Biology subjects

Abisambra, J. F.

Publications and source records attributed to Abisambra, J. F..

6 recordsLinked to original sources

bioRxiv2026

PERK Deficiency Amplifies Molecular, Structural, and Network Vulnerability to Repetitive Mild Traumatic Brain Injury

Repetitive mild traumatic brain injury (rmTBI) produces cumulative cellular stress that can lead to progressive brain dysfunction, yet the mechanisms governing vulnerability to repeated injury remain unclear. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) regulates cellular proteostasis through the unfolded protein response and is implicated in neurodegeneration and acute brain injury. Here, we directly tested the role of PERK deficiency in shaping the brains response to rmTBI. Using a mouse model of neuronal PERK deficiency, we combined spatial proteomics and tissue analyses with resting-state functional MRI and diffusion tensor imaging to assess molecular, functional, and structural outcomes after rmTBI. PERK deficiency increased susceptibility to rmTBI-induced disruption of protein homeostasis, altered large-scale functional connectivity, and exacerbated white matter microstructural changes consistent with axonal and myelin damage. Molecular alterations were spatially aligned with imaging-defined network and white matter abnormalities. These findings identify PERK signaling as a key determinant of brain resilience to repetitive mild injury and link ER stress dysregulation to network-level dysfunction following rmTBI.

neuroscience↗

bioRxiv2024

Interrogating the plasma proteome of repetitive head impact exposure and chronic traumatic encephalopathy

BackgroundExposure to repetitive head impacts (RHI) is associated with increased risk for chronic traumatic encephalopathy (CTE), a neurodegenerative tauopathy, and other neuropathological changes. Biological drivers of RHI-related neurodegeneration are not well understood. We interrogated the plasma proteome in aging adults with prior RHI compared to healthy controls (CTL) and individuals with Alzheimers disease (AD), including a subset characterized neuropathologically at autopsy. MethodsProximity extension assay (Olink Explore(R)) quantified 2,779 plasma proteins in 22 RHI patients (all AD-biomarker negative), 39 biomarker-confirmed AD, and 44 CTL. A subset of participants went to autopsy (N=16) allowing for comparisons of the antemortem plasma proteome between autopsy-confirmed CTE+ (N=7) and CTE-(N=9). Differential abundance and co-expression network analyses identified plasma proteomic signatures of RHI, which were functionally annotated using gene ontology and cell type enrichment analysis. Nonparametric correlations examined plasma proteomic associations with orthogonally-measured plasma biomarkers, global cognitive function, and semi-quantitative ratings of neuropathology burden at autopsy. ResultsDifferential abundance analysis revealed 434 increased (vs. 6 decreased) proteins in RHI vs. CTL and 193 increased (vs. 14 decreased) in RHI vs. AD. Network analysis identified 9 protein co-expression modules (M1-M9), of which 7 were elevated in RHI compared to AD or CTL. Modules with increased abundance in RHI were enriched for mitochondrial/metabolic, cell division, and immunovascular (e.g., cell adhesion, TNF-signaling) processes. RHI-related modules exhibited strong and selective correlations with immunoassay-based plasma IL-6 in RHI cases, including the M2 TNF-signaling/cell adhesion module which harbored proteins that strongly tracked with cognitive function. RHI-related plasma protein signatures were similar in the subset of participants with autopsy-confirmed CTE, including immune and metabolic modules that positively correlated with medial temporal lobe tau and TDP-43 burden. ConclusionsMolecular pathways in plasma most consistently implicated in RHI were tied to immune response, mitochondrial function, and cell metabolism. RHI-related proteomic signatures tracked with antemortem cognitive severity and postmortem neuropathological burden, providing converging evidence for their role in disease progression. Differentially abundant proteins and co-expression modules in RHI may inform mechanisms linking RHI to increased dementia risk, thus guiding diagnostic biomarker and therapeutic development for at-risk populations.

molecular biology↗

bioRxiv2024

Age dictates brain functional connectivity and axonal integrity following repetitive mild traumatic brain injuries

