bims-blobar 2025-07-27 papers

bims-blobar

Biomed News

on Blood brain barrier repair

Issue of 2025–07–27
sixteen papers selected by
Nicolas Rebergue

Overexpression of endothelial β4integrin has no impact on blood-brain barrier integrity or the pathogenesis of experimental autoimmune encephalomyelitis.
Assessing blood-brain barrier (BBB) integrity in an Alzheimer's disease mouse model: is the BBB globally or locally disrupted?
Tirzepatide mitigates Stroke-Induced Blood-Brain barrier disruption by modulating Claudin-1 and C/EBP-α pathways.
Knockdown SIRT6 Alleviates Blood-Brain Barrier Disruption after Subarachnoid Hemorrhage through Inhibiting Ferroptosis by Promoting SMARCA2 Acetylation.
Correction to: Inflammation and Blood-Brain Barrier in Depression: Interaction of CLDN5 and IL6 Gene Variants in Stress-Induced Depression.
Neuroprotective role of pyrroloquinoline quinone in folate deficiency-induced blood-brain barrier disruption.
Blood‑brain barrier dysfunction in schizophrenia: Mechanisms and implications (Review).
Targeting PD-L1 for Ischemic Stroke Recovery: Age-Dependent Modulation of Immune and BBB Pathways.
VCAM-1 in Cognitive Impairment: Mechanisms, Biomarker Potential, and Therapeutic Targeting.
Cerebral Small Vessel Disease: Therapeutic Approaches Targeting Neuroinflammation, Oxidative Stress, and Endothelial Dysfunction.
Regulation of BBB function and pathological evolution of PD by microenvironment "spatiotemporal gradient": unique advantages of microfluidic chips.
Periodontitis-induced neuroinflammation triggers IFITM3-Aβ axis to cause alzheimer's disease-like pathology and cognitive decline.
Ambroxol alleviates hippocampus injury after BRIR through suppression of the IRE1α/TRAF2 signaling pathway.
Adaptive Immune Dyshomeostasis as a Mediator of Vascular Cognitive Decline: Unraveling Neurovascular Crosstalk.
Neisseria meningitidis regulates P-glycoprotein transporter activity in brain endothelial cells via sphingosine 1-phosphate receptor 1.
Acetamiprid mediates cognitive dysfunction through the gut-brain axis: Synaptic damage and immune-mediated blood-brain barrier dysfunction.

Exp Neurol. 2025 Jul 19. pii: S0014-4886(25)00245-6. [Epub ahead of print] 115381

Overexpression of endothelial β4integrin has no impact on blood-brain barrier integrity or the pathogenesis of experimental autoimmune encephalomyelitis.

Arjun Sapkota, Sebok K Halder, Richard Milner.

  Laminin is a major component of the vascular basement membrane and transgenic mice deficient in astrocyte or pericyte laminin manifest blood-brain barrier (BBB) disruption, implying an important stabilizing role for laminin in BBB integrity. As the laminin receptor α6β4 integrin is strongly induced on CNS blood vessels in the neuroinflammatory animal model experimental autoimmune encephalomyelitis (EAE), and mice deficient in endothelial β4 integrin (β4-EC-KO) display worse EAE, here we tested in a novel transgenic knock-in mouse, whether constitutive overexpression of endothelial β4 integrin (β4-EC-KI) would enhance BBB integrity and reduce EAE development and progression. In immunofluorescent analysis of brain and spinal cord tissue, β4-EC-KI mice showed strong constitutive endothelial β4 integrin expression in all blood vessels, along with upregulation of its α6 integrin subunit partner and the β4 subunit of its physiological ligand, laminin 411. Under disease-free conditions, vascular structure and activation were unchanged in β4-EC-KI mice. In the EAE model, β4-EC-KI mice were no different from WT LM controls in the time of onset, peak clinical score, or progression of EAE. Consistent with this, histopathological analysis revealed no observable differences in levels of BBB disruption, vascular activation, leukocyte infiltration, endothelial tight junction protein expression, or microglial and astrocyte activation. These data demonstrate that while β4-EC-KI mice show strong constitutive expression of endothelial β4 integrin, this had no discernible impact on blood-brain barrier integrity or the pathogenesis of EAE.

Keywords:  Blood-brain barrier; Endothelial; Extracellular matrix; Integrin; Laminin; Microglia; Vascular

DOI:  https://doi.org/10.1016/j.expneurol.2025.115381
Fluids Barriers CNS. 2025 Jul 23. 22(1): 79

Assessing blood-brain barrier (BBB) integrity in an Alzheimer's disease mouse model: is the BBB globally or locally disrupted?

