Cognitive decline frequently occurs during typical aging, yet the molecular mechanisms underlying this process remain poorly understood, especially in the absence of classical neuropathology such as amyloid. Vascular dysfunction and increased blood-brain barrier (BBB) permeability have emerged as potential contributors. This study examined whether thromboinflammation, indicated by fibrinogen levels in cerebrospinal fluid (CSF), affects synaptic health and cognition in amyloid-negative, typical aging. We measured CSF fibrinogen and synaptic/neurodegenerative markers (pTau, GAP43, NRGN, and SNAP25) in cognitively normal older adults ( N  = 70). An unbiased proteomic screen (SomaScan 7k) was then performed to identify specific mediators linking fibrinogen to these markers, followed by validation in an independent cohort ( N  = 482). To assess potential interactions with amyloid pathology, we further examined these mediators in a separate group of amyloid-positive older adults ( N  = 752). Higher CSF fibrinogen was significantly associated with elevated pTau, GAP43, NRGN, and SNAP25, independent of amyloid status. Mediation analysis revealed 14 proteins that consistently linked fibrinogen to neurodegeneration, including factors regulating vascular plasticity and immune activation. Cell-type mapping showed enrichment in endothelial cells, pericytes, and microglia. Results were validated in a large, independent typical aging cohort, confirming core pathways of fibrinogen-mediated neurovascular dysfunction. In the amyloid-positive cohort, vascular-specific mediators were relatively reduced, indicating possibly altered molecular mechanisms in amyloid aging compared with typical aging. These findings highlight a thromboinflammatory pathway underlying synaptic decline in typically aging older adults, driven by fibrinogen at the neurovascular interface. Targeting BBB integrity and its vascular-immune signaling may offer therapeutic opportunities to preserve cognition in aging, even in the absence of amyloid pathology.

Brain network dysfunction-including hyperexcitability, altered oscillations, and sleep disruption-is prominent in Alzheimer's disease (AD), but the contribution of vascular-neuroimmune processes to these alterations remains unclear. Here, we blocked the pro-inflammatory interaction of the blood protein fibrin with microglia using genetic (Fggγ390-396A mice) and antibody-based (5B8 and THN392) strategies to test its role in AD-related network dysfunction. The 5xFAD model of AD exhibited network hyperexcitability associated with oscillatory slowing, sleep states, and disrupted sleep-circadian rhythms. These deficits were largely attenuated by blocking fibrin-microglia interactions in 5xFAD;Fggγ390-396A mice. Notably, pharmacological interventions after disease onset with both anti-fibrin antibodies similarly attenuated these AD-related network deficits and behavioral abnormalities. We conclude that vascular-neuroimmune processes driven by fibrin-microglia interactions promote AD-related network dysfunction and that targeting the fibrin-microglia axis-currently under clinical evaluation with the humanized antibody THN391- represents a promising therapeutic strategy for AD. There is a companion manuscript submitted to bioRxiv (Yan et al., 2026).110.

INTRODUCTION:Blood-brain barrier (BBB) dysfunction is an early feature of Alzheimer's disease (AD). Fibrinogen represents a sensitive marker of BBB leakage, but whether it modifies longitudinal tau progression in cognitively unimpaired (CU) individuals remains unknown. METHODS:CU older adults underwent clinical evaluation and cerebrospinal fluid (CSF) assessment of fibrinogen, Aβ42, total tau (tTau), phosphorylated tau 181 (pTau181), and YKL-40. Linear regression tested baseline associations. Linear mixed-effects models tested whether baseline fibrinogen predicted longitudinal pTau181 change. RESULTS:Among 169 CU participants with baseline fibrinogen, 87 had longitudinal pTau181 measurements (mean follow-up 2.5-years). Higher fibrinogen was associated with elevated YKL-40 (β = 0.28, 95% confidence interval [CI] [0.11, 0.45]) but not Aβ42, tTau, or pTau181 at baseline. Baseline fibrinogen modified longitudinal pTau181 trajectories (interaction β = 0.11, 95% CI [0.04, 0.19]), with only participants above the median showing significant pTau181 increases (β = 0.13, 95% CI [0.08, 0.18]). DISCUSSION:CSF fibrinogen associates cross-sectionally with glial inflammation and predicts accelerated tau accumulation in preclinical AD.

