Biology subjects

Keller, J. N.

Publications and source records attributed to Keller, J. N..

4 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↗

bioRxiv2025

A Functional Resting-State Network Atlas Based on 420 Older Adults with Hypertension

The Risk Reduction for Alzheimers Disease (rrAD) trial included 513 cognitively normal, sedentary, hypertensive older adults (aged 60 to 85 years) with dementia risk factors. We utilized 420 high-quality baseline resting-state functional MRI (rs-fMRI) scans from this cohort to develop a functional atlas tailored for aging populations. Typical rs-fMRI atlases derived from healthy young adults do not account for age-related changes, such as cortical atrophy, enlarged ventricles, and altered connectivity. To address this gap, we created a cohort-specific MNI-adjacent anatomical template, rrAD420, using SPM12s DARTEL registration. In this space, we derived a comprehensive functional atlas using both group independent component analysis (GICA) and probabilistic functional mode decomposition (PROFUMO). The rrAD420 atlas offers detailed representations of Resting-State Network (RSN) connectivity, encompassing unique configurations and overlapping interactions. It features two Default-Mode Network (DMN)-specific seed-based maps (DMN24 with cerebellum, DMN18 without) and data-driven components resembling the major RSNs. Furthermore, PROFUMO allowed for the identification of multimodal and combinatory networks, capturing connections within and between RSNs. While optimized for hypertensive older adults, the rrAD420 atlas serves as a versatile tool for broader aging populations, aiding in the study of neurodegenerative processes and biomarker discovery.

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↗

bioRxiv2024

Plasma Proteomics of Genetic Brain Arteriosclerosis and Dementia Syndrome Identifies Signatures of Fibrosis, Angiogenesis, and Metabolic Alterations

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of vascular cognitive impairment and dementia. A genetic arteriolosclerotic disease, the molecular mechanisms driving vascular brain degeneration and decline remain unclear. With the goal of driving discovery of disease-relevant biological perturbations in CADASIL, we used machine learning approaches to extract proteomic disease signatures from large-scale proteomics generated from plasma collected from three distinct cohorts in US and Colombia: CADASIL-Early (N = 53), CADASIL-Late (N = 45), and CADASIL-Colombia (N = 71). We extracted molecular signatures with high predictive value for early and late-stage CADASIL and performed robust cross- and external-validation. We examined the biological and clinical relevance of our findings through pathway enrichment analysis and testing of associations with clinical outcomes. Our study represents a model for unbiased discovery of molecular signatures and disease biomarkers, combining non-invasive plasma proteomics with clinical data. We report on novel disease-associated molecular signatures for CADASIL, derived from the accessible plasma proteome, with relevance to vascular cognitive impairment and dementia.

neuroscience↗