Biology subjects

Wegmann, S.

Publications and source records attributed to Wegmann, S..

11 recordsLinked to original sources

bioRxiv2026

Acute exposure of mouse and human hippocampal slices to tau oligomers reversibly impairs sharp-wave ripples

Sharp-wave ripple (SWR) oscillations are crucial for memory consolidation and deteriorate in Alzheimers disease (AD). Tau oligomers are suggested to lead to synaptic and neuronal degeneration in AD, but their effects on SWRs are unknown. To study this, we prepared mouse and human hippocampal slices and bath-applied tau oligomer preparations after spontaneous SWR generation. In human slices, acute exposure to tau resulted in decreased ripple duration, whereas in mouse slices it was SWR rate, amplitude, and power that decreased, sparing duration. In a different set of experiments, mouse slices were pre-incubated directly in either tau-ACSF or control-ACSF right after slicing for 2.5-5.5 hours, resulting only in diminished SWR rate. These effects were specific to the presence of {beta}-sheets, as a different tau preparation that lacked {beta}-sheets failed to alter SWRs. This method is therefore suitable to study SWR alterations after short-term exposure to different tau and/or A{beta} species, allows a higher throughput screening of possible therapeutics compared to in vivo animal experiments, and permits direct comparison of SWR alterations in mice and humans.

neuroscience↗

bioRxiv2026

Inhomogeneous Tau polymerization, core-shell organization, and seed formation during Tau condensate aging

Several proteins aggregating in neurodegenerative diseases spontaneously segregate into liquid condensates, which can catalyze protein aggregation. How liquid-solid transitions are catalyzed in the confined condensate volume is not clear. For the microtubule associated protein Tau, aggregating intra-neuronally in Alzheimer's disease, we show that, during maturation, Tau condensates convert into elastic protein networks, accompanied by inhomogeneous polymerization of the condensate interior and the formation of high-density nodes and a 'shell'. During condensation, Tau molecules extend, favoring intermolecular interactions and priming for progressive parallel Tau arrangement that can enable amyloid-like Tau oligomerization. In cells, aged condensates seed small Tau clusters in cytosol and at the nuclear envelope, precursors of larger aggregates. By bridging molecular to condensate level, we present mechanistic insight into how Tau condensates evolve into pathological, beta-structure containing seeds. The interior of aged Tau condensates remains accessible for smaller molecules, providing the opportunity to molecularly target Tau seed formation inside condensates.

biochemistry↗

bioRxiv2026

A calcium imaging pipeline to detect and quantify compound-specific effects in human and mouse astrocytes and astrocyte-neuron cocultures

Astrocytes are crucial mediators of diverse aspects of brain function, including energy metabolism and synapse formation and maturation. Calcium is the primary information carrier in astrocytes, reporting cellular health and activity, and can be measured using fluorescent indicators. However, this readout is not yet widely used to screen and evaluate disease models and drug candidates. Here, we adapted a simple automated calcium imaging pipeline with key output parameters that characterize changes in astrocytic calcium signaling. We compared calcium responses in mouse astrocyte monocultures and astrocyte-neuron cocultures using GFAP-driven membrane-targeted GCaMP6f, with human astrocytes differentiated from two different induced pluripotent stem-cell lines using the calcium dye Cal520-AM. Event-based analysis reported similarities and differences in mean fluorescence, amplitude, frequency, duration, and area of calcium responses. We benchmarked the pipeline using the purinergic receptor agonist ATP to increase astrocyte activity, and the ER calcium pump blocker CPA to decrease activity across all culture models. Glutamatergic and serotonergic receptor function was tested with glutamate and lysergic acid diethylamide (LSD). LSD decreased activity in mouse cocultured astrocytes, but increased activity in human astrocytes. Furthermore, the addition of human recombinant Tau oligomers, an in vitro model of Alzheimers disease pathology, decreased activity in both mouse and human astrocytes. This pipeline can be used to quickly and easily characterize effects of astrocyte-targeting compounds, effects of non-astrocyte-targeting compounds on astrocyte activity, and rescue of disease models that affect astrocyte function, in mouse and human astrocytes and astrocyte-neuron cocultures.

