITM3-mediated mechanisms, providing novel insights into therapeutic strategies targeting metabolic-immune interactions in AD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"130 ","pages":"Article 106094"},"PeriodicalIF":7.6,"publicationDate":"2025-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144943383","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}