Lecanemab blocks the effects of the Aß/fibrinogen complex on blood clots and synapse toxicity in organotypic culture.

Proteinaceous brain inclusions, neuroinflammation, and vascular dysfunction are common pathologies in Alzheimer's disease (AD). Vascular deficits include a compromised blood-brain barrier, which can lead to extravasation of blood proteins like fibrinogen into the brain. Fibrinogen's interaction with the amyloid-beta (Aß) peptide is known to worsen thrombotic and cerebrovascular pathways in AD. Lecanemab, an FDA-approved antibody therapy for AD, clears Aß plaque from the brain and slows cognitive decline. Here, we show that lecanemab blocks fibrinogen's binding to Aß protofibrils, preventing Aß/fibrinogen-mediated delayed fibrinolysis and clot abnormalities in vitro and in human plasma. Additionally, we show that lecanemab dissociates the Aß/fibrinogen complex and prevents fibrinogen from exacerbating Aß-induced synaptotoxicity in mouse organotypic hippocampal cultures. These findings reveal a possible protective mechanism by which lecanemab may slow disease progression in AD.

A possible mechanism for the enhanced toxicity of beta-amyloid protofibrils in Alzheimer's disease.

The amyloid-beta peptide (Aß) is a driver of Alzheimer's disease (AD). Aß monomers can aggregate and form larger soluble (oligomers/protofibrils) and insoluble (fibrils) forms. There is evidence that Aß protofibrils are the most toxic form, but the reasons are not known. Consistent with a critical role for this form of Aß in AD, a recently FDA-approved therapeutic antibody targeted against protofibrils, lecanemab, slows the progression of AD in patients. The plasma contact system, which can promote coagulation and inflammation, has been implicated in AD pathogenesis. This system is activated by Aß which could lead to vascular and inflammatory pathologies associated with AD. We show here that the contact system is preferentially activated by protofibrils of Aß. Aß protofibrils bind to coagulation factor XII and high molecular weight kininogen and accelerate the activation of the system. Furthermore, lecanemab blocks Aß protofibril activation of the contact system. This work provides a possible mechanism for Aß protofibril toxicity in AD and why lecanemab is therapeutically effective.

Characteristics of Tongue Pressure Measured by Novel Multisite Flexible Sensors in Nasopharyngeal Carcinoma Patients With Dysphagia.

OBJECTIVE: To explore characteristics of tongue pressure changes in nasopharyngeal carcinoma (NPC) patients with dysphagia after radiotherapy using a novel system with multisite flexible sensors. DESIGN: Prospective observational study. SETTING: Inpatient rehabilitation centers and community dwellings. PARTICIPANTS: Nineteen patients with dysphagia after radiotherapy for NPC and 19 healthy participants were recruited for this study (N=38). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: A new 9-site (3 × 3) flexible tongue pressure sensor was used to measure tongue-to-palate pressure across different parts of the tongue. The oral tongue was divided into 3 parts: anterior tongue region (TAR), central tongue region (TCR), and posterior tongue region (TPR); 3 sensors were placed on each part. The mean tongue pressure and endurance time at the 3 sites in the TAR, TCR, and TPR were analyzed. The ratios of the mean TAR, TCR, and TPR values were calculated. RESULTS: Pressures of TAR, TCR, and TPR in NPC patients with dysphagia were significantly lower than those in healthy participants (P<.05). The pressure in TPR decreased most significantly, followed by that in TCR. The endurance times of TAR and TCR were longer than those of healthy participants (P<.05). The endurance time of TPR was not significantly different between the patients and healthy participants (P>.05). Ratios of pressure between TAR and TCR and TAR and TPR in patients were lower than that in healthy participants (P<.05). There was no significant difference in the TCR to TPR pressure ratio between patients and healthy participants (P>.05). CONCLUSIONS: Tongue pressure significantly decreased in NPC patients with dysphagia, and the drop in pressure was most pronounced in the TPR area. The results of our study indicate that we should pay attention to the pressure training of the TPR during treatments. The endurance time of the TAR and TCR increased significantly, which may be due to bolus transport compensation. Therefore, clinical rehabilitation strategies should aim to increase the endurance time training in NPC patients after radiotherapy to help increase the effectiveness of the swallowing process in patients.

