Biology subjects

Akassoglou, K.

Publications and source records attributed to Akassoglou, K..

6 recordsLinked to original sources

bioRxiv2026

Resilience to neuronal hyperactivity and restoration of the neuroimmune interactome by blocking fibrin-induced microglia activation in Alzheimers disease

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 submitted to bioRxiv (Lauderdale et al., 2026) HighlightsO_LIVascular-microglia axis drives neuronal hyperactivity C_LIO_LIFibrin inflammatory activity disrupts the microglia-neuron interactome C_LIO_LIMicroglia activation by fibrin impairs decision-making in AD mice C_LIO_LISynaptic dysfunction and immune biomarkers correlate with CSF fibrinogen in AD patients C_LI

neuroscience↗

bioRxiv2026

Therapeutic targeting of fibrin-microglia interactions ameliorates Alzheimer disease-related hyperexcitability and brain network dysfunction

Brain network dysfunction--including hyperexcitability, altered oscillations, and sleep disruption--is prominent in Alzheimers 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 (Fgg{gamma}390-396A 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;Fgg{gamma}390-396A 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 HIGHLIGHTSO_LIFibrin promotes AD-related network hyperexcitability and oscillatory slowing in 5xFAD mice C_LIO_LIFibrin promotes AD-related disruption of sleep and circadian rhythms in 5xFAD mice C_LIO_LIGenetic blocking of fibrin-microglia interactions rescues AD-related brain network dysfunction C_LIO_LIAnti-fibrin antibodies (5B8 and THN392) show acute and chronic therapeutic benefit C_LI

neuroscience↗

bioRxiv2025

A proteomic signature of vascular dysfunction linked to tauopathy and degeneration in the aging brain

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 fibrinogens 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.

neuroscience↗

bioRxiv2023

A novel mouse model of cerebral adrenoleukodystrophy highlights NLRP3 activity in lesion pathogenesis

ObjectiveWe sought to create and characterize a mouse model of the inflammatory, cerebral demyelinating phenotype of X-linked adrenoleukodystrophy (ALD) that would facilitate the study of disease pathogenesis and therapy development. We also sought to cross-validate potential therapeutic targets such as fibrin, oxidative stress, and the NLRP3 inflammasome, in post-mortem human and murine brain tissues. BackgroundALD is caused by mutations in the gene ABCD1 encoding a peroxisomal transporter. More than half of males with an ABCD1 mutation develop the cerebral phenotype (cALD). Incomplete penetrance and absence of a genotype-phenotype correlation imply a role for environmental triggers. Mechanistic studies have been limited by the absence of a cALD phenotype in the Abcd1-null mouse. MethodsWe generated a cALD phenotype in 8-week-old, male Abcd1-null mice by deploying a two-hit method that combines cuprizone (CPZ) and experimental autoimmune encephalomyelitis (EAE) models. We employed in vivo MRI and post-mortem immunohistochemistry to evaluate myelin loss, astrogliosis, blood-brain barrier (BBB) disruption, immune cell infiltration, fibrin deposition, oxidative stress, and Nlrp3 inflammasome activation in mice. We used bead-based immunoassay and immunohistochemistry to evaluate IL-18 in CSF and post-mortem human cALD brain tissue. ResultsMRI studies revealed T2 hyperintensities and post-gadolinium enhancement in the medial corpus callosum of cALD mice, similar to human cALD lesions. Both human and mouse cALD lesions shared common histologic features of myelin phagocytosis, myelin loss, abundant microglial activation, T and B-cell infiltration, and astrogliosis. Compared to wild-type controls, Abcd1-null mice had more severe cerebral inflammation, demyelination, fibrin deposition, oxidative stress, and IL-18 activation. IL-18 immunoreactivity co-localized with macrophages/microglia in the perivascular region of both human and mouse brain tissue. InterpretationThis novel mouse model of cALD suggests loss of Abcd1 function predisposes to more severe cerebral inflammation, oxidative stress, fibrin deposition, and Nlrp3 pathway activation, which parallels the findings seen in humans with cALD. We expect this model to enable long-sought investigations into cALD mechanisms and accelerate development of candidate therapies for lesion prevention, cessation, and remyelination. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/564025v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1fbfebforg.highwire.dtl.DTLVardef@111e1e8org.highwire.dtl.DTLVardef@10647eborg.highwire.dtl.DTLVardef@15b9af4_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Extensive and Persistent Extravascular Dermal Fibrin Deposition Characterizes Systemic Sclerosis

Systemic sclerosis (SSc) is an autoimmune disease characterized by progressive multiorgan fibrosis. While the cause of SSc remains unknown, a perturbed vasculature is considered a critical early step in the pathogenesis. Using fibrinogen as a marker of vascular leakage, we found extensive extravascular fibrinogen deposition in the dermis of both limited and diffuse systemic sclerosis disease, and it was present in both early and late-stage patients. Based on a timed series of excision wounds, retention on the fibrin deposit of the splice variant domain, fibrinogen EC, indicated a recent event, while fibrin networks lacking the EC domain were older. Application of this timing tool to SSc revealed considerable heterogeneity in EC domain distribution providing unique insight into disease activity. Intriguingly, the fibrinogen-EC domain also accumulated in macrophages. These observations indicate that systemic sclerosis is characterized by ongoing vascular leakage resulting in extensive interstitial fibrin deposition that is either continually replenished and/or there is impaired fibrin clearance. Unresolved fibrin deposition might then incite chronic tissue remodeling.

pathology↗

bioRxiv2021

SARS-CoV-2 spike protein induces abnormal inflammatory blood clots neutralized by fibrin immunotherapy

Blood clots are a central feature of coronavirus disease-2019 (COVID-19) and can culminate in pulmonary embolism, stroke, and sudden death. However, it is not known how abnormal blood clots form in COVID-19 or why they occur even in asymptomatic and convalescent patients. Here we report that the Spike protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) binds to the blood coagulation factor fibrinogen and induces structurally abnormal blood clots with heightened proinflammatory activity. SARS-CoV-2 Spike virions enhanced fibrin-mediated microglia activation and induced fibrinogen-dependent lung pathology. COVID-19 patients had fibrin autoantibodies that persisted long after acute infection. Monoclonal antibody 5B8, targeting the cryptic inflammatory fibrin epitope, inhibited thromboinflammation. Our results reveal a procoagulant role for the SARS-CoV-2 Spike and propose fibrin-targeting interventions as a treatment for thromboinflammation in COVID-19. One-Sentence SummarySARS-CoV-2 spike induces structurally abnormal blood clots and thromboinflammation neutralized by a fibrin-targeting antibody.

immunology↗