Brain, Behavior, and Immunity最新文献

{"title":"Beneficial and adverse effects of THC on cognition in the HIV-1 transgenic rat model: Importance of exploring task- and sex-dependent outcomes","authors":"Samantha M. Ayoub ,&nbsp;Sunitha Vemuri ,&nbsp;Elizabeth B. Hoang ,&nbsp;Neal A. Jha ,&nbsp;Arpi Minassian ,&nbsp;Jared W. Young","doi":"10.1016/j.bbi.2025.04.030","DOIUrl":"10.1016/j.bbi.2025.04.030","url":null,"abstract":"<div><div>HIV-associated neurocognitive impairment (NCI) is an untreated concern among people living with HIV (PLWH). Cannabis use in PLWH may complicate outcomes on cognition, with evidence to suggest function-dependent effects that are modulated by several factors including use patterns (e.g., frequency of use) and demographic influences (e.g., age). Animal studies can control for these factors.</div><div>Here, we characterized the impact of the primary psychoactive ingredient in cannabis (delta-9-tetrahydrocannabinol; THC), on function-dependent cognitive outcomes in HIV-1 transgenic (Tg) rats using cross-species translatable assays. Female and male HIV-1Tg rats and their controls were tested in the rat Iowa Gambling Task (IGT; to measure risk-based decision-making), and the Probabilistic Reversal Learning Task (PRLT; to measure learning and cognitive flexibility). Rats were tested at baseline, then retested following acute and chronic exposures to THC (0, 0.3, 3 mg/kg, intraperitoneal injection).</div><div>At baseline, HIV-1Tg rats took longer to make decisions, but exhibited intact cognition across tasks, suggestive of a speed-accuracy trade-off and early cognitive deficits. Both acute and chronic THC exposures produced selective effects on primary performance measures in HIV-1Tg rats, including enhanced learning performance but worsened risk-based decision-making, not observed in controls.</div><div>This work confirms function-dependent effects of THC on cognitive function in an animal model of HIV using cross-species translatable tasks used in the clinic. Findings are consistent with evidence for function-dependent cannabis effects observed in HIV, and suggest THC may drive cannabis-induced changes observed on cognitive performance in PLWH. These data may serve as guidance for clinicians prescribing cannabis to patients with HIV, and for further research exploring the interactive effects of HIV and cannabinoid treatment on cognitive function.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 571-588"},"PeriodicalIF":8.8,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143899940","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":"Decreased excitatory and increased inhibitory transmission in the hippocampal CA1 drive neuroinflammation-induced cognitive impairments in mice","authors":"Xin-miao Wu ,&nbsp;Cui-na Shi ,&nbsp;Kai Liu ,&nbsp;Xiao-yi Hu ,&nbsp;Qiu-li He ,&nbsp;Hao Yao ,&nbsp;Di Fan ,&nbsp;Da-qing Ma ,&nbsp;Jian-jun Yang ,&nbsp;Jin-chun Shen ,&nbsp;Mu-huo Ji","doi":"10.1016/j.bbi.2025.04.027","DOIUrl":"10.1016/j.bbi.2025.04.027","url":null,"abstract":"<div><div>Neuroinflammation is one of crucial pathogenic mechanisms underlying Alzheimer’s disease, sepsis-associated encephalopathy, and postoperative cognitive dysfunction. These diseases or conditions are often accompanied by typical clinical manifestations of cognitive impairments, including impaired learning and memory but underlying mechanisms are unknown. Hence, effective treatments are not available. In the current study, mice received intraperitoneal administrations of LPS (0.5 mg/kg, daily, Escherichia coli<!--> <!