The development of anti-amyloid-beta (Aβ) immunotherapies as the first disease modifying therapy for Alzheimer's Disease (AD) is a breakthrough of basic research and translational science.

Genetically modified mouse models developed to study AD neuropathology and physiology were used for the discovery of Aβ immunotherapies and helped ultimately propel therapies to FDA approval. Nonetheless, the combination of modest efficacy and significant rates of an adverse side effect (amyloid related imaging abnormalities, ARIA), has prompted reverse translational research in these same mouse models to better understand the mechanism of the therapies.

This review considers the use of these mouse models in understanding the mechanisms of Aβ clearance, cerebral amyloid angiopathy (CAA), blood brain barrier breakdown, neuroinflammation, and neuronal dysfunction in response to Aβ immunotherapy.

Integrin Mac-1 plays a critical role in the development of multiple sclerosis (MS); however, the underlying mechanism is not fully understood. Here, we developed a myeloid-specific Mac-1-deficient mouse. Using an experimental autoimmune encephalomyelitis (EAE) mouse model of MS, we report that Mac-1 on myeloid cells is key to disease development. Our data reveal that myeloid-specific Mac-1 significantly increases EAE severity and hinders disease regression. Loss of Mac-1 increases Gr-1+ cells in peripheral tissues and the CNS and preferably accelerates the transition of Ly6Chi monocytes from a pro-inflammatory to an immunosuppressive phenotype in a disease stage-dependent manner. Mechanistically, our results demonstrate that Mac-1 suppresses interferon-γ production and prevents monocytes from acquiring immunosuppressive functions by reducing the expression of iNOS, IDO, and CD84. Administration of a NOS-specific inhibitor in Mac-1-deficient EAE mice abolishes disease regression. These insights could help develop Mac-1-targeting strategies for better treatment of MS.

Alzheimer's disease (AD) is characterized by a multifactorial pathophysiology. Beyond its classical hallmarks, growing evidence highlights vascular contributions, including hemostatic dysregulation and a prothrombotic state in AD. This review focuses on recent findings concerning two key blood clot components-fibrin(ogen) and platelets-and their roles in AD pathology, including fibrinogen's abnormal accumulation in the AD brain, its interaction with amyloid-β, together with the associated impacts on clot stability, vascular occlusion, and neuroinflammation; and the potential switch of platelets along the AD continuum from protective to deleterious. This review provides an update on the interplay between vascular dysfunction and AD, underscoring the need for comprehensive integrative research to address AD's complexity and advocating for personalized approaches to tackle this multifaceted disorder.

Alzheimer's disease (AD) is a progressive debilitating neurodegenerative disorder that is usually diagnosed after irreversible brain damage has occurred. The detection and morphological characterization of amyloid-β fibrils, which are predominantly implicated in the pathogenic process of the disease, in the cerebrospinal fluid (CSF), emphasized the significance of examining such biofluid. In this work the crude CSF samples collected from patients with Alzheimer's disease and with other neurological conditions were analyzed by atomic force microscopy (AFM). This approach allowed for the identification of peculiar fibrillar structures, exhibiting the regular repetition of dimeric globular units along the longitudinal axis, which share morphological similarities with fibrin protofibrils. Several studies have consistently shown that the disruption of the blood-brain barrier (BBB) and the infiltration of fibrinogen and components of the coagulation cascade are linked with a wide range of neurological diseases, including AD. Therefore, the role of the fibrillar structures we identified must be clarified, in order to ascertain if they contribute to the etiology of the disease, and their use as possible biomarkers of brain damage and disease progression should be assessed.

This study aimed to explore the factors associated with hemorrhagic transformation (HT) in acute ischemic stroke patients after intravenous thrombolysis (IVT), with a specific focus on the relationship with the post-thrombolysis fibrinogen-to-albumin ratio (FAR).

The clinical records of 569 acute ischemic stroke (AIS) patients admitted to our department from 2020 to 2023 were retrospectively analyzed. All eligible patients were stratified into HT and non-HT (NHT) groups. Propensity score matching (PSM) was performed between the two groups. Receiver operating characteristic (ROC) curves were used to assess the predictive performance of the FAR, determining the optimal predictive value.

Ultimately, 142 patients were included, with 71 in the HT group and 71 in the NHT group. After propensity score matching, a significant association was observed between the FAR and HT (OR = 1.40, 95% CI, 1.187-1.645; p <0.001). The ROC curve analysis indicated that the FAR predicted HT after intravenous thrombolysis, with an area under the curve (AUC) value of 0.751 (95% CI, 0.669-0.831; p <0.001) and an optimal cutoff value of 0.0918. The corresponding sensitivity and specificity were 78.9 and 60.9%, respectively.

In ischemic stroke patients undergoing IVT, the FAR may serve as a promising biochemical marker for predicting HT following treatment.

To investigate the relationships between fibrinogen levels at baseline and 24 hours after intravenous thrombolysis (IVT) and early neurological deterioration (END); and to investigate whether stroke severity influences the correlation between fibrinogen and END.

The fibrinogen levels were measured at admission and 24 hours after intravenous thrombolysis (IVT) in 364 consecutive AIS patients. Regression analysis, stratified analyses and interaction tests were utilized to assess the relationship between fibrinogen and END and whether stroke severity (NIHSS<6 vs NIHSS≥6) influences the correlation.

Fibrinogen at admission was not independently associated with END after adjusting for potential confounders (OR, 1.00; 95 % CI, 0.66-1.53; P = 0.9874). However, increased fibrinogen levels after IVT were associated with increased risk of END (OR, 1.49; 95 % CI, 1.00-2.21; P = 0.0479). Fibrinogen after IVT was not independently associated with END (OR, 1.12; 95 % CI, 0.26-4.80; P = 0.8737) in patients with NIHSS<6, but was independently associated with END in patients with NIHSS≥6 (OR, 1.90; 95 % CI, 1.15-3.15; P = 0.0120). And the interaction test for NIHSS (NIHSS<6 vs NIHSS≥6) was statistically significant (P = 0.0366). Similar results were still found when we used the median NIHSS score of our study population (<10 vs ≥10) as a stratification criterion (Pinteraction = 0.0487).

Fibrinogen after IVT but not on admission was independently associated with END. And stroke severity influenced the correlation between fibrinogen after IVT and END.