Ehsan Nozohouri, Behnam Noorani, Dhavalkumar Patel, Yeseul Ahn, Sumaih Zoubi, Ulrich Bickel.

  Alzheimer's disease (AD), marked by amyloid-beta (Aβ) plaques and tau tangles, involves cerebral amyloid angiopathy (CAA), which may compromise blood-brain barrier (BBB) integrity. However, the extent and nature of BBB disruption in AD remain unclear. This study assessed BBB permeability in Tg2576 AD mice by evaluating unidirectional paracellular transport from blood to brain following intravenous injection of the stable isotope-labeled marker [¹³C₁₂]sucrose. Pharmacokinetic analysis of plasma and brain concentrations 30 min post-injection revealed minimal sucrose passage across the BBB in both AD and wild-type (WT) mice, suggesting preserved BBB integrity despite Aβ deposition. Regional clearance rates in the hippocampus, cortex, and cerebellum were similar across groups, with only the olfactory bulbs showing increased uptake. Immunohistochemical analysis of BBB tight junction proteins (claudin-5, occludin, ZO-1) revealed no significant differences between AD and WT mice. High-resolution imaging showed minor tight junction disruptions near Aβ plaques, but laser microdissection and LC-MS/MS analysis revealed no increased sucrose concentrations in regions with vascular Aβ-deposition, indicating localized changes do not substantially affect BBB permeability. Our findings challenge the assumption of widespread BBB leakiness in the Tg2576 AD model, highlighting the need for multi-method approaches to assess BBB integrity and optimize drug delivery in AD.

Keywords:  Alzheimer’s mouse model; Blood-Brain barrier; LC-MS/MS; Laser Micro-dissection; Permeability; Pharmacokinetics; Tg2576; [13C]sucrose

DOI:  https://doi.org/10.1186/s12987-025-00685-2
Mol Med. 2025 Jul 23. 31(1): 263

Tirzepatide mitigates Stroke-Induced Blood-Brain barrier disruption by modulating Claudin-1 and C/EBP-α pathways.

Duozi Wang, Jianhong Wang, Binghu Li, Shu Yang, Fuqiang Guo, Bo Zheng, Jian Wang.

   BACKGROUND: Stroke is a major cause of disability and mortality worldwide, with ischemic stroke (IS) being the most common form. The blood-brain barrier (BBB) plays a critical role in protecting the brain, and its dysfunction after stroke exacerbates neuronal damage. Therefore, restoring BBB integrity is a promising therapeutic strategy. Tirzepatide (TZP), a dual GLP-1 and GIP receptor agonist, has demonstrated neuroprotective effects, but its role in BBB restoration post-stroke remains unclear.
OBJECTIVE: This study aims to evaluate the potential of TZP in preventing BBB dysfunction and restoring its integrity in ischemic stroke models.
METHODS: Using a middle cerebral artery occlusion (MCAO) mouse model of ischemic stroke, we assessed the effects of TZP on neurological deficits, BBB permeability, and the expression of tight junction (TJ) proteins, particularly Claudin-1. In vitro, human brain microvascular endothelial cells (HBMVECs) were subjected to oxygen-glucose deprivation/reperfusion (OGD/R) to simulate ischemic conditions. The involvement of C/EBP-α, a key transcription factor regulating TJ proteins, was also investigated.
RESULTS: TZP treatment significantly improved neurological scores and reduced BBB permeability in MCAO mice. It also restored Claudin-1 expression, which was downregulated in stroke conditions. In vitro, TZP reduced endothelial permeability and enhanced Claudin-1 expression in OGD/R-treated HBMVECs. Silencing C/EBP-α abolished the protective effects of TZP on both BBB integrity and Claudin-1 expression, indicating that C/EBP-α signaling is crucial for TZP's action.
CONCLUSION: TZP ameliorates BBB dysfunction and protects against ischemic stroke by activating C/EBP-α signaling and restoring Claudin-1-mediated tight junction integrity. These findings suggest that TZP holds promise as a therapeutic agent for stroke, offering a novel strategy for maintaining BBB function and reducing neuronal damage. Further studies are needed to explore the detailed mechanisms underlying TZP's neuroprotective effects and its clinical potential in stroke therapy.