Cerebrovascular pathology and neuronal network dysfunction are early features of Alzheimers disease (AD) associated with neuroinflammation and cognitive decline, but the vascular and immune triggers of neuronal hyperactivity remain largely unknown. Here, we show that the blood coagulation protein fibrin disrupts microglia-neuron interactions, promoting neuronal hyperactivity in an AD mouse model. Genetic elimination of the fibrin inflammatory domain reduced neuronal hyperactivity, restored dynamic microglial interactions with active neurons and protected from high-risk decision making in 5XFAD mice. Leveraging the transcriptional signatures of microglia and inhibitory and excitatory neurons, a ligand-receptor atlas revealed fibrin-dependent disruption of innate immune and glutamatergic signaling between microglia and neurons in AD mice. Patients with AD also showed a correlation of cerebrospinal fluid (CSF) fibrinogen levels with biomarkers of inflammation, vascular and synaptic dysfunction. Thus, resilience to neuronal hyperactivity and restoration of the neuroimmune interactome by targeting fibrin may have therapeutic implications for Alzheimers disease and related conditions. There is a companion manuscript cited as Ref #62 submitted to bioRxiv (Lauderdale et al., 2026).

Summary Cerebrovascular pathology and neuronal network dysfunction are early features of Alzheimer’s disease (AD) associated with neuroinflammation and cognitive decline, but the vascular and immune triggers of neuronal hyperactivity remain largely unknown. Here, we show that the blood coagulation protein fibrin disrupts microglia-neuron interactions, promoting neuronal hyperactivity in an AD mouse model. Genetic elimination of the fibrin inflammatory domain reduced neuronal hyperactivity, restored dynamic microglial interactions with active neurons and protected from high-risk decision making in 5XFAD mice. Leveraging the transcriptional signatures of microglia and inhibitory and excitatory neurons, a ligand–receptor atlas revealed fibrin-dependent disruption of innate immune and glutamatergic signaling between microglia and neurons in AD mice. Patients with AD also showed a correlation of cerebrospinal fluid (CSF) fibrinogen levels with biomarkers of inflammation, vascular and synaptic dysfunction. Thus, resilience to neuronal hyperactivity and restoration of the neuroimmune interactome by targeting fibrin may have therapeutic implications for Alzheimer’s disease and related conditions. There is a companion manuscript submitted to bioRxiv (Lauderdale et al., 2026) Highlights Vascular-microglia axis drives neuronal hyperactivity Fibrin inflammatory activity disrupts the microglia-neuron interactome Microglia activation by fibrin impairs decision-making in AD mice Synaptic dysfunction and immune biomarkers correlate with CSF fibrinogen in AD patients

Abstract Background Microgliosis and severe coagulation, including fibrinogen deposition, are features of both experimental and human cerebral malaria (CM), a lethal disease. Vascular-associated microglia migrate to coagulated cerebral vessels containing inflammatory monocytes and T cells in experimental CM. We previously showed that microglial depletion exacerbates coagulation and disease severity, including hypothermia, while anticoagulant treatment reduces microgliosis and prevents mortality. These data suggest an overall protective effect of microglia on eCM, and indicate a link between microgliosis, hypothermia, and coagulation. Therefore, mechanisms of migration and activation of microglia, T cells, and monocytes were studied in relation to the role of fibrin(ogen) in eCM. Methods Using both Plasmodium berghei ANKA infection or experimental CM, and P. chabaudi infection of IL-10-deficient mice (IL-10 KO), which causes a hyperinflammatory response including neuropathology, intravital two-photon microscopy and flow cytometry, were used to test patterns and mechanisms of migration. In vivo methods included intranasal administration of CCL5 receptor antagonist Met-CCL5; systemic integrin-blocking antibodies and mutant animals (IL-10 KO, ICAM1 KO), and anticoagulant treatment. Clotting-deficient mice ( Fga KO, Fib AEK ) were tested for the absence of fibrinogen in clotting, while fibrinogen γ-chain mutation (Fibγ 390–396 A ) mice and intranasal administration of a fibrinogen γ-derived inhibitory peptide (Fibrin γ 377–395 ), which disrupts CD11b-fibrin interactions, assessed the role of CD11b-fibrin interactions in microglial activation in eCM. Results Intraluminal adhesion and crawling of CCR2 RFP+ cells, including T cells and inflammatory monocytes, was observed in cerebral vessels; however, there was no evidence that brain adherence of T cells or monocytes depends on classical adhesion molecules or coagulation. Intranasal administration of met-CCL5 reduced both microglial recruitment to vessels and CD8 T cell adherence and fibrin(ogen) deposition. Despite the previously published protective effects of the anticoagulant drug in IL-10 KO, clotting-deficient mice showed no change in P. berghei ANKA mortality. However, disruption of fibrin-CD11b interactions by both genetic and peptide inhibition led to exacerbated hypothermia in both experimental CM models. Reduced microglial hypertrophy also occurred in Fibrin γ 377–395 peptide-treated IL-10 KO mice infected with P. chabaudi . Conclusions These data support our previous study suggesting that microglia are involved in the regulation of hypothermia in eCM and reveal CCL5 and fibrin-CD11b signaling in microglia as key molecular pathways modulating neuroinflammation in malaria.