Tau is essential for amyloid beta (Aβ)-induced synaptic and cognitive deficits in Alzheimer's disease (AD), making its downregulation a therapeutic target. Cerebral amyloid angiopathy (CAA), a major vascular contributor to cognitive decline, affects over 90% of patients with AD. This study explores the impact of tau downregulation on CAA pathogenesis.

We crossed the Familial Danish Dementia mouse model (Tg-FDD), which develops vascular amyloid, with tau-null (mTau-/-) mice to generate a CAA model lacking endogenous tau (Tg-FDD/mTau-/-). Behavioral, electrophysiological, histological, and transcriptomic analyses were performed.

Tau depletion ameliorated motor and synaptic impairments, reduced vascular amyloid deposition, and prevented vascular damage. Tau ablation also mitigated astrocytic reactivity and neuroinflammation associated with vascular amyloid accumulation.

These findings provide the first in vivo evidence of the beneficial effects of tau downregulation in a CAA mouse model, supporting tau reduction as a potential therapeutic strategy for patients with parenchymal and vascular amyloid deposition.

Tau ablation improves motor function and synaptic impair, reduces cerebrovascular amyloid deposits, and prevents vascular damage in a mouse model of cerebral amyloid angiopathy (CAA). Tau reduction decreases astrocytic reactivity, alters neuroinflammatory gene expression, and enhances oligodendrocyte function, suggesting a protective role against neuroinflammation in CAA. These findings highlight tau reduction as a potential therapeutic strategy to mitigate CAA-induced pathogenesis, with implications for treating patients with both parenchymal and vascular amyloid deposition.

The blood-brain barrier (BBB) is a vascular endothelial membrane which restricts entry of toxins, cells, and microorganisms into the brain. At the same time, the BBB supplies the brain with nutrients, key substrates for DNA and RNA synthesis, and regulatory molecules, and removes metabolic waste products from brain to blood. BBB breakdown and/or dysfunction have been shown in neurogenerative disorders including Alzheimer's disease (AD). Current data suggests that these BBB changes may initiate and/or contribute to neuronal, synaptic, and cognitive dysfunction, and possibly other aspects of neurodegenerative processes.

We first briefly review recent studies uncovering molecular composition of brain microvasculature and examine the BBB as a possible therapeutic target in neurodegenerative disorders with a focus on AD. Current strategies aimed at protecting and/or restoring altered BBB functions are considered. The relevance of BBB-directed approaches to improve neuronal and synaptic function, and to slow progression of neurodegenerative processes are also discussed. Lastly, we review recent advancements in drug delivery across the BBB.

BBB breakdown and/or dysfunction can significantly affect neuronal and synaptic function and neurodegenerative processes. More attention should focus on therapeutics to preserve or restore BBB functions when considering treatments of neurodegenerative diseases and AD.

Mutations in the TARDBP gene encoding TDP-43 protein are linked to loss of function in neurons and familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). We recently identified reduced nuclear TDP-43 in capillary endothelial cells (ECs) of donors with ALS-FTD. Because blood-brain barrier (BBB) permeability increases in ALS-FTD, we postulated that reduced nuclear TDP-43 in ECs might contribute. Here, we show that nuclear TDP-43 is reduced in ECs of mice with an ALS-FTD-associated mutation in TDP-43 (TardbpG348C) and that this leads to cell-autonomous loss of junctional complexes and BBB integrity. Targeted excision of TDP-43 in brain ECs recapitulates BBB defects and loss of junctional complexes and ultimately leads to fibrin deposition, gliosis, phospho-Tau accumulation, and impaired memory and social interaction. Transcriptional changes in TDP-43-deficient ECs resemble diseased brain ECs. These data show that nuclear loss of TDP-43 in brain ECs disrupts the BBB and causes hallmarks of FTD.

Central nervous system (CNS) malignancies include primary tumors, such as gliomas, and brain metastases (BrMs) originating from diverse extracranial cancers. The blood-brain barrier (BBB) is a key structural component of both primary and metastatic brain cancers. Here, we comprehensively analyzed the two major BBB cell types, endothelial and mural cells, across non-tumor brain tissue, isocitrate dehydrogenase (IDH) mutant (IDH mut) low-grade gliomas, IDH wild-type (IDH WT) high-grade glioblastomas (GBMs), and BrMs from various primary tumors. Bulk and single-cell RNA sequencing, integrated with spatial analyses, revealed that GBMs, but not low-grade gliomas, exhibit significant alterations in the tumor vasculature, including the emergence of diverse pathological vascular cell subtypes. However, these alterations are less pronounced in GBMs than in BrMs. Notably, the BrM vasculature shows higher permeability and more extensive interactions with distinct immune cell populations. This vascular atlas presents a resource toward understanding of tumor-specific vascular features in the brain, providing a foundation for developing vascular- and immune-targeting therapies.

Stroke remains a leading cause of death and disability worldwide. Recent evidence suggests that stroke pathophysiology extends beyond vascular dysfunction to include complex interactions within the neurovascular unit (NVU), particularly involving fibrinogen. This blood-derived protein accumulates in the brain following blood-brain barrier (BBB) disruption and plays crucial roles in neuroinflammation and tissue repair. Through its unique structural domains, fibrinogen interacts with multiple cellular components, including astrocytes, microglia, and neural stem cells, thereby modulating inflammatory responses and neural repair mechanisms. This review examines fibrinogen's structure and its diverse functions in stroke pathophysiology, focusing on its interactions with vascular cells, glial cells, and peripheral immune cells. We also discuss emerging therapeutic strategies targeting fibrinogen-mediated pathways and the challenge of translating experimental results into effective clinical treatments.

This study aimed to assess the acute developmental toxicity of perchlorate exposure and identify its manifestation of neurotoxicity in zebrafish (Danio rerio) model.

Zebrafish larvae were exposed to sodium perchlorate at early developmental stages and the phenotypes of various developmental abnormalities were observed and recorded. Neurodevelopmental toxicity has been studied in particular in terms of central nervous system apoptosis, peripheral motor abnormalities, and abnormal autonomic motor behavior. Samples were processed for pathological, transcriptomic, and PCR analyses.