Keywords:  Blood-brain barrier (BBB); C/EBP-α; Claudin-1; Stroke; Tirzepatide

DOI:  https://doi.org/10.1186/s10020-025-01312-4
ACS Chem Neurosci. 2025 Jul 23.

Knockdown SIRT6 Alleviates Blood-Brain Barrier Disruption after Subarachnoid Hemorrhage through Inhibiting Ferroptosis by Promoting SMARCA2 Acetylation.

Li Lv, Long Zhang, Yan Wang, Haipeng Xi.

  Ferroptosis has been identified as a mechanism underlying subarachnoid hemorrhage (SAH), attributed to blood-brain barrier (BBB) disruption. This study aimed to explore whether SIRT6 mediates ferroptosis affecting BBB disruption after SAH and the potential mechanism. Knockdown SIRT6 improved the neural function score in SAH rats, reduced the escape latency, increased the number of entering the target quadrant and the time of staying in the platform quadrant, and inhibited apoptosis while reducing brain water content and BBB disruption, leading to an improvement in neurological deficits after SAH. Concomitantly, knockdown SIRT6 increased OxyHB-induced brain microvascular endothelial cells (BMECs) viability, inhibited apoptosis, preserved tight junction proteins (Claudin-3, Occludin, and ZO-1) levels, and decreased adhesion molecules (ICAM-1 and VCAM-1) levels, thereby mitigating endothelial barrier dysfunction. Additionally, knockdown SIRT6 inhibited the OxyHb-induced ferroptosis in BMECs. Furthermore, ferroptosis inhibitor ferrostatin 1 reversed the proferroptosis effects of SIRT6 overexpression. Mechanically, SIRT6 knockdown reduced ferroptosis and endothelial barrier dysfunction after SAH by promoting SMARCA2 acetylation. Our results suggested that knockdown SIRT6 inhibited ferroptosis by promoting SMARCA2 acetylation, thereby alleviating BBB disruption after SAH. These findings establish a novel SIRT6-SMARCA2 axis governing ferroptosis in SAH, providing mechanistic insights into BBB protection. Our findings may represent promising strategies for the clinical management of SAH.

Keywords:  SIRT6; SMARCA2; acetylation; blood–brain barrier; ferroptosis; subarachnoid hemorrhage

DOI:  https://doi.org/10.1021/acschemneuro.5c00300
Int J Neuropsychopharmacol. 2025 Jul 23. pii: pyaf054. [Epub ahead of print]28(7):

Correction to: Inflammation and Blood-Brain Barrier in Depression: Interaction of CLDN5 and IL6 Gene Variants in Stress-Induced Depression.

DOI: https://doi.org/10.1093/ijnp/pyaf054
Fluids Barriers CNS. 2025 Jul 22. 22(1): 77

Neuroprotective role of pyrroloquinoline quinone in folate deficiency-induced blood-brain barrier disruption.

Sara Aboulhassane, Vishal Sangha, Md Tozammel Hoque, Reina Bendayan.

  Healthy neurodevelopment requires adequate folates (vitamin B9), which are critical for key biosynthetic and homeostatic processes in the central nervous system (CNS). In the brain, folate transport is mediated by three major pathways: folate receptor alpha (FRα), proton-coupled folate transporter (PCFT), and reduced folate carrier (RFC). Folate uptake primarily occurs at the blood-cerebrospinal fluid barrier (BCSFB) by concerted actions of FRα and PCFT. Alterations in this transport pathway can result in cerebral folate deficiency (CFD), a rare but devastating pediatric condition associated with neuroinflammation and oxidative stress. Recent findings highlight the blood-brain barrier (BBB) as an alternative route for folate delivery, particularly through RFC upregulation. We hypothesized that pyrroloquinoline quinone (PQQ), an activator of nuclear respiratory factor 1 (NRF-1) and PGC-1α, key regulators of mitochondrial biogenesis, could enhance RFC expression at the BBB and mitigate CFD-induced damage. Using in vitro and in vivo models of folate deficiency, we investigated its impact on BBB integrity, inflammation, oxidative stress, mitochondrial dysfunction, and assessed PQQ's ability to reverse these effects. Human brain microvessel endothelial cells (hCMEC/D3) cultured in control folate-sufficient (FS) or folate-deficient (FD) medium were treated with PQQ (1 or 5 µM) or vehicle control for 24 h. Wildtype (C57BL6/N) mice received FD (0 mg/kg folate), or FS (2 mg/kg folate) diet and underwent a 10-day (20 mg/kg/day, i.p) PQQ treatment. Following treatment, hCMEC/D3 cells and isolated mouse brain capillaries were analyzed using qPCR, ELISA, and immunoblotting to assess gene and protein expression of tight junction proteins, inflammatory and oxidative stress markers, mitochondrial transcription factors, and folate transporters. BBB permeability was evaluated in vivo using the sodium fluorescein (NaFl) assay. FD significantly increased the gene and/or protein expression of inflammatory cytokines/chemokines, endothelial adhesion molecules and oxidative stress markers, while tight junction proteins were significantly downregulated both in vitro and in vivo. The NaFl assay confirmed increased BBB permeability in FD mice. PQQ treatment effectively reversed these changes by upregulating RFC and PCFT expression, restoring BBB permeability, mitigating inflammatory and oxidative stress responses and improving mitochondrial biogenesis via PGC-1α/NRF-1 signaling. These results highlight the impact of brain FD on BBB integrity, potentially contributing to neurological deficits seen in CFD disorders with PQQ providing a promising therapeutic strategy.