Individuals with Down syndrome (DS) have an increased genetic risk of developing Alzheimer’s disease (AD), with most adults developing AD neuropathology in their 40s. Despite having a low frequency of systemic vascular risk factors such as hypertension and atherosclerosis, adults with DS display cerebrovascular pathology, including microbleeds, microinfarcts, and cerebral amyloid angiopathy. This suggests that blood-brain barrier (BBB) integrity may be compromised allowing the extravasation of blood proteins in the brain parenchyma. The blood coagulation factor fibrin promotes immune-mediated neurodegeneration and is a marker of BBB disruption in a wide range of neurological diseases. This study investigated the severity of fibrin deposition as a measure of BBB integrity in the brains of adults with DS and AD pathology (DSAD). We hypothesized that fibrin deposition is increased in DSAD in comparison to neurotypical controls without DS or AD. Fibrin immunoreactivity was assessed by free-floating immunohistochemistry in 30µm tissue sections from the occipital cortex from neurotypical controls (n = 12; 41-65 years old) and DSAD (n = 12; 46-66 years old). Using whole slide imaging, brain sections were digitized, and the severity of fibrin deposition was scored using Aperio Imagescope. Individuals with DSAD display significantly higher fibrin deposition in the white and grey matter of the occipital cortex in comparison to the age-matched neurotypical controls (p<0.0001). Neurotypical controls display minimal fibrin deposition in the brain parenchyma and perivascular space. However, compared to neurotypical controls, adults with DS at advanced stages of AD neuropathology display significant fibrin deposition in the occipital cortex, suggesting that the BBB may be compromised in this population. Funding : NIH U19AG068054, RF1AG079519, P30AG066519 and 23AARFD-1022715.

Small vessel disease (SVD) impacts healthy aging of organs across the body, yet its contributions to adverse brain aging remain poorly defined. Here we show thromboinflammation, a core feature of SVD, as a driver of adverse brain aging. We identify cerebrospinal fluid fibrinogen as a marker of brain thromboinflammation and screen neurovascular biosignatures mediating its impact on synaptic vulnerability along the full spectrum of brain aging from cognitively typical, amyloid-negative to cognitively impaired, amyloid-positive older adults. We identified 53 proteins mediating fibrinogen's effects on synaptic markers in 1,655 donors from three independent cohorts. Single-cell transcriptomic mapping revealed mediator enrichment in neurovascular unit cells. Pathway analysis demonstrated dysregulation of angiogenesis, fibrosis, and immune signaling. Vascular and microglial-enriched biosignatures associated with compromised white matter integrity. These findings indicate thromboinflammation as an early, amyloid-independent pathway to neurodegeneration and tauopathy, establishing vascular health as fundamental to preserving brain healthspan.