-->O55:B5) for seven consecutive days and after which, different cohorts were used for behavioral assessments with open field, Y maze, and novel object recognition test or for electrophysiology recordings of mEPSC, mIPSC or LTP in <em>ex vivo</em> preparations. Their hippocampi were harvested for immunostaining or Western blotting of PSD95, vGLUT1, vGAT, gephyrin, PV, and SST. <em>In vivo</em> optical fiber calcium recording was used to evaluate the neuronal excitability. During the early stage of neuroinflammation induced by LPS, there was a decrease of excitatory afferent synapses and transmission in the CA1. During the later stage of neuroinflammation, there was an increase of inhibitory afferent synapses and transmission in the CA1, resulting in excessive inhibition on excitatory neurons. Both of them contributed to the decreased hippocampal neuronal excitability and impaired LTP, ultimately leading to cognitive impairments. Overexpression of CREB in the early stage or inactivation of PV-positive interneurons in the later stage in the CA1 both improved cognitive impairments. Our work suggests that negating decreased excitatory and increased inhibitory afferent in the hippocampus may improve cognitive impairments relate to neuroinflammation associated with neurological diseases.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 416-428"},"PeriodicalIF":8.8,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143874411","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":"Cell-type-specific and inflammatory DNA methylation patterns associated with PTSD","authors":"Alicia K. Smith ,&nbsp;Seyma Katrinli ,&nbsp;Adam X. Maihofer ,&nbsp;Allison E. Aiello ,&nbsp;Dewleen G. Baker ,&nbsp;Marco P. Boks ,&nbsp;Leslie A. Brick ,&nbsp;Chia-Yen Chen ,&nbsp;Shareefa Dalvie ,&nbsp;Negar Fani ,&nbsp;Catherine B. Fortier ,&nbsp;Joel Gelernter ,&nbsp;Elbert Geuze ,&nbsp;Charles F. Gillespie ,&nbsp;Jasmeet P. Hayes ,&nbsp;Suzi Hong ,&nbsp;Ronald C. Kessler ,&nbsp;Anthony P. King ,&nbsp;Nastassja Koen ,&nbsp;Karestan C. Koenen ,&nbsp;Anthony S. Zannas","doi":"10.1016/j.bbi.2025.04.031","DOIUrl":"10.1016/j.bbi.2025.04.031","url":null,"abstract":"<div><h3>Background</h3><div>Epigenetic modifications, including DNA methylation (DNAm), can change in response to traumatic stress exposure, and may help to distinguish between individuals with and without PTSD. Here, we examine the DNAm patterns specific to immune cell types and inflammation in those with PTSD.</div></div><div><h3>Methods</h3><div>This study includes 3,277 participants from 11 cohorts participating in the Psychiatric Genomics Consortium (PGC) PTSD Epigenetics Workgroup. DNAm was assayed from blood with the MethylationEPIC BeadChip. A standardized QC pipeline was applied and used to impute cell composition. Within each cohort, we identified cell-type-specific DNAm patterns associated with PTSD, controlling for sex (if applicable), age, and ancestry. Meta-analyses were performed from summary statistics.</div></div><div><h3>Results</h3><div>PTSD cases had lower proportions of B cells and NK cells as well as higher proportions of neutrophils when compared to trauma-exposed controls. Overall, we identified 96 PTSD-associated CpGs across six types of immune cells. Most of these differences were identified in B cells, with 95 % exhibiting lower methylation levels in those with PTSD. Interestingly, the PTSD-associated CpGs annotated to a gene in B cells were enriched in a recent GWAS of PTSD (p &lt; 0.0001).</div></div><div><h3>Conclusions</h3><div>This study identifies novel PTSD-associated CpGs in individual immune cell types and supports the role of immune dysregulation and inflammation in PTSD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 540-548"},"PeriodicalIF":8.8,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143886469","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":"Peripheral-central immune crosstalk in Parkinson’s disease and its association with clinical severity","authors":"Julia C. Greenland ,&nbsp;Jonathan Holbrook ,&nbsp;Lakmini Kahanawita ,&nbsp;Marta Camacho ,&nbsp;Tim D. Fryer ,&nbsp;Young T. Hong ,&nbsp;Caroline H. Williams-Gray","doi":"10.1016/j.bbi.2025.04.028","DOIUrl":"10.1016/j.bbi.2025.04.028","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;div&gt;Increasingly, the immune system is implicated in the aetiology and progression of Parkinson’s disease (PD). Immune activation is seen both peripherally in the blood, with a tendency towards a pro-inflammatory profile, and centrally in the cerebrospinal fluid and brain parenchyma, with microglial activation and increased numbers of immune cells in the central nervous system. However, the relationship between this peripheral and central immune profile, as well as the association with clinical measures of disease severity is not clear.