Keywords:  BBB permeability; Blood-brain barrier; Cerebral folate deficiency; Folate transporters; Neuroinflammation; Oxidative stress; Pyrroloquinoline quinone; Tight-Junction proteins

DOI:  https://doi.org/10.1186/s12987-025-00689-y
Int J Mol Med. 2025 Oct;pii: 153. [Epub ahead of print]56(4):

Blood‑brain barrier dysfunction in schizophrenia: Mechanisms and implications (Review).

Shuang Lv, Chunxia Luo.

  The present review explored the emerging role of blood‑brain barrier (BBB) dysfunction in schizophrenia. Findings from biochemical markers, neuroimaging, genetic studies and experimental models are integrated to examine the impact of BBB dysfunction on the development and progression of schizophrenia. Additionally, the mechanisms by which BBB dysfunction exacerbates the schizophrenia were examined, including disruptions in cerebral blood flow, the facilitation of neuroinflammation and alterations in neurotransmitter systems. Finally, the potential for integrating BBB‑targeted interventions into broader therapeutic strategies for schizophrenia were discussed, with the goal of improving drug efficacy and minimizing side effects in clinical practice.

Keywords:  blood‑brain barrier integrity; neuroin‑flammation; neurophysiological mechanisms; psychiatric neuroimaging; schizophrenia; therapeutic innovations

DOI:  https://doi.org/10.3892/ijmm.2025.5594
CNS Neurosci Ther. 2025 Jul;31(7): e70523

Targeting PD-L1 for Ischemic Stroke Recovery: Age-Dependent Modulation of Immune and BBB Pathways.

Hang Hang, Can Xu, Likun Wang, Cuiying Liu, Rongping Zhang, Guofeng Wu, Heng Zhao.

   OBJECTIVE: Aging has a profound impact on the pathophysiology of ischemic stroke and the effectiveness of therapeutic interventions. This study aims to evaluate the therapeutic efficacy of programmed death-ligand 1 (PD-L1) monoclonal antibody (mAb) in modulating immune responses and neurovascular repair following ischemic stroke, with a focus on age-dependent differences.
METHODS: Young and aged mice were subjected to middle cerebral artery occlusion (MCAO) followed by PD-L1 mAb treatment. RNA sequencing, immunofluorescence, and molecular analyses were employed to assess immune modulation, blood-brain barrier (BBB) integrity, and functional recovery.
RESULTS: RNA sequencing revealed significant differential gene expression in ischemic brain tissues, with CD274 (PD-L1) prominently upregulated among immune checkpoint-related genes in young mice. Immunofluorescence confirmed PD-L1 expression in microglia/macrophages, with significantly higher upregulation in young mice. PD-L1 mAb treatment showed superior efficacy in young mice, significantly reducing infarct volume, enhancing neurological recovery, and preserving BBB integrity through greater upregulation of tight junction proteins such as ZO-1, Claudin-5, and Occludin compared to aged mice. It also more effectively reduced neuroinflammation, apoptosis, and pro-inflammatory cytokines (TNF-α, IL-1β), eliciting stronger spleen responses in young mice. These findings underscore the age-dependent advantages of PD-L1-targeted therapies for ischemic stroke recovery.
CONCLUSIONS: PD-L1 plays a critical role in ischemic stroke recovery, with PD-L1 mAb treatment demonstrating age-dependent therapeutic efficacy by enhancing BBB integrity, reducing neuroinflammation and apoptosis, and modulating peripheral immune responses.