Acute exposure of zebrafish larvae to perchlorate resulted in developmental toxicity in a concentration-dependent manner. Heart rate abnormality (33 %), slow blood flow (37 %), abnormal size of liver (23 %), delayed yolk absorption (70 %), and abnormal body pigmentation (100 %) were observed in the 3.83 mg/mL group. Heart edema (10 %), heart rate abnormality (60 %), slow blood flow (67 %), abnormal size of liver (77 %), delayed yolk absorption (100 %), abnormalities in intestinal morphology (30 %), abnormal body pigmentation (100 %), and shorter body length (47 %) were observed in the 4.03 mg/mL group. Developmental neurotoxicity was characterized by brain apoptosis, damage to the central nervous system (P < 0.01) and peripheral motor neurons (P < 0.0001), and reduced autonomous motor distance (P < 0.01). Transcriptomic analysis revealed that c3a.1, c5, fga, fgb, and fgg were upregulated in the complement and coagulation cascades, and the mRNA levels of c3a.1, dusp1, slc2a6, purba, and klf9 were found upregulated in PCR.

Acute perchlorate exposure on zebrafish larvae caused various developmental toxicity in a concentration-dependent manner, notably neurotoxicity. We believed the immunological and inflammatory responses were involved.

Fibrinogen, a pivotal plasma glycoprotein, plays an essential role in hemostasis by serving as the precursor to fibrin, which forms the structural framework of blood clots. Beyond coagulation, fibrinogen influences immune responses, inflammation, and tissue repair. Oxidative stress, characterized by an imbalance between reactive oxygen species (ROS) and antioxidants, induces fibrinogen oxidation, significantly altering its structure and function. This narrative review synthesizes findings from in vitro, ex vivo, and clinical studies, emphasizing the impact of fibrinogen oxidation on clot formation, architecture, and degradation. Oxidative modifications result in denser fibrin clots with thinner fibers, reduced permeability, and heightened resistance to fibrinolysis. These structural changes exacerbate prothrombotic conditions in cardiovascular diseases, diabetes, chronic inflammatory disorders and cancer. In contrast, "low-dose" oxidative stress may elicit protective adaptations in fibrinogen, preserving its function. The review also highlights discrepancies in experimental findings due to variability in oxidation protocols and patient conditions. Understanding the interplay between oxidation and fibrinogen function could unveil therapeutic strategies targeting oxidative stress. Antioxidant therapies or selective inhibitors of detrimental oxidation hold potential for mitigating thrombotic risks. However, further research is essential to pinpoint specific fibrinogen oxidation sites, clarify their roles in clot dynamics, and bridge the gap between basic research and clinical practice.

Traumatic brain injury (TBI) has emerged as a significant risk factor for Alzheimer's disease (AD), a complex and devastating neurodegenerative disorder characterized by progressive cognitive decline and memory loss. Both conditions share a common feature: blood‒brain barrier (BBB) dysfunction, which is believed to play a pivotal role in linking TBI to the development of AD. This review delves into the intricate relationship between TBI and AD, with a focus on BBB dysfunction and its critical role in disease mechanisms and therapeutic development. We first present recent evidence from epidemiological studies highlighting the increased incidence of AD among individuals with a history of TBI, as well as pathological and animal model studies that demonstrate how TBI can accelerate AD-like pathology. Next, we explore the mechanisms by which BBB dysfunction may mediate TBI-induced AD pathology. Finally, we investigate the shared molecular pathways associated with BBB dysfunction in both TBI and AD conditions and discuss the latest findings on how targeting these pathways and employing regenerative approaches, such as stem cell therapy and pharmacological interventions, can enhance BBB function and mitigate neurodegeneration.

Traumatic brain injury (TBI) causes neurovascular unit (NVU) dysfunction, including hyperpermeability of the blood-brain barrier to fibrinogen, glial activation, and neuronal damage, possibly leading to secondary brain damage. However, no known substance can inhibit its pathogenesis. In this study, we investigated noggin, a bone morphogenetic protein (BMP) 4 inhibitor, as a TBI pathogenesis-inhibiting substance. We induced acute TBI in C57BL/6J mice through a controlled cortical impact (CCI) and evaluated the effects of noggin on fibrinogen leakage into the brain and NVU-constituting cells, including pericytes, microglia, astrocytes, and neurons. CCI mice showed increased BMP4 levels and extravascular fibrinogen in the hippocampus. Noggin treatment significantly suppressed fibrinogen leakage four days post-CCI in a dose-dependent manner. Immunofluorescence staining revealed that noggin administration did not inhibit the activation of NVU cells such as pericytes, microglia, and astrocytes, which were characterized by increased PDGFRβ, Iba1, and GFAP expression levels, respectively. On postoperative day 4, CCI mice showed neuronal cell and myelinated neuronal fiber loss, which were not significantly affected by noggin administration. In conclusion, noggin administration suppresses fibrinogen leakage into the brain in the acute phase after TBI. However, the suppression of fibrinogen leakage through noggin administration did not alleviate neuronal damage and activation of NVU cells during the acute phase of TBI.

Traumatic brain injury (TBI) is a modifiable risk factor for Alzheimer's disease (AD). TBI and AD share several histopathological hallmarks: namely, beta-amyloid aggregation, tau hyperphosphorylation, and plasma protein infiltration. The relative contributions of these proteinopathies and their interplay in the pathogenesis of both conditions remains unclear although important differences are emerging. This review synthesises emerging evidence for the critical role of the neurovascular unit in mediating protein accumulation and neurotoxicity in both TBI and AD. We propose a shared pathogenic cascade centred on a neurovascular unit, in which increased blood-brain barrier permeability induces a series of noxious mechanisms leading to neuronal loss, synaptic dysfunction and ultimately cognitive dysfunction in both conditions. We explore the application of this hypothesis to outstanding research questions and potential treatments for TBI and AD, as well as other neurodegenerative and neuroinflammatory conditions. Limitations of this hypothesis, including the challenges of establishing a causal relationship between neurovascular damage and proteinopathies, are also discussed.