Temporal Characteristics of Penetration and Aspiration in Patients with Severe Dysphagia Associated with Lateral Medullary Syndrome.

To assess the severity and timing of penetration and aspiration (PA) of severe dysphagia after lateral medullary syndrome (LMS) and its association with temporal characteristics. We performed videofluoroscopic swallowing studies (VFSS) in 48 patients with LMS and severe dysphagia and 26 sex- and age-matched healthy subjects. The following temporal measures were compared between groups: velopharyngeal closure duration (VCD); hyoid bone movement duration (HMD); laryngeal vestibular closure duration (LCD); upper esophageal sphincter (UES) opening duration (UOD); stage transition duration (STD) and the interval between laryngeal vestibular closure and UES opening (LC-UESop). The association between temporal measures and Penetration-Aspiration Scale (PAS) scores was analyzed. Differences in timing measures were compared between subgroups (safe swallows, and swallows with PA events during and after the swallow). PAS scores ≥ 3 were seen in 48% of swallows (4% occuring before, 35% occurred during and 61% after the swallow) from the LMS patients. Significantly longer STD and LC-UESop were found in the patients compared to the healthy subjects (p < 0.05). Significant negative correlations with PA severity were found for HMD, LCD, and UOD. Short UOD was the strongest predictor with an area under the receiver-operating-characteristic curve of 0.66. UOD was also significantly shorter in cases of PA after the swallow (p < 0.01). Patients with LMS involving severe dysphagia exhibit a high frequency of PA (mostly during and after swallowing). PA events were associated with shorter UOD, HMD, and LCD. Notably, shortened UOD appears to be strongly associated with PA.

Effect of Co-exposure to Additional Substances on the Bioconcentration of Per(poly)fluoroalkyl Substances: A Meta-Analysis Based on Hydroponic Experimental Evidence.

A consensus has yet to emerge regarding the bioconcentration responses of per(poly)fluoroalkyl substances under co-exposure with other additional substances in aqueous environments. This study employed a meta-analysis to systematically investigate the aforementioned issues on the basis of 1,085 published datasets of indoor hydroponic simulation experiments. A hierarchical meta-analysis model with an embedded variance covariance matrix was constructed to eliminate the non-independence and shared controls of the data. Overall, the co-exposure resulted in a notable reduction in PFAS bioaccumulation (cumulative effect size, CES = - 0.4287, p < 0.05) and bioconcentration factor (R2 = 0.9507, k < 1, b < 0) in hydroponics. In particular, the inhibition of PFAS bioconcentration induced by dissolved organic matter (percentage form of the effect size, ESP = - 48.98%) was more pronounced than that induced by metal ions (ESP = - 35.54%), particulate matter (ESP = - 24.70%) and persistent organic pollutants (ESP = - 18.66%). A lower AS concentration and a lower concentration ratio of ASs to PFASs significantly promote PFAS bioaccumulation (p < 0.05). The bioaccumulation of PFASs with long chains or high fluoride contents tended to be exacerbated in the presence of ASs. Furthermore, the effect on PFAS bioaccumulation was also significantly dependent on the duration of co-exposure (p < 0.05). The findings of this study provide novel insights into the fate and bioconcentration of PFAS in aquatic environments under co-exposure conditions.

Plasmin-mediated cleavage of high-molecular-weight kininogen contributes to acetaminophen-induced acute liver failure.