Keywords:  PD‐L1 monoclonal antibody; age‐dependent immune response; blood–brain barrier integrity; ischemic stroke; neuroinflammation

DOI:  https://doi.org/10.1111/cns.70523
Aging Dis. 2025 Jul 11.

VCAM-1 in Cognitive Impairment: Mechanisms, Biomarker Potential, and Therapeutic Targeting.

Xilong Guan, Xiaoling Zhu, Linan Zha, Wen Yu, Xiuqin Rao, Yanhong Xiong, Yu Jin, Mojiao Zhang, Tao Luo, Xiangfei Huang, Xifeng Wang, Fuzhou Hua, Jing Xu.

Cognitive impairment (CI), a progressive decline in memory, reasoning, and executive functions, arises from neurodegenerative and cerebrovascular pathologies. Globally, 10% of adults aged ≥65 exhibit mild CI (MCI), with 15% progressing annually to dementia. Alzheimer's disease (AD) constitutes 60-70% of dementia cases, showing a higher incidence in women, while vascular dementia (VaD) accounts for 20%. By 2050, dementia cases may reach 152 million, straining healthcare systems. Vascular cell adhesion molecule 1 (VCAM-1), a key immune-inflammatory mediator, is implicated in CI pathogenesis. Expressed abundantly on endothelial cells, VCAM-1 disrupts blood-brain barrier (BBB) integrity and exacerbates neuroinflammation. This review delineates VCAM-1's role in BBB dysregulation, neuroinflammatory interactions, and its potential as a biomarker/therapeutic target. Future research should clarify VCAM-1 signaling mechanisms and develop targeted interventions for early CI management.

DOI: https://doi.org/10.14336/AD.2025.0675
Curr Issues Mol Biol. 2025 Mar 27. pii: 232. [Epub ahead of print]47(4):

Cerebral Small Vessel Disease: Therapeutic Approaches Targeting Neuroinflammation, Oxidative Stress, and Endothelial Dysfunction.

Habibe Yılmaz, Ulvi Bayraktutan.

  Cerebral small vessel disease (cSVD) is a common cause of stroke and dementia. Ageing, hypertension, hyperglycaemia, and smoking make up the biggest risk factors for cSVD. They individually or collectively increase the levels of reactive oxygen species, pro-inflammatory cytokines and matrix metalloproteinases, decrease the bioavailability of nitric oxide, and, in the process, compromise the structural integrity and function of the vascular endothelium, blood-brain barrier, and brain parenchyma. These then appear as white matter hyperintensities, enlarged perivascular spaces, cerebral microbleeds, and atrophy in cerebral imaging. As there is currently no curative therapy for cSVD, prevention or delay of cSVD remains of particular importance to preserve quality of life for as long as possible. Bearing that in mind, this review explores whether drugs used for other neurovascular conditions may prevent neuroinflammation and oxidative damage and effectively maintain endothelial function and blood-brain barrier integrity. It also examines whether potential benefits may be extended to cSVD. The list of drugs includes anti-anginal drugs, acetylcholine esterase inhibitors, β-hydroxy β-methylglutaryl-CoA reductase inhibitors, lithium drugs, phosphodiesterase inhibitors, oral antihyperglycaemic drugs, and tetracycline antibiotics. This review discusses the mechanisms of action of these agents and critically evaluates preclinical, translational, and clinical research pertaining to cSVD.

Keywords:  HMG-CoA reductase inhibitors; acetylcholine esterase inhibitors; anti-anginal drugs; brain; lithium drugs; oral antihyperglycaemic drugs; phosphodiesterase inhibitors; small vessel disease; tetracycline antibiotics

DOI:  https://doi.org/10.3390/cimb47040232
Front Aging Neurosci. 2025 ;17 1599509

Regulation of BBB function and pathological evolution of PD by microenvironment "spatiotemporal gradient": unique advantages of microfluidic chips.

Sixun Yu, Lingli Jiang, Min Song, Tao Yang, Ma Yuan, Xin Chen, Haifeng Shu.