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;div&gt;61 people with PD, within three years of diagnosis and no immune comorbidities, and 51 matched controls underwent detailed blood immunophenotyping using a flow cytometry panel with markers to characterise adaptive and innate immune populations. In the PD cohort, 35 also had cerebrospinal fluid (CSF) immune cell analysis and 31 underwent positron emission tomography (PET) brain imaging with the radioligand [&lt;sup&gt;11&lt;/sup&gt;C]-PK11195 to assess microglial activation. PD participants were assessed with the Movement Disorder Society-Unified Parkinson’s disease rating Scale (MDS-UPDRS) and the Addenbrooke’s Cognitive Examination (ACE-III). The immune profiles of PD and control participants were compared. In the PD group, relationships between peripheral and CSF immune cell populations, [&lt;sup&gt;11&lt;/sup&gt;C]-PK11195 binding, and clinical measures were investigated in exploratory analyses using multiple linear regression.&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;div&gt;Compared to controls, PD participants had a pro-inflammatory profile in the blood with an elevated Systemic Inflammatory Index (SII) (&lt;em&gt;p&lt;/em&gt; = 0.049), a higher percentage of classical monocytes (&lt;em&gt;p =&lt;/em&gt; 0.046), and decreased expression of functional markers of T regulatory cells (FoxP3 (&lt;em&gt;p =&lt;/em&gt; 0.030) and Helios (&lt;em&gt;p =&lt;/em&gt; 0.015)) and B regulatory cells (CD1d (&lt;em&gt;p =&lt;/em&gt; 0.031)).&lt;/div&gt;&lt;div&gt;Immune cell subset numbers in blood and CSF were correlated for CD8+ cells (rho = 0.42, &lt;em&gt;p&lt;/em&gt; = 0.011), CD16+ NK cells (rho = 0.49, &lt;em&gt;p&lt;/em&gt; = 0.004) and classical monocytes (rho = −0.38, &lt;em&gt;p&lt;/em&gt; = 0.028). CSF immune populations were also correlated with [&lt;sup&gt;11&lt;/sup&gt;C]-PK11195 binding in disease-relevant regions of interest.&lt;/div&gt;&lt;div&gt;Several blood and CSF immune cell subsets and regional [&lt;sup&gt;11&lt;/sup&gt;C]-PK11195 binding showed relationships with motor and cognitive scores, with a consistent trend of pro-inflammatory markers being related to a more severe disease phenotype. Increased Toll-like receptor 2 expression on classical monocytes in the CSF and [&lt;sup&gt;11&lt;/sup&gt;C]-PK11195 binding in the substantia nigra independently predicted motor score (MDS-UPDRS-III).&lt;/div&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusion&lt;/h3&gt;&lt;div&gt;This exploratory study suggests that peripheral and central immune changes are closely linked in PD, and relevant to clinical disease severity. These findings warrant further validation and exploration ","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 558-570"},"PeriodicalIF":8.8,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143894899","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":"I see sick people: Beliefs about sensory detection of infectious disease are largely consistent across cultures","authors":"Joshua M. Ackerman ,&nbsp;Theodore Samore ,&nbsp;Daniel M.T. Fessler ,&nbsp;Tom R. Kupfer ,&nbsp;Soyeon Choi ,&nbsp;Wilson N. Merrell ,&nbsp;Lene Aarøe ,&nbsp;Toivo Aavik ,&nbsp;Stephen Acabado ,&nbsp;Grace Akello ,&nbsp;Ilham N. Alfian ,&nbsp;Laith Al-Shawaf ,&nbsp;Marinés M. Alvarez ,&nbsp;Jeanine Ammann ,&nbsp;Gizem Arikan ,&nbsp;Saiyeda A. Asha ,&nbsp;Anibal M. Astobiza ,&nbsp;Carmen G. Baeza-Ugarte ,&nbsp;Pat Barclay ,&nbsp;Fiona Kate Barlow ,&nbsp;Iris Žeželj","doi":"10.1016/j.bbi.2025.04.020","DOIUrl":"10.1016/j.bbi.2025.04.020","url":null,"abstract":"<div><div>Identifying cues to contagious disease is critical for effectively tracking and defending against interpersonal infection threats. People hold lay beliefs about the types of sensory information most relevant for identifying whether others are sick with transmissible illnesses. Are these beliefs universal, or do they vary along cultural and ecological dimensions? Participants in 58 countries (N = 19,217) judged how effective, and how likely they were to use, cues involving each of