Acetaminophen (APAP)-induced liver injury is associated with activation of coagulation and fibrinolysis. In mice, both tissue factor-dependent thrombin generation and plasmin activity have been shown to promote liver injury after APAP overdose. However, the contribution of the contact and intrinsic coagulation pathways has not been investigated in this model. Mice deficient in individual factors of the contact (factor XII [FXII] and prekallikrein) or intrinsic coagulation (FXI) pathway were administered a hepatotoxic dose of 400 mg/kg of APAP. Neither FXII, FXI, nor prekallikrein deficiency mitigated coagulation activation or hepatocellular injury. Interestingly, despite the lack of significant changes to APAP-induced coagulation activation, markers of liver injury and inflammation were significantly reduced in APAP-challenged high-molecular-weight kininogen-deficient (HK-/-) mice. Protective effects of HK deficiency were not reproduced by inhibition of bradykinin-mediated signaling, whereas reconstitution of circulating levels of HK in HK-/- mice restored hepatotoxicity. Fibrinolysis activation was observed in mice after APAP administration. Western blotting, enzyme-linked immunosorbent assay, and mass spectrometry analysis showed that plasmin efficiently cleaves HK into multiple fragments in buffer or plasma. Importantly, plasminogen deficiency attenuated APAP-induced liver injury and prevented HK cleavage in the injured liver. Finally, enhanced plasmin generation and HK cleavage, in the absence of contact pathway activation, were observed in plasma of patients with acute liver failure due to APAP overdose. In summary, extrinsic but not intrinsic pathway activation drives the thromboinflammatory pathology associated with APAP-induced liver injury in mice. Furthermore, plasmin-mediated cleavage of HK contributes to hepatotoxicity in APAP-challenged mice independently of thrombin generation or bradykinin signaling.

Regulatory mechanisms and context-dependent roles of TAL1 in T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive malignancy derived from thymic T-cell precursors. Approximately 40-60% of T-ALL cases exhibit aberrant overexpression of the TAL1 oncogenic transcription factor. Here, we provide a comprehensive view of the TAL1-induced transcriptional program in human T-ALL cells using a rapid protein degradation system coupled with integrative approaches. Our study demonstrates that TAL1 targets can be classified into several groups, each of which exhibits unique gene expression kinetics, chromatin features, and regulatory mechanisms. Group A genes are highly dependent on TAL1, many of which are not expressed in normal T-cells or TAL1-negative T-ALL cells, representing an oncogenic TAL1 signature. The TAL1 complex predominantly activates Group A genes. TAL1's effect is not replaceable with its regulatory partners GATA3 or RUNX1. In contrast, Group B genes, many of which are generally expressed across different T-ALL subgroups, exhibit densely-connected chromatinchromatin interactions and demonstrate the collaborative roles played by TAL1 with other transcription factors. Interestingly, TAL1 cooperates with NOTCH1 to regulate gene expression in TAL1-positive T-ALL cells, whereas it potentially antagonizes the NOTCH1-MYC pathway and leads to lethality in TAL1-negative/TLX3-positive cells, demonstrating the context-dependent roles of TAL1.

Iron-Nitrogen Amendment Reduced Perfluoroalkyl Acids' Phyto-Uptake in the Wheat-Soil Ecosystem: Contributions of Dissolved Organic Matters in Soil Solution and Root Extracellular Polymeric Substances.

Understanding the mechanisms underlying perfluoroalkyl acids (PFAAs) translocation, distribution, and accumulation in wheat-soil ecosystems is essential for agricultural soil pollution control and crop ecological risk assessment. This study systematically investigated the translocation of 13 PFAAs under different iron and nitrogen fertilization conditions in a wheat-soil ecosystem. Short-chain PFAAs including PFBA, PFPeA, PFHxA, and PFBS mostly accumulated in soil solution (10.43-55.33%) and soluble extracellular polymeric substances (S-EPS) (11.39-14.77%) by the adsorption to amino- (-NH2) and hydroxyl (-OH) groups in dissolved organic matter (DOM). Other PFAAs with longer carbon chain lengths were mostly distributed on the soil particle surface by hydrophobic actions (74.63-94.24%). Iron-nitrogen amendments triggered (p < 0.05) soil iron-nitrogen cycling, rhizospheric reactive oxygen species fluctuations, and the concentration increases of -NH2 and -OH in the DOM structure. Thus, the accumulation capacity of PFAAs in soil solution and root EPS was increased. In sum, PFAAs' translocation from soil particles to wheat root was synergistically reduced by iron and nitrogen fertilization through increased adsorption of soil particles (p < 0.05) and the retention of soil solution and root EPSs. This study highlights the potential of iron-nitrogen amendments in decreasing the crop ecological risks to PFAAs' pollution.