Multiple system atrophy (MSA) is a rapidly progressive neurodegenerative disease arising from accumulation of the α-synuclein and aberrant protein clearance in oligodendrocytes. The mechanisms of autophagy involved in the progression of MSA remain poorly understood. It is reported that MSA patients have blood-brain barrier impairments, which may increase the entry of fibrinogen into the brain. However, the roles of fibrinogen and its degradation products (FDPs) on autophagy and α-synuclein accumulation in MSA remain unknown. Here, we established the MSA animal model by intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine (MPTP) and 3-nitropropionic acid (3-NP), and cellular models by adding fibrillar α-syn into oligodendrocytes to investigate the mechanisms of FDPs on autophagy and accumulation of α-synuclein in oligodendrocytes. We found that FDPs inhibit the entry of α-synuclein into lysosomes for degradation, increasing aggregation of α-synuclein in oligodendrocytes (OLN-93). Our findings indicated that in OLN-93, FDPs inhibited the expressions of Beclin1 and Bif-1, which could promote the fusion of autophagosomes with lysosomes. Furthermore, the expression of α-synuclein was elevated in FDPs-injected mice, accompanied by an increase in the protein level of p62. We detected elevated expression of FDPs in the striatum of MSA mice. Finally, FDPs inhibited the expression of Beclin1 and Bif-1, which led to aberrant autophagic degradation and increased aggregation of α-synuclein and phospho-α-synuclein in MSA mice. Our study illustrates that FDPs can cause aggregation of α-synuclein in MSA by inhibiting Beclin1-mediated autophagy, which may exacerbate disease progression. These results provide a new therapeutic approach for MSA, that targets the inhibitory effect of FDPs on oligodendrocyte autophagy.

This study aims to investigate the risk factors associated with blood-brain barrier(BBB) disruption in patients with myelin oligodendrocyte glycoprotein antibody associated disease(MOGAD).

We collected clinical data from 95 patients diagnosed with MOGAD at the Department of Neurology, the First Affiliated Hospital of Zhengzhou University from October 2018 to May 2024. Patients were classified into normal or damaged BBB groups based on cerebrospinal fluid (CSF) albumin/serum albumin (QAlb). Binary logistic regression analysis was used to evaluate the risk factors for BBB disruption in MOGAD patients.

Our study revealed that in MOGAD patients with BBB damaged, there is a higher proportion of acute phase high EDSS scores, higher incidence of prodromal symptoms, and a higher rate of viral infections. Myelitis is the main clinical phenotype, with clinical manifestations primarily including limb weakness and bladder/bowel dysfunction. Laboratory tests showed higher levels of CSF protein, immunoglobulin (IgG), 24-hour intrathecal IgG synthesis rate, peripheral blood leukocytes, neutrophil percentage, NLR, anti-thyroglobulin antibodies(TGAbs), and fibrinogen levels, while free triiodothyronine (FT3) and lymphocyte percentage were lower. Multivariate regression analysis indicated that an increased neutrophil percentage is an independent risk factor for BBB damage in MOGAD patients (OR=1.068, 95% CI: 1.018-1.122, P=0.008).

Neutrophil percentage is a readily available and widely used indicator reflecting the immune system's state and the body's inflammation level. The change in neutrophil percentage is independently associated with BBB damage in MOGAD patients. This finding helps provide more reference information for personalized treatment decisions and further research into the pathogenesis of MOGAD.

Ischemic stroke results in inhibition of axonal regeneration but the roles of fibrinogen (Fg) in neuronal signaling and energy crises in experimental stroke are under-investigated. We explored the mechanism of Fg modulation of axonal regeneration and neuronal energy crisis after cerebral ischemia using a permanent middle cerebral artery occlusion (MCAO) rat model and primary cortical neurons under low glucose-low oxygen. Behavioral tests assessed neurological deficits; immunofluorescence, immunohistochemistry, and Western-blot analyzed Fg and protein levels. Fluo-3/AM fluorescence measured free Ca2+ and ATP levels were gauged via specific assays and F560nm/F510nm ratio calculations. Mito-Tracker Green labeled mitochondria and immunoprecipitation studied protein interactions. Our comprehensive study revealed that Fg inhibited axonal regeneration post-MCAO as indicated by reduced GAP43 expression along with elevated free Ca2+, both suggesting an energy crisis. Fg impeded mitochondrial function and mediated impairment through the EGFR/Ca2+ axis by trans-activating EGFR via integrin αvβ3 interaction. These results indicate that the binding of Fg with integrin αvβ3 leads to the trans-activation of the EGFR/Ca2+ signaling axis thereby disrupting mitochondrial energy transport and axonal regeneration and exacerbating the detrimental effects of ischemic neuronal injury.

Vascular damage plays a significant role in the onset and progression of Alzheimer's disease (AD). However, the precise molecular mechanisms underlying the induction of neuronal injury by vascular damage remain unclear. The present study aimed to examine the impact of fibrinogen (Fg) on tau pathology. The results showed that Fg deposits in the brains of tau P301S transgenic mice interact with tau, enhancing the cytotoxicity of pathological tau aggregates and promoting tau phosphorylation and aggregation. Notably, Fg-modified tau fibrils caused enhanced neuronal apoptosis and synaptic damage compared to unmodified fibrils. Furthermore, intrahippocampal injection of Fg-modified tau fibrils worsened the tau pathology, neuroinflammation, synaptic damage, neuronal apoptosis, and cognitive dysfunction in tau P301S mice compared to controls. The present study provides compelling evidence linking Fg and tau, thereby connecting cerebrovascular damage to tau pathology in AD. Consequently, inhibiting Fg-mediated tau pathology could potentially impede the progression of AD.

The opioid epidemic endangers not only public health but also social and economic welfare. Growing clinical evidence indicates that chronic use of prescription opioids may contribute to an elevated risk of ischemic stroke and negatively impact poststroke recovery. In addition, NLRP3 inflammasome activation has been related to several cerebrovascular diseases, including ischemic stroke. Interestingly, an increase in NLRP3 inflammasome activation has also been reported in chronic opioid exposure. Given the pivotal roles of the blood-brain barrier (BBB) and oxidative stress in ischemic stroke pathophysiology, this study focuses on the impact of chronic exposure to prescription opioids on the integrity of cerebrovascular microvasculature, endothelial mitochondrial homeostasis, and the outcomes of ischemic stroke in male wild-type and NLRP3-deficient mice. Our results demonstrate that chronic opioid exposure can compromise the integrity of the BBB and elevate the generation of reactive oxygen species (ROS), resulting in endothelial mitochondrial dysfunction and apoptosis activation. We also provide evidence that opioid exposure enhances inflammasome activation and inflammatory responses and increases the severity of an ischemic stroke. The antioxidant N-acetylcysteine ameliorated these opioid-induced alterations and accelerated the poststroke tissue restoration and functional recovery processes in opioid-exposed mice. Importantly, there was also a significant decrease in ischemic stroke damage in the NLRP3-deficient mice with chronic opioid exposure as compared with wild-type controls. These findings indicate that chronic exposure to prescription opioids impacts the outcome of ischemic stroke by damaging microvascular cerebral integrity through inflammasome activation and mitochondrial dysfunction.

Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis are characterized by progressive destruction of neurons and cognitive impairment, and thorough studies have provided evidence that these pathologies have a close relationship to the failure of the blood-brain barrier (BBB). Nattokinase (NK), a protease found in fermented soybeans, has been extensively studied because it displays powerful neuroprotective abilities, which is why current research was reviewed in the present article. It was concluded that there is enough evidence in preclinical studies using experimental animals that NK supplementation can alleviate the condition related to BBB dysfunction, reduce brain inflammation, and improve cognitive ability. Furthermore, the study of NK on the cardiovascular system leads to certain assumptions, which include the impact on vasculature function and the ability to manage blood flow, which is the key feature of BBB integrity. Such assumed mechanisms are fibrinolytic action, anti-inflammatory and antioxidant action, and endothelium function modulation. There are many positive research findings, and it seems that NK may serve as an effective opponent for BBB breakdown; however, a new research level should be taken to disclose the application and therapeutic use of NK in brain neurodegenerative disease.

Multiple sclerosis (MS) is a central nervous system (CNS) autoimmune disorder, with limited treatment options. This disease is characterized by differential pathophysiology between grey matter (GM) and white matter (WM). The predominant WM hallmark is the perivascular plaque, associated with blood brain barrier (BBB) loss of function, lymphocytic infiltration, microglial reactivity, demyelination and axonal injury and is adequately addressed with immunomodulatory drugs. By contrast, mechanisms underlying GM damage remain obscure, with consequences for neuroprotective strategies. Cortical GM pathology is already significant in early MS and characterized by reduced BBB disruption and lymphocytic infiltration relative to WM, but a highly inflammatory environment, microglial reactivity, demyelination and neuro/axonal loss. There is no satisfactory explanation for the occurrence of neurodegeneration without large-scale inflammatory cell influx in cortical GM. A candidate mechanism suggests that it results from soluble factors originating from meningeal inflammatory cell aggregates, which diffuse into the underlying cortical tissue and trigger microglial activation. However, the recent literature highlights the central role of platelets in inflammation, together with the relationship between coagulation factors, particularly fibrinogen, and tissue damage in MS. Using the experimental autoimmune encephalomyelitis (EAE) model, we identified platelets as drivers of neuroinflammation and platelet-neuron associations from the pre-symptomatic stage. We propose that fibrinogen leakage across the BBB is a signal for platelet infiltration and that platelets represent a major and early participant in neurodegeneration. This concept is compatible with the new appreciation of platelets as immune cells and of neuronal damage driven by inflammatory cells sequestered in the meninges.

Converging evidence supports the role of Matrix Metalloproteinases (MMPs) in psychiatric disorders. Originally identified as regulators of the extracellular matrix (ECM), MMPs' functions span multiple processes, including inflammation, synaptic plasticity, neuronal migration, and blood-brain barrier maintenance. Tissue Inhibitors of Metalloproteinases (TIMPs) are major regulators of MMPs. In the present study we examined the associations of plasma MMPs and TIMPs with mental disorders in young adults aged 24 years in the Avon Longitudinal Study of Parents and Children (ALSPAC).

The present study was a nested case control study within the Avon Longitudinal Study of Parents and Children and comprised 374 participants who met criteria for psychiatric disorders (35 met the criteria for psychotic disorder, 201 for mild/moderate depressive disorder, and 266 for generalised anxiety disorder) and 401 controls. All cases and controls had were selected from the group of 4019 participants who had attended at age 24 years, completed psychiatric assessments and provided plasma samples. Plasma concentrations of MMP2, MMP3, MMP9 and TIMP-4 were quantified using proximity extension assays available on Olink® Cardiovascular Panel III. Logistic regression analysis compared standardised MMPs and TIMPs levels in cases and controls. Models were adjusted for sex, body mass index, and cigarette smoking.

There was evidence for an association between MMP3 and depressive disorder (Odds ratio [OR] 1.35, 95 % confidence interval [CI] 1.06-1.73). There was evidence for an association between TIMP4 and depressive disorder (OR 1.51, 95 % CI 1.22-1.88) and generalised anxiety disorder (OR 1.43, 95 % CI 1.19-1.72). There was no evidence for an association between MMPs and psychotic disorders.

The study revealed that 24-year-olds with depressive and anxiety disorders exhibited elevated plasma concentrations of TIMP-4 compared to controls. There was evidence for an association between MMP3 and depressive disorder. These findings provide further support for the involvement of metalloproteinases as biomarkers in the pathophysiology of mental disorders during early adulthood.

Alzheimer's disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau. Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer's disease treatments in the last decades. However, existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic, necessitating the exploration of alternative therapeutic strategies. Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer's disease patients, with dysregulated astrocytic purinergic receptors, particularly the P2Y1 receptor, all of which constitute the pathophysiology of Alzheimer's disease. These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer's disease. This review delves into recent insights into the association between P2Y1 receptor and Alzheimer's disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer's disease by mitigating neuroinflammation, thus offering promising avenues for developing drugs for Alzheimer's disease and potentially contributing to the development of more effective treatments.

Hip fracture and acute ischemic stroke (AIS) are prevalent conditions among the older population. The prognosis for older patients who experience AIS subsequent to hip fracture is frequently unfavorable.

Patients were categorized into the AIS group and the non-AIS group. A predictive model was developed using six different machine learning algorithms. The SHapley Additive exPlanations (SHAP) method was then utilized to provide both local and global explanations. We performed adjusted mediation analyses. Furthermore, a nomogram was created to present the outcomes obtained from the LASSO regression examination. The main objective was to ascertain influential elements that can predict the occurrence of AIS. To alleviate the influence of confounding variables, propensity score matching was utilized to compare the occurrence of additional complications. Survival was compared by Kaplan-Meier methods.

The AUC of 6 ML models ranged from 0.73 to 0.87. The SVM model exhibited the greatest efficacy in forecasting AIS among older individuals with hip fractures. The leading 6 variables in the support vector machines (SVM) model were identified as systemic inflammatory response index (SIRI), carotid atherosclerosis, prior stroke, C-reactive protein (CRP), fibrinogen (FIB), and hypertension. The leading 2 variables in SHAP were identified as FIB at admission and SIRI index. There wasn't potential mediating effect of admission FIB between the SIRI index and AIS. There were statistically significant differences between the two groups in survival (P=0.003).

The model displayed good performance for prediction of AIS after hip fracture in patients 65 years and older, which might facilitate to establishment of a better clinical assessment plan.