BACKGROUND:Cognitive decline frequently occurs during typical aging, yet the molecular mechanisms underlying this process remain poorly understood, especially in the absence of classical neuropathology such as amyloid. Vascular dysfunction and increased blood-brain barrier (BBB) permeability have emerged as potential contributors. This study examined whether thromboinflammation, indicated by fibrinogen levels in cerebrospinal fluid (CSF), affects synaptic health and cognition in amyloid-negative, typical aging. METHOD:We measured CSF fibrinogen and synaptic/neurodegenerative markers (pTau, GAP43, NRGN, and SNAP25) in cognitively normal older adults (N = 70). An unbiased proteomic screen (SomaScan 7k) was then performed to identify specific mediators linking fibrinogen to these markers, followed by validation in an independent cohort (N = 482). To assess potential interactions with amyloid pathology, we further examined these mediators in a separate group of amyloid-positive older adults (N = 752). RESULT:Higher CSF fibrinogen was significantly associated with elevated pTau, GAP43, NRGN, and SNAP25, independent of amyloid status. Mediation analysis revealed 14 proteins that consistently linked fibrinogen to neurodegeneration, including factors regulating vascular plasticity and immune activation. Cell-type mapping showed enrichment in endothelial cells, pericytes, and microglia. Results were validated in a large, independent typical aging cohort, confirming core pathways of fibrinogen-mediated neurovascular dysfunction. In the amyloid-positive cohort, vascular-specific mediators were relatively reduced, indicating possibly altered molecular mechanisms in amyloid aging compared with typical aging. CONCLUSION:These findings highlight a thromboinflammatory pathway underlying synaptic decline in typically aging older adults, driven by fibrinogen at the neurovascular interface. Targeting BBB integrity and its vascular-immune signaling may offer therapeutic opportunities to preserve cognition in aging, even in the absence of amyloid pathology.

The communication between the brain, immune and vascular systems is a key contributor to the onset and progression of neurological diseases. We discovered the coagulation factor fibrinogen as a blood-derived driver for neuroinflammation and inhibitor of repair in a wide range of neurologic diseases, such as multiple sclerosis, Alzheimer's disease and brain trauma. We showed that fibrinogen is necessary and sufficient for neurodegeneration and a new culprit for microglia-mediated oxidative stress-dependent spine elimination and cognitive impairment. By developing Tox-Seq, we reported the oxidative stress innate immune cell atlas in neuroinflammation. We developed cutting-edge imaging tools to study brain network synchronization and the neurovascular interface. We discovered a first-in-class fibrin-targeting immunotherapy to selectively target inflammatory functions of fibrin without interference with clotting with potent therapeutic effects in autoimmune- and amyloid-driven neurotoxicity. High throughput drug screens identified small molecule compounds to block fibrin-induced activation of microglia with therapeutic effects in neuroinflammatory disease. These findings could be a common thread for the understanding of the etiology, progression, and new treatments for neurologic diseases with neuroimmune and cerebrovascular dysfunction. As fibrin is a global activator of toxic innate immune responses in the brain and periphery, these studies could provide the basis for the development of a new class of therapeutics for autoimmune and inflammatory diseases1.

Cerebrovascular alterations and innate immune activation are key features of Alzheimer’s disease (AD). However, the mechanisms that link blood-brain barrier disruption to neurodegeneration are poorly understood and well-defined druggable targets at the neurovascular interface are limited. By developing a multiomic and genetic loss-of-function pipeline, we reported the transcriptomic and global phosphoproteomic landscape of blood-induced microglia activation and the causal role for fibrin in induction of neurodegenerative genes and oxidative stress pathways in innate immune cells 1 . Volume imaging in cleared mouse and human AD brains combined with repetitive in vivo two-photon imaging showed focal fibrinogen deposits associated with loss of dendritic spines independent of amyloid plaques. We developed a first-in-class fibrin-targeting immunotherapy to selectively inhibit fibrin-induced inflammation without interfering with its beneficial coagulation effects 2 . We identified the blood coagulation factor fibrinogen as necessary and sufficient for the induction of pathogenic neuroinflammation in neurologic diseases 3 . Fibrinogen induces spine elimination and promotes cognitive deficits in AD mouse models mediated by oxidative stress induction in microglia 4 . Fibrin-targeting immunotherapy entered the CNS, bound to fibrin, and inhibited amyloid-driven neurotoxicity and neurotoxic inflammatory gene programs in AD mice 2 . Thus, fibrinogen links cerebrovascular damage with immune-mediated neurodegeneration and fibrin therapeutics may have important therapeutic implications inhibiting vascular-driven neurodegeneration in AD and related conditions. References 1. Mendiola et al. Nat Immunol 2023, 24:1173-1187 2. Ryu et al. Nat Immunol 2018, 19:1212-1223 3. Petersen et al., Nat Rev Neurosci . 2018, 19:283-301 4. Merlini et al. Neuron 2019, 101:1099-1108