Electronic and thermal transport properties of the metallic antiferromagnet MnSn2.

We report the structure, magnetic and electrical/thermal transport properties of the antiferromagnet MnSn2. Importantly, the existence of the two antiferromagnetic states below TN2 (∼320 K) is confirmed by magnetism and electrical transport measurements. An unsaturated positive magnetoresistance up to 150% at ∼9 T was observed at 5 K, whereas the magnetoresistance becomes negative in the whole range at high temperatures (T > 74 K). Systematic investigations of the Hall transport and thermoelectric properties reveal that the hole-type carriers are the majority carriers in MnSn2. The kink around 320 K in the Seebeck coefficient originates from the effect of the antiferromagnetic phase on the band structure, while the pronounced peak around 231 K is attributed to the phonon-drag effect. The results suggest that the spin arrangement plays a vital role in the magnetic, electrical, and thermal transport properties in MnSn2.

Global development and future trends of artificial sweetener research based on bibliometrics.

Artificial sweeteners have sparked a heated debate worldwide due to their ambiguous impacts on public and environmental health and food safety and quality. Many studies on artificial sweeteners have been conducted; however, none scientometric studies exist in the field. This study aimed to elaborate on the knowledge creation and development of the field of artificial sweeteners and predict the frontiers of knowledge based on bibliometrics. In particular, this study combined VOSviewer, CiteSpace, and Bibliometrix to visualize the mapping of knowledge production, covered 2389 relevant scientific publications (1945-2022), and systematically analyzed articles and reviews (n = 2101). Scientific publications on artificial sweeteners have been growing at an annual rate of 6.28% and globally attracting 7979 contributors. Susan J. Brown with total publications (TP) of 17, average citation per article (AC) of 36.59, and Hirsch (h)-index of 12 and Robert F. Margolskee (TP = 12; AC = 2046; h-index = 11) were the most influential scholars. This field was clustered into four groups: eco-environment and toxicology, physicochemical mechanisms, public health and risks, and nutrition metabolism. The publications about environmental issues, in particular, "surface water," were most intensive during the last five years (2018-2022). Artificial sweeteners are gaining importance in the monitoring and assessment of environmental and public health. Results of the dual-map overlay showed that the future research frontiers tilt toward molecular biology, immunology, veterinary and animal sciences, and medicine. Findings of this study are conducive to identifying knowledge gaps and future research directions for scholars.

Effects of Escherichia pollution and salinity on nutrient levels in submerged vegetated wetlands: Insights into benthic community stability and metabolisms.

Inner coastal wetland ecosystems are generally eutrophic and are often exposed to both salinity stress and Escherichia coli pollution. However, the effects of these stressors on nutrient-cycling and microbial communities are under-researched. Here, we established a vegetated wetland ecosystem in a saline environment to understand the effects of E. coli pollution on nutrient removal and benthic microorganisms. The results show that E. coli significantly inhibited nutrient removal, especially total nitrogen (TN) and ammonium (78.89-84.98 and 3.45-44.65% were removed from the non-E. coli-treated and the E. coli-treated water, respectively). Compared with non-vegetated systems, archaeal community variations at both compositional and phylogenetic levels were weakened in vegetated systems (p < 0.05). Among all the environmental factors, the ratios of PO43--P to total phosphorus and NO3--N to TN contributed the most to archaeal and bacterial community structural variations, respectively. E. coli pollution affected archaeal community succession more than bacteria (p < 0.05). E. coli also weakened the trophic transferring efficiencies between Cyanobacteria and Myxobacteria (p < 0.05). Metabolically, E. coli inhibited bacterial genetic metabolic pathways but made human infection more likely (p < 0.05). Our findings provide new insights into aquatic ecological conservation and environmental management.