Focused ultrasound (FUS) with microbubbles opens the blood-brain barrier (BBB) to allow targeted drug delivery into the brain. The mechanisms by which endothelial cells (ECs) respond to either low acoustic pressures known to open the BBB transiently, or high acoustic pressures that cause brain damage, remain incompletely characterized. Here, we use a mouse strain where tight junctions between ECs are labelled with eGFP and apply FUS at low (450 kPa) and high (750 kPa) acoustic pressures, after which mice are sacrificed at 1 or 72 hours. We find that the EC response leading to FUS-mediated BBB opening at low pressures is localized primarily in arterioles and capillaries, and characterized by a transient loss and reorganization of tight junctions. BBB opening still occurs at low safe pressures in mice lacking caveolae, suggesting that it is driven primarily by transient dismantlement and reorganization of tight junctions. In contrast, BBB opening at high pressures is associated with obliteration of EC tight junctions that remain unrepaired even after 72 hours, allowing continuous fibrinogen passage and persistent microglial activation. Single-cell RNA-sequencing of arteriole, capillary and venule ECs from FUS mice reveals that the transcriptomic responses of ECs exposed to high pressure are dominated by genes belonging to the stress response and cell junction disassembly at both 1 and 72 hours, while lower pressures induce primarily genes responsible for intracellular repair responses in ECs. Our findings suggest that at low pressures transient reorganization of tight junctions and repair responses mediate safe BBB opening for therapeutic delivery.

Focused ultrasound with microbubbles is used as a noninvasive method to safely open the BBB at low acoustic pressures for therapeutic delivery into the CNS, but the mechanisms mediating this process remain unclear. Kugelman et al., demonstrate that FUS-mediated BBB opening at low pressures occurs primarily in arterioles and capillaries due to transient reorganization of tight junctions. BBB opening still occurs at low safe pressures in mice lacking caveolae, suggesting a transcellular route-independent mechanism. At high unsafe pressures, cell junctions are obliterated and remain unrepaired even after 72 hours, allowing fibrinogen passage and persistent microglial activation. Single-cell RNA-sequencing supports cell biological findings that safe, FUS-mediated BBB opening may be driven by transient reorganization and repair of EC tight junctions.

Blood-brain barrier dysfunction is one characteristic of Alzheimer's disease (AD) and is recognized as both a cause and consequence of the pathological cascade leading to cognitive decline. The goal of this study was to assess markers for barrier dysfunction in postmortem tissue samples from research participants who were either cognitively normal individuals (CNI) or diagnosed with AD at the time of autopsy and determine to what extent these markers are associated with AD neuropathologic changes (ADNC) and cognitive impairment.

We used postmortem brain tissue and plasma samples from 19 participants: 9 CNI and 10 AD dementia patients who had come to autopsy from the University of Kentucky AD Research Center (UK-ADRC) community-based cohort; all cases with dementia had confirmed severe ADNC. Plasma samples were obtained within 2 years of autopsy. Aβ40, Aβ42, and tau levels in brain tissue samples were quantified by ELISA. Cortical brain sections were cleared using the X-CLARITY™ system and immunostained for neurovascular unit-related proteins. Brain slices were then imaged using confocal microscopy and analyzed for microvascular diameters and immunoreactivity coverage using Fiji/ImageJ. Isolated human brain microvessels were assayed for tight-junction protein expression using the JESS™ automated Western blot system. S100 calcium-binding protein B (S100β), matrix metalloproteinase (MMP)-2, MMP-9, and neuron-specific enolase (NSE) levels in plasma were quantified by ELISA. All outcomes were assessed for linear associations with global cognitive function (MMSE, CDR) and cerebral atrophy scores by Pearson, polyserial, or polychoric correlation, as appropriate, along with generalized linear modeling or generalized linear mixed-level modeling.

As expected, we detected elevated Aβ and tau pathology in brain tissue sections from AD patients compared to CNI. However, we found no differences in microvascular diameters in cleared AD and CNI brain tissue sections. We also observed no differences in claudin-5 protein levels in capillaries isolated from AD and CNI tissue samples. Plasma biomarker analysis showed that AD patients had 12.4-fold higher S100β plasma levels, twofold lower NSE plasma levels, 2.4-fold higher MMP-9 plasma levels, and 1.2-fold lower MMP-2 plasma levels than CNI. Data analysis revealed that elevated S100β plasma levels were predictive of AD pathology and cognitive impairment.

Our data suggest that among different markers relevant to barrier dysfunction, plasma S100β is the most promising diagnostic biomarker for ADNC. Further investigation is necessary to assess how plasma S100β levels relate to these changes and whether they may predict clinical outcomes, particularly in the prodromal and early stages of AD.

Fibrinogen (FBG) has been discovered to be associated with cognitive impairment (CI) and dementia. However, the exact correlation between FBG levels and CI after acute ischemic stroke (AIS) remains uncertain. Plasma FBG levels were measured in 398 patients with AIS who underwent comprehensive neuropsychological evaluation. To assess the correlation of FBG with global cognitive function, physical status, anxiety, depression, and psychiatric symptoms. Multifactorial logistic regression was used to analyze risk factors for CI. Constructed and plotted a nomogram graph to visualize the CI prediction model. The model was further evaluated for discrimination, calibration, and clinical utility. The results indicate that plasma FBG levels are significantly elevated in patients with CI compared to those with non-cognitive impairment (NCI). Analysis of the overall population reveals that elevated FBG levels are correlated with both reduced cognitive function and decreased activity status. After adjusting for other influencing factors, high FBG levels were identified as a risk factor for the incidence of CI. We developed an intuitive and valid predictive model for CI, demonstrating its suitability for clinical application. In conclusion, our study demonstrates that plasma FBG serves as a potential biomarker of CI following AIS, offering a novel perspective for the identification of CI.