neuroscience↗

bioRxiv2025

Tau interactions with inner nuclear envelope proteins modulates chromatin

Abstract/SummaryThe intracellular re-distribution of the neuronal microtubule-associated protein Tau, from the axon into the somatodendritic compartment, is a physiological stress-related event and occurs early in Alzheimers disease (AD). Nuclear envelope distortions have been linked to the presence and aggregation of pathological Tau near the nucleus in these diseases. How physiologically increased soma Tau levels, enabling Tau interactions with the nucleus, impact nuclear integrity and neuronal physiology is unclear. Combining proximity biotinylation interactomics with chromatin imaging and molecular assays, we show that soluble Tau interacts with proteins coordinating chromatin at the inner nuclear membrane, including lamin B receptor and SUN1. This interaction promotes nuclear envelope invaginations and damage and changes the coordination of DNA at the nuclear lamina. Increasing somatodendritic Tau is sufficient to upregulate the expression of multiple transcription factors implicated in AD pathogenesis and to reduce expression of genes involved in cholesterol biosynthesis, which seem coordinated at lamin associated domains. These nuclear envelope-related mechanisms suggest that physiological, neuronal stress-related somatodendritic Tau missorting can initiate chromatin-related cascades important for early changes in AD and tauopathies.

neuroscience↗

bioRxiv2025

Membrane protein condensates polymerize actin and form filopodia

Neuronal morphogenesis is guided by filopodia, dynamically generated plasma membrane protrusions filled with parallel actin filaments. However, how filopodial actin filaments are locally produced, organized, and maintained remains unclear. The transmembrane protein PLPPR3 induces filopodia in neurons and other cells. We find that the intracellular domain (ICD) of PLPPR3 forms liquid condensates, which exhibit strong co-partitioning of actin monomers. These condensates promote actin polymerization within the condensates at the expense of actin monomers in the environment, consistent with thermodynamic coupling of actin partitioning and polymerization, which we recapitulate in a modified polymerization kinetics model. This mechanism requires favorable actin partitioning into the condensate relative to the environment. Using crosslinking mass spectrometry, we identify a WH2-like actin-affinity domain within the PLPPR3 ICD. Deleting this domain lowers actin partitioning in vitro and decreases filopodia formation in vivo. Our findings establish a previously unrecognized mechanism for actin network remodeling, in which condensates act as actin sinks, locally boosting monomer concentrations and facilitating polymerization of actin filaments. One sentence summaryOur study uncovers PLPPR3 condensates to locally enrich actin monomers and promote actin polymerization, driving actin network remodeling and neuronal filopodia formation.

cell biology↗

bioRxiv2025

Direct binding of TDP-43 and Tau drives their co-condensation, but suppresses Tau fibril formation and seeding

Neuronal Tau aggregates are a hallmark of Alzheimers disease (AD), but more than half of the patients exhibit additional TDP-43 inclusions and some have co-aggregates of both proteins. The presence of Tau/TDP-43 co-pathology is associated with increased disease severity, although the causal relationship remains unclear. Here we demonstrate that Tau and TDP-43 mutually promote each others condensation through direct interaction in vitro, forming irregularly shaped or multiphasic co-condensates with lower TDP-43 mobility, but higher Tau dynamics. While Tau promotes TDP-43 aggregation in vitro, TDP-43 suppresses formation of Tau fibrils and instead causes formation of oligomeric Tau and Tau/TDP-43 species. These co-assemblies hinder Tau seeding in a biosensor assay specific for proteopathic Tau seeds. Consistent with this data, SarkoSpin extracts from AD brains with Tau/TDP-43 co-pathology exhibit reduced Tau seeding compared to Tau-only AD brains. In contrast, patient-derived extracts from AD brains with Tau/TDP-43 co-pathology are highly potent in seeding TDP-43 neoaggregates in a TDP-43 reporter cell line. Our results suggest that direct interaction of TDP-43 and Tau may suppress Tau pathology, while promoting TDP-43 pathology. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=133 SRC="FIGDIR/small/662960v1_ufig1.gif" ALT="Figure 1"> View larger version (23K): org.highwire.dtl.DTLVardef@1ed5dfaorg.highwire.dtl.DTLVardef@b4ef07org.highwire.dtl.DTLVardef@b8dbe8org.highwire.dtl.DTLVardef@6d9b49_HPS_FORMAT_FIGEXP M_FIG C_FIG

biochemistry↗

bioRxiv2024

14-3-3 binding regulates Tau assembly and microtubule association.