the five major sensory modalities in an imagined social interaction during a flu outbreak. Belief patterns were strongly consistent across countries (sight &gt; audition &gt; touch &gt; smell &gt; taste), suggesting a largely universal conceptualization of the role of sensory information for interpersonal respiratory disease detection. Results also support a safe senses hypothesis, with perceivers reporting that they would use senses that function at a distance—and thus reduce pathogen transmission risk—more than would be expected given participants’ beliefs as to the efficacy of these senses for disease detection. Where societal variation did emerge, it was captured by a cohesive set of socio-ecological factors, including human development, latitude, pathogen prevalence, and population density. Together, these findings reveal a shared lens through which contagious respiratory disease is assessed, one that prioritizes minimizing risk to perceivers, and may offer leverage for designing interventions to improve public health.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 737-750"},"PeriodicalIF":8.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143953885","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":"SOAT1 dysregulation in astrocytes drives Blood–Brain barrier dysfunction and neuroinflammation in Alzheimer’s disease","authors":"Lian Huang ,&nbsp;Fu Zeng ,&nbsp;Hui Wei ,&nbsp;Tong Su ,&nbsp;Yuwen Su ,&nbsp;Yarong Lin ,&nbsp;Qi Niu ,&nbsp;Qi Xu","doi":"10.1016/j.bbi.2025.04.032","DOIUrl":"10.1016/j.bbi.2025.04.032","url":null,"abstract":"<div><div>Alzheimer’s disease (AD) is a neurodegenerative disorder that leads to memory loss and cognitive decline, in which blood–brain barrier (BBB) and astrocyte dysfunction are significantly involved. Recent evidence suggests that dysregulation of lipid metabolism in astrocytes contributes to BBB disruption and neuroinflammation in AD. Sterol O-acyltransferase 1 (SOAT1), an enzyme involved in cholesterol esterification, has been implicated in BBB disruption and neuroinflammation, but its specific role in AD remains unclear. This study aimed to investigate the impact of SOAT1 on lipid metabolism, BBB integrity, and neuroinflammation in AD. Using Oil Red O staining of human autopsy brain tissue and reanalysis of publicly available single-nucleus RNA sequencing (snRNA-seq) data, we identified a significant increase in lipid droplet accumulation and lipid metabolism gene expression, particularly in astrocytes, in the brains of AD patients. Furthermore, in vitro BBB models and the 5 × FAD mouse model were used to explore how SOAT1 expression influences BBB function. Our results demonstrated that elevated SOAT1 expression in astrocytes was positively correlated with increased lipid droplet accumulation and compromised BBB integrity. Knockdown of SOAT1 using siRNA or treatment with the SOAT1 inhibitor K604 restored BBB function, reduced neuroinflammation, and improved cognitive function in 5 × FAD mice. These findings suggest that SOAT1 plays a critical role in astrocytic lipid metabolism and BBB dysfunction in AD. Targeting SOAT1 may be a promising therapeutic approach to alleviate neuroinflammation and restore cognitive function in AD patients.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 497-509"},"PeriodicalIF":8.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143886466","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 endotoxin tolerance is retained after enforced repopulation","authors":"Tiago Medeiros-Furquim,&nbsp;Anneke Miedema,&nbsp;Edwin Schilder,&nbsp;Nieske Brouwer,&nbsp;Inge R. Holtman,&nbsp;Susanne M. Kooistra,&nbsp;Bart J.L. Eggen","doi":"10.1016/j.bbi.2025.04.014","DOIUrl":"10.1016/j.bbi.2025.04.014","url":null,"abstract":"<div><div>Microglia are crucial for CNS homeostasis and are involved in a wide range of neurodegenerative and neuroinflammatory diseases. Systemic inflammation and infections can contribute to neurodegeneration later in life by affecting microglia. Like other innate immune cells, microglia can develop innate immune memory (IIM) in response to an inflammatory challenge, altering their response to