  Parkinson's disease (PD), a prevalent neurodegenerative disorder, exhibits an exceedingly intricate pathological process characterized by multifaceted neuronal loss, inflammatory responses, protein misfolding, and blood-brain barrier (BBB) dysfunction. In the pathogenesis of PD, the BBB serves not only as a protective interface for the central nervous system but also actively contributes to the regulation of neural microenvironment homeostasis. Consequently, its impaired functionality can markedly exacerbate disease progression. Within the in vivo microenvironment, factors such as chemical gradients, fluid shear stress, and physical-mechanical signals play pivotal roles in modulating cellular behavior and organ function. The spatiotemporal dynamics of these gradients critically influence BBB integrity and neuroinflammatory responses. However, traditional in vitro models struggle to faithfully replicate such multidimensional dynamic microenvironmental changes. Recently, microfluidic chip technology has emerged as a transformative platform capable of simulating in vivo conditions through precise control of microenvironmental spatiotemporal gradients. This review examines the advancements of microfluidic chips in reproducing in vivo dynamic microenvironment gradients, regulating BBB function, and elucidating the pathological evolution of PD. It delves into the fundamental principles of microfluidic technology, gradient generation and control methodologies, and provides examples of BBB organoid models and PD pathological environment simulations constructed on this platform. Additionally, it systematically evaluates the technical bottlenecks, standardization challenges, and data integration issues associated with current model development, while exploring the potential for future technological convergence and interdisciplinary collaboration in advancing PD precision simulation and personalized treatment.

Keywords:  Parkinson’s disease; blood-brain barrier; microfluidic chip; organoid models; pathological simulation; spatiotemporal gradients

DOI:  https://doi.org/10.3389/fnagi.2025.1599509
Alzheimers Res Ther. 2025 Jul 19. 17(1): 166

Periodontitis-induced neuroinflammation triggers IFITM3-Aβ axis to cause alzheimer's disease-like pathology and cognitive decline.

Lingwenyao Kong, Juanjuan Li, Lu Gao, Yonggang Zhao, Weixian Chen, Xumeng Wang, Songlin Wang, Fu Wang.

   BACKGROUND: Periodontitis is a risk factor linked to Alzheimer's disease (AD), and characterized by amyloid-beta (Aβ) pathology. Mounting evidence suggests a contributory role of periodontitis in the onset and progression of AD. Type I interferons are upregulated in Porphyromonas gingivalis (Pg)-induced periodontitis in murine models. Colonization of Pg has been identified in the brains of patients with AD. Recently, interferon-induced transmembrane protein 3 (IFITM3), an inflammation-induced innate immunity protein, was identified as a novel γ-secretase modulatory protein for Aβ production in AD. However, whether periodontitis triggers an increase in type I interferons in the brain, subsequently inducing AD-like pathology by eliciting the innate immune response of glial cells and activating the IFITM3-Aβ axis, remains unclear. Additionally, the question of whether colonization of Pg in brain induces innate immune in astrocytes and microglia remains unanswered.
METHODS: We assessed the impact of Pg-induced periodontitis on cognitive impairment in C57BL/6J and APP/PS1 mice using behavioral tests. The effects of Periodontitis/Pg on microglia and astrocytes were measured using quantitative reverse transcriptase PCR (qRT-PCR), western blotting, and histological staining.
RESULTS: Pg-induced periodontitis led to cognitive impairment in C57BL/6J mice and exacerbated a cognitive decline in APP/PS1 mice. Furthermore, Pg-induced periodontitis elevated the levels of interferon (IFN)-β, IFITM3, and Aβ deposition in the brains of both C57BL/6J and APP/PS1 mice. We also identified Pg DNA, glial activation, and the expression of inflammatory mediators in the brain of a Pg-induced periodontitis model. Additionally, our findings confirmed astrocytes as the primary responders to Pg-induced innate immunity and inflammation both in vitro and in vivo. Periodontitis also induces an increase in IFITM3 expression in periodontal tissue, salivary glands.
CONCLUSIONS: We define a previously unidentified link between periodontitis and cognitive decline, and provide new evidence linking oral pathogenic bacteria-induced innate immunity and neuroinflammation to AD pathogenesis and cognitive decline, partly through increased blood-brain barrier (BBB) permeability, triggered neuroinflammation, and elevated IFITM3 in glial cells for Aβ deposition. Moreover, periodontitis exacerbates innate immunity and cognitive impairment in AD mice, underscoring the importance of preventive and therapeutic strategies for periodontal disease in AD patients.