Recent findings indicate that fibrinogen, a protein involved in blood clotting, plays a significant role in neuroinflammation and mood disorders. Elevated fibrinogen levels are consistently observed in individuals with depression, potentially contributing to microglial activation. This could impair fibrinolysis and contribute to a pro-inflammatory environment in the brain. This neuroinflammatory response can impair neuroplasticity, a key process for learning, memory, and mood regulation. Fibrinogen may also indirectly influence neurotransmitters like serotonin, which play a vital role in mood regulation. Furthermore, fibrinogen's interaction with astrocytes may trigger a cascade of events leading to demyelination, a process where the protective sheath around nerve fibers deteriorates. This can disrupt communication within the nervous system and contribute to depression symptoms. Intriguingly, targeting fibrinogen or related pathways holds promise for therapeutic interventions. For instance, modulating PAI-1 (Plasminogen activator inhibitor-1) activity or inhibiting fibrinogen's interaction with brain cells could be potential strategies. This review explores the multifaceted relationship between fibrinogen and neurological disorders with a focus on depression highlighting its potential as a therapeutic target. Further research is necessary to fully elucidate the mechanisms underlying this association and develop effective therapeutic strategies targeting the fibrinolytic system for mood disorders.

Nerve injury causes neuropathic pain and multilevel nerve barrier disruption. Nerve barriers consist of perineurial, endothelial and myelin barriers. So far, it is unclear whether resealing nerve barriers fosters pain resolution and recovery. To this end, we analysed the nerve barrier property portfolio, pain behaviour battery and lipidomics for precursors of specialized pro-resolving meditators (SPMs) and their receptors in chronic constriction injury of the rat sciatic nerve to identify targets for pain resolution by resealing the selected nerve barriers. Of the three nerve barriers-perineurium, capillaries and myelin-only capillary tightness specifically against larger molecules, such as fibrinogen, recuperated with pain resolution. Fibrinogen immunoreactivity was elevated in rats not only at the time of neuropathic pain but also in nerve biopsies from patients with (but not without) painful polyneuropathy, indicating that sealing of the vascular barrier might be a novel approach in pain treatment. Hydroxyeicosatetraenoic acid (15R-HETE), a precursor of aspirin-triggered lipoxin A4, was specifically upregulated at the beginning of pain resolution. Repeated local application of resolvin D1-laden nanoparticles or Fpr2 agonists sex-independently resulted in accelerated pain resolution and fibrinogen removal. Clearing macrophages (Cd206) were boosted and fibrinolytic pathways (Plat) were induced, while inflammation (Tnfα) and inflammasomes (Nlrp3) were unaffected by this treatment. Blocking TAM receptors (Tyro3, Axl and Mer) and tyrosine kinase receptors linking haemostasis and inflammation completely inhibited all the effects. In summary, nanoparticles can be used as transporters for fleeting lipids, such as SPMs, and therefore expand the array of possible therapeutic agents. Thus, the Fpr2-Cd206-TAM receptor axis may be a suitable target for strengthening the capillary barrier, removing endoneurial fibrinogen and boosting pain resolution in patients with chronic neuropathic pain.

Multiple system atrophy (MSA) is a rare neurodegenerative disease characterized by an accumulation of phosphorylated α-synuclein (p-αsyn) in oligodendrocytes in the form of glial cytoplasmic inclusions (GCIs). In MSA, not only mature oligodendrocytes but also oligodendrocyte precursor cells (OPCs) are affected. The latter play an important role in remyelination by differentiating into mature oligodendrocytes, as well as maintaining the blood-brain barrier (BBB) by promoting the expression of tight junction proteins. We have hypothesized that in MSA, the BBB is impaired as a result of aberrant interactions between affected OPCs and the cerebral vasculature. To verify this hypothesis, we conducted a neuropathological examination of postmortem brains from MSA patients and control subjects, focusing on the primary motor area, one of the main regions affected in MSA. Using double immunofluorescence, we quantified the expression of tight junction protein claudin-5 in capillary endothelial cells and found that it was significantly lower in MSA than in controls in both the gray matter and white matter. Furthermore, a significantly higher amount of fibrinogen was extravasated into the brain parenchyma in MSA patients than in controls. In addition, leakage of IgG was detected almost specifically in MSA brain parenchyma, as visualized in three dimensions by combining techniques of chemical tissue clearing and light sheet microscopy. Finally, we confirmed accumulation of p-αsyn-positive GCIs along the cerebral vasculature within OPCs. These results suggest that BBB dysfunction and associated fibrinogen extravasation are constant findings in MSA, presumably triggered by the deposition of p-αsyn in perivascular OPCs.

We aimed to assess perioperative changes in fibrinogen in the cerebrospinal fluid (CSF), their association with markers of blood-brain barrier breakdown and neuroinflammation, and their association with postoperative delirium severity.

We conducted a secondary analysis of the Interventions for Postoperative Delirium-Biomarker 2 (IPOD-B2, NCT02926417) study, a prospective observational cohort study. We included 24 patients aged >21 yr undergoing aortic aneurysm repair. CSF samples were obtained before (n=24) and after surgery (n=13), with some participants having multiple postoperative samples. Our primary outcome was the perioperative change in CSF fibrinogen. Delirium was assessed using the Delirium Rating Scale-Revised-98.

CSF fibrinogen increased after surgery (P<0.001), and this was associated with an increase in CSF/plasma albumin ratio (β=1.09, 95% CI 0.47-1.71, P=0.004). The peak change in CSF fibrinogen was associated with the change in CSF interleukin (IL)-10 and IL-12p70. The peak change in CSF fibrinogen was associated with the change in CSF total tau (β=0.47, 95% CI 0.24-0.71, P=0.002); however, we did not observe an association with postoperative delirium severity (incidence rate ratio = 1.20, 95% CI 0.66-2.17, P=0.540).

Our preliminary findings support the hypothesis that fibrinogen enters the brain via blood-brain barrier disruption, promoting neuroinflammation and neuronal injury. However, we did not observe an association between cerebrospinal fluid fibrinogen and peak delirium severity in this limited cohort.