subsequent stimuli. IIM can ameliorate or worsen CNS pathology, but it is unclear if IIM can be reversed to restore microglia functions. Here, we investigated whether microglia depletion-repopulation by inhibition of the colony-stimulating factor 1 receptor with BLZ945 reversed LPS-induced microglia endotoxin tolerance in mice. Repopulated microglia displayed a reduced expression of homeostatic genes and genes related to mitochondrial respiration and TCA cycle metabolism and an increased expression of immune effector and activation genes. Nonetheless, the blunted inflammatory gene response after LPS-preconditioning was retained after a depletion-repopulation cycle. Our study highlights the persistence of endotoxin tolerance in microglia after a depletion-repopulation cycle, which might impact the potential effectiveness of strategies targeted at microglia depletion for clinical applications.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 512-528"},"PeriodicalIF":8.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143886467","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":"SARS-CoV2 vaccination during pregnancy – Vetting the impact on maternal health and long-term consequences for offspring brain function","authors":"Anna Gundacker ,&nbsp;Ron Schaer ,&nbsp;Arnold Pollak ,&nbsp;Ulrike Weber-Stadlbauer ,&nbsp;Daniela D. Pollak","doi":"10.1016/j.bbi.2025.04.029","DOIUrl":"10.1016/j.bbi.2025.04.029","url":null,"abstract":"<div><div>The COVID-19 pandemic has shown the critical importance of vaccination strategies to protect vulnerable populations, including pregnant women, from severe disease and its lingering consequences. Although growing evidence demonstrates that COVID-19 vaccines are both safe and highly beneficial during pregnancy, vaccine hesitancy among pregnant women persists, partly fueled by the persistent, decade-old “urban myth” linking vaccination during pregnancy to neuropsychiatric disorders in children.</div><div>Here we used a mouse model of passive immunization with severe acute respiratory syndrome coronavirus 2 spike neutralizing monoclonal antibodies (SaCoV-AB) to determine the effects of gestational COVID-19 vaccination on key pregnancy outcomes, maternal and offspring health, and behavior.</div><div>We show that at a higher SaCoV-AB dosage, maternal immune response is reflected in elevated TNF-α levels in maternal serum, but not in the placenta or the fetal brain, with no effect on pregnancy outcomes. We report no consequences for postpartum maternal care behavior and neonatal communication signatures. Behavioral assessment of adult female and male offspring after maternal SaCoV-AB treatment revealed no differences in phenotypes relevant to neurodevelopmental disorders.</div><div>Our findings indicate that in a preclinical model, passive immunization with SaCoV-AB during pregnancy is well-tolerated, with no discernable impact on maternal or offspring health and behavior.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 549-557"},"PeriodicalIF":8.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143886585","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 basolateral amygdala and striatum propagate alpha-synuclein pathology causing increased fear response in a Parkinson’s disease model","authors":"Thuy Thi Lai ,&nbsp;Wei Xiang ,&nbsp;Milos Stanojlovic ,&nbsp;Christopher Käufer ,&nbsp;Malte Feja ,&nbsp;Kristina Lau ,&nbsp;Friederike Zunke ,&nbsp;Franziska Richter","doi":"10.1016/j.bbi.2025.04.025","DOIUrl":"10.1016/j.bbi.2025.04.025","url":null,"abstract":"<div><div>Alpha-synuclein (aSyn)-related pathology crucially contributes to the pathogenesis of Parkinson’s disease, a frequent and incurable neurodegenerative disease characterized by progressive motor and non-motor symptoms. Anxiety and fear- related neuropsychiatric symptoms develop frequently and early in the disease, but a lack of understanding of pathogenesis hampers rational therapy. This study aimed to decipher whether aSyn pathology in the basolateral amygdala (BLA) is causative of fear and anxiety. Bilateral stereotaxic injections of human aSyn-preformed amyloid fibrils (PFF) in BLA, striatum, or