Keywords:  Alzheimer’s disease; Cognitive decline; IFITM3; Innate immunity; Neuroinflammation; Periodontitis

DOI:  https://doi.org/10.1186/s13195-025-01818-3
Life Sci. 2025 Jul 19. pii: S0024-3205(25)00510-7. [Epub ahead of print]379 123875

Ambroxol alleviates hippocampus injury after BRIR through suppression of the IRE1α/TRAF2 signaling pathway.

Noha F Elshazly, Marwa E Elsherbiny, Azza S Awad, Ahmed F Mohamed, Nesrine S El Sayed, Yasmin S Mohamed.

  Acute kidney injury(AKI) is commonly linked to cognitive and neurological impairments. The study aims to investigate the relationship between bilateral renal ischemia reperfusion (BRIR) and hippocampal damage and evaluates the effects of ambroxol against BRIR-induced hippocampal injury and neuroinflammation. Thirty adult male rats were randomly assigned to three groups: control (laparotomy without renal occlusion), BRIR model (bilateral renal ischemia was induced by clamping both renal pedicles for 60 min, followed by 3 days of reperfusion), and ambroxol treatment (70 mg/kg, I.P., once daily during reperfusion). Hippocampal injury was assessed through biochemical (ELISA, Western blot, and PCR), histopathological, and behavioral analysis. Compared to the control group, BRIR significantly increased serum Cr, BUN, and renal injury markers (MDA, MCP-1, KIM-1) (p < 0.0001), along with notable renal tubular degeneration and necrosis. In the hippocampus, BRIR elevated inflammatory markers (NF-κB, TNF-α, MCP-1, IL-1β, G-CSF), reduced antioxidants (SOD, GSH), and altered apoptotic markers (increased Bax, decreased Bcl-2) (all p < 0.0001). Behavioral tests revealed impairments in learning, memory, and locomotor activity. Histology showed degeneration of pyramidal neurons in the CA1 region. Ambroxol treatment significantly ameliorated these effects, preserving CA1 neuronal structure, restoring blood-brain barrier (BBB) integrity (via Occludin and Claudin-5), enhancing BDNF and IBA-1 expression, and modulating MAPK/NF-κB and IRE1α/TRAF2 signaling pathways. Finally, BRIR induces both renal and hippocampal injury. Ambroxol mitigates this damage by reducing oxidative stress and inflammation, repairing BBB components, and regulating endoplasmic reticulum stress pathways (ERS).

Keywords:  Ambroxol; BRIR; IRE1α/TRAF2; MAPK/NF-κB; hippocampus injury

DOI:  https://doi.org/10.1016/j.lfs.2025.123875
Aging Dis. 2025 Jul 04.

Adaptive Immune Dyshomeostasis as a Mediator of Vascular Cognitive Decline: Unraveling Neurovascular Crosstalk.

Yating Li, Jinlin Shen, Li Zhang, Yang Luo.

Vascular cognitive impairment and dementia (VCID), the second most prevalent form of dementia worldwide, arises from cerebrovascular injury and is increasingly recognized as an immune-mediated neurovascular disorder. Mounting evidence implicates dysregulated immune responses-both central and peripheral-as critical drivers of VCID pathogenesis. This review highlights the pivotal roles of microglial activation, astrocytic reactivity, and infiltration of pro-inflammatory T and B cells in disrupting the neurovascular unit (NVU). These processes, mediated by cytokines such as IL-6, IL-17A, and IFN-γ, contribute to the blood-brain barrier (BBB) breakdown, white matter degeneration, and neuronal dysfunction. We further examine how systemic inflammation and comorbidities including hypertension, diabetes, and gut dysbiosis exacerbate immune-neurovascular crosstalk. In light of these insights, we discuss emerging therapeutic strategies aimed at modulating neuroimmune interactions and restoring neurovascular integrity. This integrated perspective provides a foundation for developing precise, immune-targeted interventions in the prevention and treatment of VCID.

DOI: https://doi.org/10.14336/AD.2025.0380
Fluids Barriers CNS. 2025 Jul 22. 22(1): 78

Neisseria meningitidis regulates P-glycoprotein transporter activity in brain endothelial cells via sphingosine 1-phosphate receptor 1.

Fatemeh Nosratabadi, Leo M Endres, Fabian Schumacher, Heike Claus, Burkhard Kleuser, Brandon J Kim, Alexandra Schubert-Unkmeir.