In the coming year, adults with Down syndrome (DS) will be included in Alzheimer's disease (AD) clinical trials involving anti-amyloid immunotherapies. Such therapies have been associated with adverse cerebrovascular events such as amyloid-related imaging abnormalities (ARIA). Moreover, cerebral amyloid angiopathy (CAA) is associated with an increased risk of ARIA. By the age of 40 years, people with DS exhibit AD neuropathology (DSAD) and cerebrovascular disease, including severe CAA, suggesting that individuals with DS may be at increased risk of ARIA. Thus, to better understand their cerebrovascular profile, our main objective is to characterize cerebrovascular pathology in individuals with DS, including blood-brain barrier (BBB) integrity and vascular morphology. Free-floating immunohistochemistry was used to label the basement membrane (BM), blood vessels, pericytes, and fibrin parenchymal deposition in the occipital cortex of adults with DSAD ( n  = 12) and age-matched neurotypical controls ( n  = 12). We measured basement membrane coverage, vessel length, and density, and the number of pericytes and string vessels (also known as collapsed capillaries or connective tissue strands with no endothelial cells) in lamina III-IV. Fibrin deposition in the brain parenchyma was visually scored using whole brain sections. Two-tailed unpaired t-tests, Mann-Whitney, and Fisher's exact test were used accordingly. We are analyzing the same measures in a second and larger autopsy cohort from young (1-33 years old, n  = 14) and old individuals with DS (42-70 years old, n  = 84), late-onset AD (75-90 years old, n  = 33), and age-matched neurotypical controls (2-90 years old, n  = 72). Compared to neurotypical controls, adults with DSAD displayed increased BM coverage [t(18)=2.145, p  = 0.045], vessel density [t(18)=5.277, p  <0.0001] and length [t(18)=3.43, p  = 0.003]. We also found an increased number of string vessels (U=13, p  = 0.0009) and pericytes [t(18)=3, p  = 0.005]. Pericyte per vessel density did not differ between groups [t(18)=1.813, p  = 0.086]. Finally, we found abundant fibrin deposition in DSAD brains compared to controls (3-fold increase, Fisher's exact test, two-tailed, p  = 0.0002). Adults with DS at late stages of AD neuropathology display vascular changes suggestive of vascular remodeling processes and BBB breakdown. The administration of anti-amyloid beta immunotherapies in this population must be carefully evaluated. Funding: NIH-U19AG068054, RF1AG079519, P30AG066519, 23AARFD-1022715.

Vascular dysfunction and subsequent innate immune activation are key players of neurodegenerative, retinal, and inflammatory diseases, including Alzheimer's disease (AD), multiple sclerosis (MS), diabetic retinopathy (DR), and age-related macular degeneration (AMD). At sites of vascular damage, conversion of the blood coagulation protein fibrinogen to fibrin exposes a cryptic inflammatory epitope, γ377–395, which can bind CD11b/CD18 and CD11c/CD18 complement receptors on microglia, macrophages, and dendritic cells. Genetic targeting of the fibrin γ377–395 epitope or its pharmacologic inhibition with the mouse monoclonal antibody 5B8 protects from inflammation and neurodegeneration in AD and MS mouse models. Here, we present the development of THN391, a first-in-class humanized antibody, to neutralize fibrin toxicity without adverse anticoagulant effects for the treatment of neurodegenerative, retinal, and inflammatory diseases. THN391 was affinity matured with 100-fold greater affinity than 5B8, engineered to lack Fc effector function, and have improved developability properties for clinical use. THN391 blocks the interaction of fibrin with CD11b/c and does not bind fibrinogen nor interfere with coagulation, consistent with the crystal structure of its binding interface to the γ377–395 epitope. THN391 and its Fc wild-type counterpart THN313 showed preclinical efficacy in experimental autoimmune encephalomyelitis (EAE) mouse models of MS and in a rodent model of retinal disease. Both THN391 and THN313 reduced demyelination, inflammatory foci, and clinical scores in EAE, demonstrating that anti-fibrin γ377-395 antibodies function as pure antagonists, blocking fibrin from activating CD11b/c complement receptors. THN391 was as effective as the standard of care vascular endothelial growth factor (VEGF) antagonists in reducing laser-induced neovascular lesions in a rat model of neovascular macular degeneration. Taken together, these results support the clinical development of THN391 for neurological diseases and ophthalmic indications.