substantia nigra were conducted in female mice overexpressing human aSyn (Thy1-aSyn) and in wildtype littermates (WT). We characterized the propagation of aSyn pathology and related neuropathological changes across brain regions and examined the behavioral and fear responses in mice up to 2 months post-injection of PFF. While PFF injections induced local aSyn fibril pathology close to all respective injection sites in transgenic mice, we observed differences in propagation, downstream pathology and behavioral alterations. The BLA and the striatum, but not the substantia nigra, effectively propagated aSyn pathology to connected brain regions at 2.5 months post injection. This involved enhanced microgliosis and astrogliosis in the nigrostriatal system and loss of GABAergic parvalbuminergic interneurons in the striatum and corticolimbic brain regions. Intra-BLA PFF injections resulted in increased cued fear response in both transgenic mice and WT mice at 1 month post injection. The effect was more pronounced in the transgenic mice. Conversely, intra-striatal PFF injections enhanced contextual fear in WT at 2 months post injection. These findings imply that increased fear is inducible by aSyn pathology, especially if originating in the BLA or striatum. Furthermore, both regions are hub regions of aSyn pathology propagation, thereby contributing to disease progression. These insights provide mechanisms that can guide rational therapeutic development.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 469-486"},"PeriodicalIF":8.8,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143878488","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":"Blockage of CCL3 with neutralizing antibody reduces neuroinflammation and reverses Alzheimer disease phenotypes","authors":"Chao Wei ,&nbsp;Jing Liu ,&nbsp;Bing Wu ,&nbsp;Tianhao Shen ,&nbsp;Jiao Fan ,&nbsp;Ye Lin ,&nbsp;Ke Li ,&nbsp;Yane Guo ,&nbsp;Yanchang Shang ,&nbsp;Bo Zhou ,&nbsp;Hengge Xie","doi":"10.1016/j.bbi.2025.04.034","DOIUrl":"10.1016/j.bbi.2025.04.034","url":null,"abstract":"<div><h3>Background</h3><div>Accumulating evidence indicates that neuroinflammation is involved in the pathogenesis of Alzheimer’s disease (AD). According to RNA sequencing and quantitative PCR (qPCR), we found that chemokine CCL3 mRNA expression was abnormally upregulated in the brains of AD transgenic mice. Moreover, the levels of CCL3 in the serum of AD patients were significantly elevated and negatively correlated with their cognitive abilities. However, the role of CCL3 in AD neuroinflammation and pathological damages remains elusive.</div></div><div><h3>Methods</h3><div>Using behavioral, histological, and biochemical methods, outcomes of CCL3 antibody treatment on neuropathology and cognitive deficits were studied in the APPswe/PS1dE9 mice.</div></div><div><h3>Results</h3><div>In the present study, we reported that CCL3 protein expression was increased in the APPswe/PS1dE9 mice, whereas blockage of CCL3 with neutralizing antibody potently inhibited CCL3 activation in the APPswe/PS1dE9 mice down to the levels of wild-type mice. Specifically, CCL3 antibody significantly improved the learning and memory abilities of APPswe/PS1dE9 mice. In addition, CCL3 antibody treatment decreased cerebral amyloid-β (Aβ) levels and plaque burden via inhibiting amyloid precursor protein (APP) processing by reducing beta-site APP cleaving enzyme 1 (BACE1) expression in the APPswe/PS1dE9 mice. We also found that CCL3 antibody treatment alleviated neuroinflammation and reduced synaptic defects in the APPswe/PS1dE9 mice. Furthermore, the activated NF-κB signaling pathway in APPswe/PS1dE9 mice was inhibited by CCL3 antibody treatment.</div></div><div><h3>Conclusions</h3><div>Collectively, our findings provide evidence that CCL3 activation may contribute to the AD pathogenesis and may serve as a novel therapeutic target in the treatment of AD.</div></div>","PeriodicalId":9199,"journal":{"name":"Brain, Behavior, and Immunity","volume":"128 ","pages":"Pages 400-415"},"PeriodicalIF":8.8,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143864098","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}