Traumatic brain injuries (TBI) present a major public health challenge, demanding an in-depth understanding of age-specific signs and vulnerabilities. Aging not only significantly influences brain function and plasticity but also elevates the risk of hospitalizations and death following repetitive mild traumatic brain injuries (rmTBIs). In this study, we investigate the impact of age on brain network changes and white matter properties following rmTBI employing a multi-modal approach that integrates resting-state functional magnetic resonance imaging (rsfMRI), graph theory analysis, diffusion tensor imaging (DTI), and Neurite Orientation Dispersion and Density Imaging (NODDI). Utilizing the CHIMERA model, we conducted rmTBIs or sham (control) procedures on young (2.5-3 months old) and aged (22-month-old) male and female mice to model high risk groups. Functional and structural imaging unveiled age-related reductions in communication efficiency between brain regions, while injuries induced opposing effects on the small-world index across age groups, influencing network segregation. Functional connectivity analysis also identified alterations in 79 out of 148 brain regions by age, treatment (sham vs. rmTBI), or their interaction. Injuries exerted pronounced effects on sensory integration areas, including insular and motor cortices. Age-related disruptions in white matter integrity were observed, indicating alterations in various diffusion directions (mean, radial, axial diffusivity, fractional anisotropy) and density neurite properties (dispersion index, intracellular and isotropic volume fraction). Inflammation, assessed through Iba-1 and GFAP markers, correlated with higher dispersion in the optic tract, suggesting a neuroinflammatory response in aged animals. These findings provide a comprehensive understanding of the intricate interplay between age, injuries, and brain connectivity, shedding light on the long-term consequences of rmTBIs.

neuroscience↗

bioRxiv2023

Spatial Metabolome Lipidome and Glycome from a Single brain Section

Metabolites, lipids, and glycans are fundamental biomolecules involved in complex biological systems. They are metabolically channeled through a myriad of pathways and molecular processes that define the physiology and pathology of an organism. Here, we present a blueprint for the simultaneous analysis of spatial metabolome, lipidome, and glycome from a single tissue section using mass spectrometry imaging. Complimenting an original experimental protocol, our workflow includes a computational framework called Spatial Augmented Multiomics Interface (Sami) that offers multiomics integration, high dimensionality clustering, spatial anatomical mapping with matched multiomics features, and metabolic pathway enrichment to providing unprecedented insights into the spatial distribution and interaction of these biomolecules in mammalian tissue biology.

systems biology↗

bioRxiv2022

Brain mapping and spatial protein profiling reveal functional connectivity deficits and molecular changes following repetitive mild traumatic brain injury in wild-type mice.

Repetitive mild traumatic brain injury (rmTBI) is a leading and severe threat to cognition that often goes undiagnosed. A major challenge in developing diagnostics and treatments for the consequences of rmTBI is the fundamental knowledge gaps that explain how rmTBI promotes brain dysfunction. It is both critical and urgent to understand the neuropathological and functional consequences of rmTBI to develop effective therapeutic strategies. In this study, we sought to define the extent of altered brain functional connectivity (FC) and expression of neuropathological markers after rmTBI. We performed two rmTBI (2x 0.6{square}J impacts 24{square}h apart) in male and female C57BL/6J wild-type (WT) (~2.5-3mo) mice using closed head injury model of engineered rotational acceleration (CHIMERA) or sham procedures. At 5-6 days post-injury (dpi), we measured changes in brain volume and FC using T2-weighted images, resting-state functional MRI (rsfMRI), and graph theory analyses. We used diffusion tensor imaging (DTI) to assess microstructural changes in white matter tracts. In addition, at 7dpi, we measured changes in Iba1 and GFAP to determine the extent of gliosis. The expression of disease-associated protein markers in grey and white matter regions were evaluated using the NanoString-GeoMx digital spatial protein profiling (DSP) platform. The rsfMRI data revealed aberrant changes in connectivity such as node clustering coefficient, global and local efficiency, participation coefficient, eigenvector centrality, and betweenness centrality in thalamus and other key brain regions that process visual, auditory, and somatosensory information. In addition, DTI revealed significantly decreased fractional anisotropy (FA) and axial diffusivity in the optic tract. Also, mean, radial, and axial diffusivity (L1) were significantly increased in the hippocampus. DSP revealed that phospho-serine 199 tau (pS199) as well as glial markers such as GFAP, cathepsin-D, and Iba1 were significantly increased in the optic tract. In thalamic nuclei, the neuroinflammatory marker GPNMB was increased significantly, and the cell proliferation marker Ki-67 was decreased in the rmTBI group. Our data suggest that rmTBI significantly alters brain functional connectivity and causes a profound inflammatory response in gray matter regions, beyond chronic white matter damage.

neuroscience↗

bioRxiv2020

Novel therapeutic targets to mitigate early neuronal dysfunction and cognitive deficits in tauopathy

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline, and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging technique called manganese-enhanced magnetic resonance imaging (MEMRI) with quantitative R1 mapping. Surprisingly, these benefits occurred despite unchanged hyperphosphorylated tau levels. To elucidate the mechanism behind these improved cognitive outcomes, we performed quantitative proteomics to determine the altered protein network during this early stage in tauopathy and compare this model with the human AD proteome. We identified a cluster of preserved pathways shared with human tauopathy with striking potential for broad multi-target kinase intervention. We further report high confidence candidate proteins as novel therapeutically relevant targets for the treatment of tauopathy. One Sentence SummaryMulti-target kinase inhibition rescues cognitive function in early stage tauopathy mice and reverses proteomic shifts common to Alzheimers disease in humans.

neuroscience↗