Cerebral small vessel disease (cSVD) refers to the age-dependent pathological processes involving the brain small vessels and leading to vascular cognitive impairment, intracerebral hemorrhage, and acute lacunar ischemic stroke. Despite the significant public health burden of cSVD, disease-specific therapeutics remain unavailable due to the incomplete understanding of the underlying pathophysiological mechanisms. Recent advances in neuroimaging acquisition and processing capabilities as well as findings from cSVD animal models have revealed critical roles of several age-dependent processes in cSVD pathogenesis including arterial stiffness, vascular oxidative stress, low-grade systemic inflammation, gut dysbiosis, and increased salt intake. These factors interact to cause a state of endothelial cell dysfunction impairing cerebral blood flow regulation and breaking the blood brain barrier. Neuroinflammation follows resulting in neuronal injury and cSVD clinical manifestations. Impairment of the cerebral waste clearance through the glymphatic system is another potential process that has been recently highlighted contributing to the cognitive decline. This review details these mechanisms and attempts to explain their complex interactions. In addition, the relevant knowledge gaps in cSVD mechanistic understanding are identified and a systematic approach to future translational and early phase clinical research is proposed in order to reveal new cSVD mechanisms and develop disease-specific therapeutics.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which was proclaimed a pandemic by the World Health Organization (WHO) in March 2020. There is mounting evidence that older patients with multimorbidity are more susceptible to COVID-19 complications than are younger, healthy people. Having neuroinvasive potential, SARS-CoV-2 infection may increase susceptibility toward the development of Parkinson's disease (PD), a progressive neurodegenerative disorder with extensive motor deficits. PD is characterized by the aggregation of α-synuclein in the form of Lewy bodies and the loss of dopaminergic neurons in the dorsal striatum and substantia nigra pars compacta (SNpc) of the nigrostriatal pathway in the brain. Increasing reports suggest that SARS-CoV-2 infection is linked with the worsening of motor and non-motor symptoms with high rates of hospitalization and mortality in PD patients. Common pathological changes in both diseases involve oxidative stress, mitochondrial dysfunction, neuroinflammation, and neurodegeneration. COVID-19 exacerbates the damage ensuing from the dysregulation of those processes, furthering neurological complications, and increasing the severity of PD symptomatology. Phytochemicals have antioxidant, anti-inflammatory, and anti-apoptotic properties. Vitamin C supplementation is found to ameliorate the common pathological changes in both diseases to some extent. This review aims to present the available evidence on the association between COVID-19 and PD, and discusses the therapeutic potential of vitamin C for its better management.

Aberrant angiogenesis could contribute to the development of cognitive impairment and represent a therapeutic target for preventing dementia. However, most studies addressing angiogenesis and cognitive impairment focus on model organisms. To test the relevance of angiogenesis to human cognitive aging, we evaluated associations of circulating blood markers of angiogenesis with brain aging trajectories in a pooled two-center sample from deeply phenotyped longitudinal human cohorts (n = 435; female = 207, age = 74 ± 9) using cognitive assessments, biospecimens, structural brain imaging, and clinical data. Blood markers included ligands involved in angiogenesis and vascular function such as basic fibroblast growth factor (bFGF), members of the vascular endothelial growth factor family (VEGFA, VEGFB, and VEGFC), and placental growth factor (PlGF), in addition to their receptors VEGF receptor 1 (VEGFR1) and tyrosine kinase with immunoglobulin and EGF homology domain 2 (Tie2). Machine learning and traditional statistics revealed sexually dimorphic associations of plasma angiogenic growth factors with brain aging outcomes, including executive function and gray matter atrophy. Specifically, markers of angiogenesis were associated with higher executive function and less brain atrophy in younger women (not men), a directionality of association that reversed around age 75. Higher concentrations of bFGF, known for pleiotropic effects on multiple cell types, predicted favorable cognitive trajectories in both women and men. An independent sample from a multicenter dataset (MarkVCID; n = 80; female = 30, age = 73 ± 9) was used to externally validate these findings. In conclusion, this analysis demonstrates the association of angiogenesis to human brain aging, with potential therapeutic implications for vascular cognitive impairment and dementia.

Computer-vision and machine-learning (ML) approaches are being developed to provide scalable, unbiased, and sensitive methods to assess mouse behavior. Here, we used the ML-based variational animal motion embedding (VAME) segmentation platform to assess spontaneous behavior in humanized App knockin and transgenic APP models of Alzheimer's disease (AD) and to test the role of AD-related neuroinflammation in these behavioral manifestations. We found marked alterations in spontaneous behavior in AppNL-G-F and 5xFAD mice, including age-dependent changes in motif utilization, disorganized behavioral sequences, increased transitions, and randomness. Notably, blocking fibrinogen-microglia interactions in 5xFAD-Fggγ390-396A mice largely prevented spontaneous behavioral alterations, indicating a key role for neuroinflammation. Thus, AD-related spontaneous behavioral alterations are prominent in knockin and transgenic models and sensitive to therapeutic interventions. VAME outcomes had higher specificity and sensitivity than conventional behavioral outcomes. We conclude that spontaneous behavior effectively captures age- and sex-dependent disease manifestations and treatment efficacy in AD models.

Staphylococcus aureus contamination continues to be a harmful foodborne pathogen threatening of human health, and there is a growing need for rapid detection technologies. This study proposed a novel paper biosensor based on a polydiacetylene (PDA) polymer functionalized fibrinogen (Fg) for the detection of S. aureus in food sources. The fluorophore was developed based on the high binding ability of fibrinogen-binding proteins on the surface of S. aureus. This binding caused twisting in the PDA backbone, leading to changes in chromatic and fluorescent. The detection limit of this method was 50.1 CFU/mL for S. aureus-contaminated foodstuffs and 65.0 CFU/mL for the pure S. aureus culture, and the novelty came from its rapidity and selectivity for S. aureus compared to other foodborne bacteria. In summary, the present work provides a rapid detection method for S. aureus detection, which will help in addressing food safety-related issues.

Osteomyelitis caused by drug-resistant pathogens is one of the most important medical challenges due to high rates of mortality and morbidity, and limited therapeutical options. The application of novel nano-scaffolds loaded with antibiotics has widely been studied and extensively evaluated for in vitro and in vivo inhibition of pathogens, regenerating damaged bone tissue, and increasing bone cell proliferation. The treatment of bone infections using the local osteogenic scaffolds loaded with antimicrobial agents may efficiently overcome the problems of the systemic use of antimicrobial agents and provide a controlled release and sufficient local levels of antibiotics in the infected sites. The present study reviewed various nano-scaffolds delivery systems of antimicrobial drugs evaluated to treat osteomyelitis. Nano-scaffolds offer promising approaches because they simulate natural tissue regeneration in terms of their mechanical, structural, and sometimes chemical properties. The potential of several nano-scaffolds prepared by natural polymers such as silk, collagen, gelatin, fibrinogen, chitosan, cellulose, hyaluronic, alginate, and synthetic compounds such as polylactic acid, polyglycolic acid, poly (lactic acid-co-glycolic acid), poly-ɛ-caprolactone have been studied for usage as drug delivery systems of antimicrobial agents to treat osteomyelitis. In addition to incorporated antimicrobial agents and the content of scaffolds, the physical and chemical characteristics of the prepared delivery systems are a determining factor in their effectiveness in treating osteomyelitis.