Observing errors in a combination of error and correct models favors observational motor learning.

BACKGROUND: Imitative learning is highly effective from infancy to old age; however, little is known about the effects of observing errors during imitative learning. This study aimed to examine how observing errors affected imitative learning performance to maximize its effect. METHODS: In the pre-training session, participants were instructed to pinch at a target force (8 N) with auditory feedback regarding generated force while they watched videos of someone pinching a sponge at the target force. In the pre-test, participants pinched at the target force and did not view a model or receive auditory feedback. In Experiment 1, in the main training session, participants imitated models while they watched videos of pinching at either the incorrect force (error-mixed condition) or target force (correct condition). Then, the exact force generated was measured without receiving auditory feedback or viewing a model. In Experiment 2, using the same procedures, newly recruited participants watched videos of pinching at incorrect forces (4 and 24 N) as the error condition and the correct force as the correct condition. RESULTS: In Experiment 1, the average force was closer to the target force in the error-mixed condition than in the correct condition. In Experiment 2, the average force in the correct condition was closer to the target force than in the error condition. CONCLUSION: Our findings indicated that observing error actions combined with correct actions affected imitation motor learning positively as error actions contained information on things to avoid in the target action. It provides further information to enhance imitative learning in mixed conditions compared to that with correct action alone.

Perfluorinated compounds (PFCs) in regional industrial rivers: Interactions between pollution flux and eukaryotic community phylosymbiosis.

Perfluorinated compounds (PFCs) pose serious threats to aquatic ecosystems, especially their microbial communities. However, little is known about the phylosymbiosis of aquatic fungal and viridiplantae communities in response to PFC accumulation. We quantified the distribution of 14 PFCs in rivers and found that PFBA was dominant in the transition from water to sediment. High through-put sequencing revealed that phyla Ascomycota, Basidiomycota, Anthophyta, and Chlorophyta were the predominant in eukaryotic community. The effects of PFCs on spatial community coalescence at taxonomic and phylogenetic levels (p < 0.05) were revealed. Fungal community coalescence triggered the spatial assembly of fungal and viridiplantae communities in riverine environments (p < 0.05). Null modeling indicated that PFBA, PFTrDA and PFOS, etc, mediated phylogenetic assembly (p < 0.05) and stochastic processes (86.67-100%) maintain phylogenetic turnover in the fungal community. Meanwhile, variable selection (27.78-54.44%) explained the viridiplantae community assemblage. Finally, we identified fungal genera Hannaella, Naganishia, Purpureocillium and Stachybotrys as indicators for PFC pollution (p < 0.001). These results help explain the effects of PFCs on riverine ecological remediation.

An antibody against HK blocks Alzheimer's disease peptide ß-amyloid-induced bradykinin release in human plasma.

Bradykinin is a proinflammatory factor that mediates angioedema and inflammation in many diseases. It is a key player in some types of hereditary angioedema and is involved in septic shock, traumatic injury, Alzheimer's disease (AD), and stroke, among others. Activation of the plasma contact system leads to elevated levels of plasma kallikrein, which cleaves high molecular weight kininogen (HK) to release bradykinin. Drug development for bradykinin-meditated pathologies has focused on designing inhibitors to the enzymes that cleave HK (to prevent bradykinin release) or antagonists of endothelial bradykinin receptors (to prevent downstream bradykinin action). Here we show a strategy to block bradykinin generation by using an HK antibody that binds to HK, preventing its cleavage and subsequent bradykinin release. We show that this antibody blocks dextran sodium sulfate-induced HK cleavage and bradykinin production. Moreover, while the pathogenic AD peptide ß-amyloid (Aß)42 cleaves HK and induces a dramatic increase in bradykinin production, our HK antibody blocked these events from occurring. These results may provide strategies for developing treatments for bradykinin-driven pathologies.