Cerebellar injury in preterm infants with central nervous system (CNS) hemorrhage results in lasting neurological deficits and an increased risk of autism. The impact of blood-induced pathways on cerebellar development remains largely unknown, so no specific treatments have been developed to counteract the harmful effects of blood after neurovascular damage in preterm infants. Here, we show that fibrinogen, a blood-clotting protein, plays a central role in impairing neonatal cerebellar development. Longitudinal MRI of preterm infants revealed that cerebellar bleeds were the most critical factor associated with poor cerebellar growth. Using inflammatory and hemorrhagic mouse models of neonatal cerebellar injury, we found that fibrinogen increased innate immune activation and impeded neurogenesis in the developing cerebellum. Fibrinogen inhibited sonic hedgehog (SHH) signaling, the main mitogenic pathway in cerebellar granule neuron progenitors (CGNPs), and was sufficient to disrupt cerebellar growth. Genetic fibrinogen depletion attenuated neuroinflammation, promoted CGNP proliferation, and preserved normal cerebellar development after neurovascular damage. Our findings suggest that fibrinogen alters the balance of SHH signaling in the neurovascular niche and may serve as a therapeutic target to mitigate developmental brain injury after CNS hemorrhage.

The brain-vascular-immune interface has emerged as a dynamic player in brain physiology and disease. We propose integrating vascular risk factors with genetic susceptibility as the nexus for the discovery of mechanisms and therapies for neuroinflammation, neurodegeneration, and neurorepair across polygenic neurologic diseases.

Background: 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. Methods: 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. Results: 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). Conclusions: 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.

Life-threatening thrombotic events and neurological symptoms are prevalent in COVID-19 and are persistent in patients with long COVID experiencing post-acute sequelae of SARS-CoV-2 infection1-4. Despite the clinical evidence1,5-7, the underlying mechanisms of coagulopathy in COVID-19 and its consequences in inflammation and neuropathology remain poorly understood and treatment options are insufficient. Fibrinogen, the central structural component of blood clots, is abundantly deposited in the lungs and brains of patients with COVID-19, correlates with disease severity and is a predictive biomarker for post-COVID-19 cognitive deficits1,5,8-10. Here we show that fibrin binds to the SARS-CoV-2 spike protein, forming proinflammatory blood clots that drive systemic thromboinflammation and neuropathology in COVID-19. Fibrin, acting through its inflammatory domain, is required for oxidative stress and macrophage activation in the lungs, whereas it suppresses natural killer cells, after SARS-CoV-2 infection. Fibrin promotes neuroinflammation and neuronal loss after infection, as well as innate immune activation in the brain and lungs independently of active infection. A monoclonal antibody targeting the inflammatory fibrin domain provides protection from microglial activation and neuronal injury, as well as from thromboinflammation in the lung after infection. Thus, fibrin drives inflammation and neuropathology in SARS-CoV-2 infection, and fibrin-targeting immunotherapy may represent a therapeutic intervention for patients with acute COVID-19 and long COVID.

Abstract Background Traumatic brain injury (TBI) causes significant blood-brain barrier (BBB) breakdown, resulting in the extravasation of blood proteins into the brain. The impact of blood proteins, especially fibrinogen, on inflammation and neurodegeneration post-TBI is not fully understood, highlighting a critical gap in our comprehension of TBI pathology and its connection to innate immune activation. Methods We combined vascular casting with 3D imaging of solvent-cleared organs (uDISCO) to study the spatial distribution of the blood coagulation protein fibrinogen in large, intact brain volumes and assessed the temporal regulation of the fibrin(ogen) deposition by immunohistochemistry in a murine model of TBI. Fibrin(ogen) deposition and innate immune cell markers were co-localized by immunohistochemistry in mouse and human brains after TBI. We assessed the role of fibrinogen in TBI using unbiased transcriptomics, flow cytometry and immunohistochemistry for innate immune and neuronal markers in Fggγ390–396A knock-in mice, which express a mutant fibrinogen that retains normal clotting function, but lacks the γ390–396 binding motif to CD11b/CD18 integrin receptor. Results We show that cerebral fibrinogen deposits were associated with activated innate immune cells in both human and murine TBI. Genetic elimination of fibrin-CD11b interaction reduced peripheral monocyte recruitment and the activation of inflammatory and reactive oxygen species (ROS) gene pathways in microglia and macrophages after TBI. Blockade of the fibrin-CD11b interaction was also protective from oxidative stress damage and cortical loss after TBI. Conclusions These data suggest that fibrinogen is a regulator of innate immune activation and neurodegeneration in TBI. Abrogating post-injury neuroinflammation by selective blockade of fibrin’s inflammatory functions may have implications for long-term neurologic recovery following brain trauma.