Biology subjects

Janson, C.

Publications and source records attributed to Janson, C..

5 recordsLinked to original sources

bioRxiv2026

Proteomic analysis of human leptomeningeal matrisome identifies changes in Alzheimer's disease

The leptomeninges (arachnoid and pia) are the inner layers of the meninges that envelope the brain. They define the borders of the subarachnoid space (SAS) where cerebrospinal fluid (CSF) circulates. Leptomeninges act as the barrier tissue and contribute to fluid exchange and immune function of the brain. These processes are identified as key factors in the development of neurodegenerative diseases. The extracellular matrix (ECM) is a critical structural component of leptomeninges. However, it remains insufficiently characterized in health and disease. Here, we performed complete proteomic profiling of ECM proteins (matrisome) of human leptomeninges from individuals with Alzheimers disease (AD) and cognitively normal controls (CN) using sequential biochemical fractionation coupled with mass spectrometry. We resolved leptomeningeal matrisome based on the biochemical properties reflected by the protein solubility. This approach identified 211 ECM proteins in human leptomeninges and revealed disease-associated shifts in leptomeningeal solubility consistent with altered matrix organization and signaling. We found that ECM-linked regulators and secreted factors extracellular sulfatase SULF2, antithrombin-III (SERPINC1), secreted frizzled-related protein 3 (sFRP3) and integrin beta-5 (ITGB5), which is a receptor for fibronectin, were differentially expressed in AD leptomeninges based on the disease status. Seven ECM proteins were identified only in AD samples, and two ECM proteins in CN samples. Pathway enrichment implicated TGF-{beta} and Wnt-related signaling and coagulation as critical for leptomeningeal function. Our findings provide the first comprehensive proteomic characterization of the human leptomeningeal matrisome and establish a biochemical framework for investigating how meningeal matrix remodeling contributes to AD.

neuroscience↗

bioRxiv2026

Proximity labeling reveals unique and shared interactomes of unmodified and pyroglutamate amyloid beta in human hippocampus in Alzheimers disease

Amyloid plaques are a hallmark neuropathological feature of Alzheimers disease (AD), composed of insoluble amyloid beta (A{beta}) peptide. A{beta} undergoes post-translational modifications that alter their biophysical properties, aggregation kinetics, and neurotoxicity, creating a heterogeneous pool of species that differentially affect AD pathogenesis. Pyroglutamate-modified A{beta} (pEA{beta}) is a particularly aggregation-prone and proteolytically resistant variant that preferentially accumulates within plaque cores, is implicated in early plaque seeding, and is a major target of emerging anti-amyloid immunotherapies. However, the molecular environment surrounding pEA{beta} versus unmodified A{beta} (pan-A{beta}) in the human hippocampus remains incompletely defined. Here, we used Biotinylation by Antibody Recognition (BAR), an in-situ proximity labeling approach, to map and compare the protein-protein interactions (proteomes) of pEA{beta} and pan-A{beta} in formalin-fixed postmortem human hippocampal tissue from pathologically confirmed AD cases and cognitively normal (CN) controls. Differential proteomic analysis identified 48 significantly enriched proteins in AD pEA{beta} captures, 28 in AD pan-A{beta} captures, and 15 in CN pan-A{beta} captures. Whereas no significant enrichment was detected in CN pEA{beta} captures, supporting pEA{beta} as a pathology-associated species. pEA{beta} in AD demonstrated the largest variant-specific signature with 31 unique proteins, pan-A{beta} showed 11 unique proteins in AD, and 14 unique proteins in CN, 16 proteins were shared between AD pEA{beta} and AD pan-A{beta}, with PCSK1N shared across AD pEA{beta}, and AD/CN pan-A{beta}. Pathway enrichment analysis revealed broader biological disruptions linked to pEA{beta}, including synaptogenesis signaling, clathrin-mediated endocytosis, mitochondrial division signaling, and neurotransmitter release. Shared pathways included SNARE signaling, glutamatergic receptor signaling, and netrin signaling. These findings demonstrate that pEA{beta} engages an expanded, variant-specific interactome in human AD hippocampus and designate intracellular trafficking, synaptic signaling, and mitochondrial pathways as network-level vulnerabilities relevant to pEA{beta} pathology in AD. Notably, comparison of CN versus AD pan-A{beta} further distinguished protein networks associated with physiological A{beta} engagement versus pathological pan-A{beta} deposition.

neuroscience↗

bioRxiv2026

Rapid functional classification of cardiac genetic variants directly informs precision cardiology