Effect of Intensive Oropharyngeal Training on Radiotherapy-Related Dysphagia in Nasopharyngeal Carcinoma Patients.

OBJECTIVE: To evaluate the effect of intensive oropharyngeal functional training on swallowing in patients with dysphagia after radiotherapy for nasopharyngeal carcinoma. METHODS: Fourteen patients with nasopharyngeal carcinomas and dysphagia after radiotherapy received intensive oropharyngeal training for two weeks. The Functional Oral Intake Scale (FOIS) and videofluoroscopic swallowing studies (VFSS) were used to evaluate swallowing function before and after intensive oropharyngeal training. Spatiotemporal parameters of the VFSS were analyzed using a digital image analysis system. RESULTS: After training, the FOIS, Rosenbek penetration-aspiration score, DIGEST, normalized residue ratio scale, and spatiotemporal parameters of VFSS were significantly improved (P < 0.05). CONCLUSIONS: This study indicated that intensive oropharyngeal training improves swallowing function after radiotherapy in patients with nasopharyngeal carcinoma.

Blood-derived plasminogen drives brain inflammation and plaque deposition in a mouse model of Alzheimer's disease.

Two of the most predominant features of the Alzheimer's disease (AD) brain are deposition of ß-amyloid (Aß) plaques and inflammation. The mechanism behind these pathologies remains unknown, but there is evidence to suggest that inflammation may predate the deposition of Aß. Furthermore, immune activation is increasingly being recognized as a major contributor to the pathogenesis of the disease, and disorders involving systemic inflammation, such as infection, aging, obesity, atherosclerosis, diabetes, and depression are risk factors for the development of AD. Plasminogen (PLG) is primarily a blood protein synthesized in the liver, which when cleaved into its active form, plasmin (PL), plays roles in fibrinolysis, wound healing, cell signaling, and inflammatory regulation. Here we show that PL in the blood is a regulator of brain inflammatory action and AD pathology. Depletion of PLG in the plasma of an AD mouse model through antisense oligonucleotide technology dramatically improved AD pathology and decreased glial cell activation in the brain, whereas an increase in PL activity through α-2-antiplasmin (A2AP) antisense oligonucleotide treatment exacerbated the brain's immune response and plaque deposition. These studies suggest a crucial role for peripheral PL in mediating neuroimmune cell activation and AD progression and could provide a link to systemic inflammatory risk factors that are known to be associated with AD development.

Increased plasma bradykinin level is associated with cognitive impairment in Alzheimer's patients.

Alzheimer's disease (AD) is characterized by the presence of proteinaceous brain deposits, brain atrophy, vascular dysfunction, and chronic inflammation. Along with cerebral inflammation, peripheral inflammation is also evident in many AD patients. Bradykinin, a proinflammatory plasma peptide, is also linked to AD pathology. For example, bradykinin infusion into the hippocampus causes learning and memory deficits in rats, and blockade of the bradykinin receptor lessens cognitive impairment in AD mouse models. Even though it has been hypothesized that plasma bradykinin could contribute to inflammation in AD, the level of plasma bradykinin and its association with beta-amyloid (Aß) pathology in AD patients had not been explored. Here, we assessed plasma bradykinin levels in AD patients and age-matched non-demented (ND) control individuals. We found significantly elevated plasma bradykinin levels in AD patients compared to ND subjects. Additionally, changes in plasma bradykinin levels were more profound in many AD patients with severe cognitive impairment, suggesting that peripheral bradykinin could play a role in dementia most likely via inflammation. Bradykinin levels in the cerebrospinal fluid (CSF) were reduced in AD patients and exhibited an inverse correlation with the CSF Aß40/Aß42 ratio. We also report that bradykinin interacts with the fibrillar form of Aß and co-localizes with Aß plaques in the post-mortem human AD brain. These findings connect the peripheral inflammatory pathway to cerebral abnormalities and identify a novel mechanism of inflammatory pathology in AD.