   BACKGROUND: The brain endothelial cells (BECs) are essential for protecting the central nervous system (CNS) from xenobiotics and pathogens, including Neisseria meningitidis, while maintaining CNS homeostasis through tight junction (TJ) proteins and specialized transporters. Among these, multidrug resistance (MDR) transporters such as P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are pivotal in restricting the entry of neurotoxic substances. Although the impact of N. meningitidis infection on BBB TJ is well-documented, its effect on MDR transporters remains largely unexplored.
METHODS: We employed induced pluripotent stem cell-derived brain-like endothelial cells (iBECs) as an in vitro BECs model due to their human-like morphology and expression of junctional proteins and MDR transporters. iBECs were exposed to various N. meningitidis strains, isogenic mutants, heat-inactivated bacteria, conditioned media, or purified capsule polysaccharide (CPS). P-gp and BCRP activities were assessed using intracellular accumulation assays with Rhodamine 123 and Chlorin e6, respectively, in the presence of P-gp inhibitors cyclosporin A and PSC833 and BCRP inhibitor Ko143. Gene expression and protein levels were determined by qPCR and western blotting, and sphingolipid quantification was performed via liquid chromatography tandem-mass spectrometry (LC-MS/MS).
RESULTS: Infection of iBECs with N. meningitidis inhibited P-gp activity, whereas BCRP activity remained unaffected. P-gp inhibition occurred without changes in gene expression or protein abundance. Cells infected with N. meningitidis showed reduced efficacy of P-gp inhibitors, an effect not seen with the BCRP inhibitor Ko143. N. meningitidis CPS was identified as a key factor in modulating P-gp activity. Notably, the inhibitory effect of N. meningitidis on P-gp activity was blocked by a specific sphingosine 1-phosphate receptor 1 (S1PR1) antagonist as well as by sphingosine kinase inhibitors, revealing a mechanistic link between S1PR1 signaling and P-gp modulation during infection. Furthermore, S1PR1 was upregulated in infected iBECs. Although LC-MS/MS measurement showed no increase in S1P levels in infected cells compared to uninfected controls, these findings suggest a crucial role for S1PR1 signaling in mediating the observed effects.
CONCLUSIONS: These findings demonstrate that N. meningitidis infection impairs P-gp function through S1PR1-dependent pathways, suggesting that targeting this signaling cascade may offer a novel therapeutic strategy to preserve BBB integrity during bacterial infections.

Keywords:   Neisseria meningitidis ; Brain endothelial cells; Breast cancer resistance protein; Efflux transporter; P-glycoprotein; Sphingosine 1-phosphate receptor 1

DOI:  https://doi.org/10.1186/s12987-025-00687-0
J Hazard Mater. 2025 Jul 17. pii: S0304-3894(25)02203-4. [Epub ahead of print]496 139287

Acetamiprid mediates cognitive dysfunction through the gut-brain axis: Synaptic damage and immune-mediated blood-brain barrier dysfunction.

Bing Wu, Xue-Yan Tian, Wen-Si Ni, Hao-Xuan Gao, Yu-Wen Wang, Ling-He Zhang, Yu-Bin Li, Yan-Ling Lv, Ya-Nan Song, Yu-Cheng Yan, Xiao-Zhe Geng, Yi-Man Li, Hui-Fang Yang, Ji Zhao.

  Acetamiprid is a widely used neonicotinoid pesticide that can increase the risk of inducing nervous system diseases. Considering the increased exposure to acetamiprid and its impact on cognitive function, further clarification is needed. Therefore, we used a mouse model of drinking water to evaluate the effects of acetamiprid on cognitive dysfunction and the possible underlying mechanisms. Our study revealed that acetamiprid can cause damage to hippocampal and synaptic structures, which in turn leads to a decline in spatial learning and memory abilities in mice. Importantly, acetamiprid exposure altered the composition and diversity of the intestinal flora and induced a systemic immune response in the gutbrain axis. Specifically, acetamiprid exposure damages the gutbrain axis, including structural disorders of the intestinal flora, related neurotransmitters and systemic immune factors. In addition, fecal microbiota transplantation restored the homeostasis of the gut microbiota and reduced the degree of damage to synaptic and spatial learning and memory. Moreover, intestinal barrier function is restored, effectively preventing the entry of harmful substances into intestinal tissue and thereby reducing damage to the bloodbrain barrier and the immune response in the gutbrain. This study provides new insights into potential new mechanisms of acetamidine exposure related to cognitive function.

Keywords:  Acetamiprid; Cognitive function; Fecal microbiota transplantation; Gut microbiota; Gut–brain axis

DOI:  https://doi.org/10.1016/j.jhazmat.2025.139287