Large-scale clinical genome sequencing yields vast numbers of variants of unknown significance (VUSs). The high frequency of VUSs and the paucity of platforms to characterize their functional impact pose significant challenges for clinical decision making. Here, we present an integrated end-to-end platform, REVi-SCOPE (Rapid evaluation of variants in single cells by optogenetics and prime editing), for characterization of the impact of VUSs on cardiac physiology. Our strategy consists of (1) introduction of variants directly into wild-type (WT) human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) via prime editing; (2) optogenetic assessment of calcium and membrane voltage dynamics in single hiPSC-CMs within the pool of edited and unedited cells; and (3) in situ single-cell genotyping of the phenotyped hiPSC-CMs with single-allele resolution. By optimizing and integrating each of these steps, we created a platform that enables VUS characterization in 10 days. We validated the REVi-SCOPEs capabilities by analyzing the properties of established arrhythmogenic variants. We then used REVi-SCOPE to reveal the functional impact of a VUS, TRPM4A320V, identified in a child with a conduction block. Together, our results show that REVi-SCOPE enables functional characterization of VUSs linked to cardiac arrhythmias with unprecedented throughput.

bioengineering↗

bioRxiv2022

Characterization of non-human primate dura in health and neurodegeneration

Brain meninges and associated vasculature participate in brain clearance and are implicated in many neurological conditions such as Alzheimers disease, meningitis, multiple sclerosis, stroke, and traumatic brain injury. However, most of our knowledge concerning brain clearance via meninges is based on rodent data, and relevance to human disease remains unclear. One of the technical barriers in studies of meningeal physiology in health and disease is that existing imaging modalities are suboptimal for large and optically non-transparent meningeal tissue of humans and non-human primate (NHP) animal models. To address this barrier, we performed first characterization of NHP dura by high resolution confocal microscopy of clarified tissue. We investigated vascular structures and resident cells in normal monkeys and primate models of tauopathy and synucleinopathy. We demonstrated the presence of an extensive meningeal vascular network covering the entire tissue surface with resolution to the smallest capillaries. This is also the first work to map lymphatic vessels in the dura of non-human primate (NHP). Overall, the NHP lymphatic meningeal system resembles the anatomy found in rat dura, but it is more complex. Analysis of dura from NPH models of tauopathy and synucleinopathy revealed an association with disease-specific biomarkers (amyloid, tau, -synuclein) with both the blood and lymphatic vasculature. This work has broad relevance to many brain diseases where solute accumulation and abnormal macromolecular clearance is a part of the pathogenesis.

neuroscience↗

bioRxiv2019

Energy-dependent transport at dural lymphatic vessels is necessary for Aβ brain clearance in Alzheimer's disease

Viewed as an imbalance between production and clearance of toxic A{beta} peptides, Alzheimers disease is a candidate for therapies to augment brain waste removal. Prior work has shown that A{beta} accumulates in meninges with aging as a byproduct of normal brain activity, in parallel with build-up of A{beta} oligomers in neurons, blood vessels, and interstitial fluid. Using the TgF344-AD rat model of Alzheimers disease, we now report that dural lymphatic vessels specifically accumulate neurotoxic pyroglutamate amyloid beta (pE3-A{beta}) with aging. Notably, accelerated amyloidosis is observed in meninges after ligation of cervical lymphatics, together with significantly increased pE3-A{beta} and A{beta}42 deposition in upstream brain regions implicated in Alzheimers disease. Blockade of lymphatic clearance is not sufficiently compensated by other efflux pathways, suggesting a necessary role of A{beta} clearance at the level of lymphatics. We further report that dural lymphatic cells actively clear A{beta} via energy-dependent mechanisms, and lymphatic A{beta} transport is significantly impaired both in normal aging and in Alzheimers disease. Dural lymphatic cells isolated from the TgF344-AD rat show ultrastructural abnormalities in mitochondria and abnormal cytoplasmic inclusions, with a distinct transcriptional profile implicating failure of energy-dependent transport. Finally, using human meninges treated with FocusDeep tissue clearing, we demonstrate using whole mount panoramic imaging that dural lymphatic vessels comprise a structurally diverse intracranial vascular network that accumulates pE3-A{beta} with aging, similar to the rat model. We conclude that intracranial meningeal and extracranial cervical lymphatic vessels are targets for Alzheimers disease therapies focused on improving amyloid clearance. One Sentence SummaryLymphatic vessels remove A{beta} from the brain via energy-dependent active transport mechanisms, and blockage of extracranial lymphatic drainage is sufficient to cause significant acceleration of intracranial Alzheimers A{beta} pathology in both meninges and brain.

biochemistry↗