The response of nitrogen cycling and bacterial communities to E. coli invasion in aquatic environments with submerged vegetation.

The effects of exogenous Escherichia coli on nitrogen cycling (N-cycling) in freshwater remains unclear. Thus, seven ecosystems, six with submerged plants-Potamogeton crispus (PC) and Myriophyllum aquaticum (MA)-and one with no plants were set up. Habitats were assessed before and after E. coli addition (107 colony-forming units/mL). E. coli colonization of freshwater ecosystems had significant effects on bacterial community structure in plant surface biofilms and surface sediments (ANOVA, P < 0.05). It reduced the relative abundance of nitrosification bacteria (-70.94 ± 26.17%) and nitrifiers (-47.86 ± 23.68%) in biofilms which lead to significant reduction of ammoxidation in water (P < 0.05). The N-cycling intensity from PC systems was affected more strongly by E. coli than were MA systems. Furthermore, the coupling coefficient of exogenous E. coli to indigenous N-cycling bacteria in sediments (6.061, average connectivity degree) was significantly weaker than that in biofilms (9.852). Additionally, at the genus level, E. coli were most-closely associated with N-cycling bacteria such as Prosthecobacter, Hydrogenophaga, and Bacillus in sediments and biofilms according to co-occurrence bacterial network (Spearman). E. coli directly changed their abundance, so that the variability of species composition of N-cycling bacterial taxa was triggered, as well. Overall, exogenous E. coli repressed ammoxidation, but promoted ammonification and denitrification. Our results provided new insights into how pathogens influence the nitrogen cycle in freshwater ecosystems.

Plasminogen mediates communication between the peripheral and central immune systems during systemic immune challenge with lipopolysaccharide.

BACKGROUND: Systemic inflammation has been implicated in the progression of many neurodegenerative diseases and may be an important driver of the disease. Dementia and cognitive decline progress more rapidly following acute systemic infection, and systemic inflammation midlife is predictive of the degree of cognitive decline. Plasmin, the active form of the serine protease plasminogen (PLG), is a blood protein that plays physiological roles in fibrinolysis, wound healing, cell signaling, extracellular matrix degradation, and inflammatory regulation. METHODS: Mice were treated with an antisense oligonucleotide to deplete liver-produced PLG prior to systemic challenge with lipopolysaccharide (LPS), a major component of the outer membrane of gram-negative bacteria, known to induce a strong immune response in animals. Following treatment, the innate immune response in the brains of these animals was examined. RESULTS: Mice that were PLG-deficient had dramatically reduced microgliosis and astrogliosis in their brains after LPS injection. We found that blood PLG regulates the brain's innate immune response to systemic inflammatory signaling, affecting the migration of perivascular macrophages into the brain after challenge with LPS. CONCLUSIONS: Depletion of plasma PLG with an antisense oligonucleotide dramatically reduced glial cell activation and perivascular macrophage migration into the brain following LPS injection. This study suggests a critical role for PLG in mediating communication between systemic inflammatory mediators and the brain.

Depletion of coagulation factor XII ameliorates brain pathology and cognitive impairment in Alzheimer disease mice.

Vascular abnormalities and inflammation are found in many Alzheimer disease (AD) patients, but whether these changes play a causative role in AD is not clear. The factor XII (FXII) -initiated contact system can trigger both vascular pathology and inflammation and is activated in AD patients and AD mice. We have investigated the role of the contact system in AD pathogenesis. Cleavage of high-molecular-weight kininogen (HK), a marker for activation of the inflammatory arm of the contact system, is increased in a mouse model of AD, and this cleavage is temporally correlated with the onset of brain inflammation. Depletion of FXII in AD mice inhibited HK cleavage in plasma and reduced neuroinflammation, fibrinogen deposition, and neurodegeneration in the brain. Moreover, FXII-depleted AD mice showed better cognitive function than untreated AD mice. These results indicate that FXII-mediated contact system activation contributes to AD pathogenesis, and therefore this system may offer novel targets for AD treatment.