The microtubule (MT) association of protein Tau is decreased upon phosphorylation. Increased levels of phosphorylated Tau in the cytosol pose the risk of pathological aggregation, as observed in neurodegenerative diseases. We show that binding of 14-3-3{zeta} enhances cytosolic Tau solubility by promoting phosphorylated Tau removal from MTs, while simultaneously inhibiting Tau aggregation both directly and indirectly via suppression of condensate formation. These 14-3-3{zeta} activities depend on site-specific binding of 14-3-3 to Tau phosphorylated at S214 and S324. At sub-stoichiometric 14-3-3{zeta} concentrations, or in the presence of other 14-3-3{zeta} binding partners, multivalent electrostatic interactions promote Tau:14-3-3{zeta} co-condensation, offering a phosphorylation-independent mode of Tau-14-3-3{zeta} interactions. Given the high abundance of 14-3-3 proteins in the brain, 14-3-3 binding could provide efficient multi-modal chaperoning activity for Tau in the healthy brain and be important for preventing Tau aggregation in disease.

biochemistry↗

bioRxiv2024

Autoimmune antibody-induced neuronal hyperactivity triggers pathological Tau in IgLON5 disease

Anti-IgLON5 disease is an autoimmune disease, in which autoantibodies (AABs) against the neuronal cell surface protein IgLON5 lead to profound brain dysfunction and Tau pathology. How -IgLON5 AABs cause neuronal Tau protein pathology and neurodegeneration remains unclear. We find that patient-derived -IgLON5 AABs cluster IgLON5 proteins with other cell surface proteins, leading to neuronal hyperactivity that triggers pathological Tau missorting and phosphorylation, typically observed early in Tau-related neurodegenerative diseases. In wildtype mice, -IgLON5 AABs induce hippocampal Tau phosphorylation and neuroinflammatory responses. Our findings establish a causal link between the -IgLON5 AABs and Tau pathology in anti-IgLON5 disease patients, and highlight the role of neuronal hyperactivity as a disease-overarching driver of Tau pathology and provide a potential target for therapeutic intervention. Teaser-IgLON5 autoantibodies induce clustering of neuronal cell surface proteins, leading to acute neuronal hyperactivity and Tau missorting.

neuroscience↗

bioRxiv2023

Copper drives prion protein phase separation and modulates aggregation

Prion diseases are characterized by prion protein (PrP) transmissible aggregation and toxicity in the brain. The physiological function of PrP seems related to sequestering and internalization of redox-active Cu2+. It is unclear whether Cu2+ contributes to PrP aggregation, recently shown to be mediated by PrP condensation. We investigated the role of Cu2+ and oxidation in PrP condensation and aggregation using multiple biophysical and biochemical methods. We find that Cu2+ promotes PrP condensation at the cell surface and in vitro through co-partitioning. Molecularly, Cu2+ inhibited PrP {beta}-structure and hydrophobic residues exposure. Oxidation, induced by H2O2, triggered liquid-to-solid transition of PrP:Cu2+ condensates and promoted amyloid-like PrP aggregation. In cells, overexpression of PrPC initially protected against Cu2+ cytotoxicity but led to PrPC aggregation upon extended copper exposure. Our data suggest that PrP condensates function as a buffer for copper that prevent copper toxicity but can transition into PrP aggregation at prolonged oxidative stress.

biophysics↗

bioRxiv2022

Biomolecular Tau condensation is linked to Tau accumulation at the nuclear envelope

Biomolecular condensation of the neuronal microtubule-associated protein Tau (MAPT) can be induced by coacervation with polyanions like RNA, or by molecular crowding. Tau condensates have been linked to both functional microtubule binding and pathological aggregation in neurodegenerative diseases. We find that molecular crowding and coacervation with RNA, likely coexisting in the cytosol, synergize to enable Tau condensation at physiological buffer conditions and produce condensates with a strong affinity to charged surfaces. During condensate-mediated microtubule polymerization, this synergy enhances bundling and spatially arranges microtubules. We further show that different Tau condensates efficiently induce pathological Tau in cells, including small accumulations at the nuclear envelope that correlate with nucleocytoplasmic transport deficits. Fluorescent lifetime imaging reveals different molecular packing densities of Tau in cellular accumulations, and a condensate-like density for nuclear envelope Tau. These findings suggest that a complex interplay between interaction partners, post-translational modifications, and molecular crowding regulates the formation and function of Tau condensates. Conditions leading to prolonged existence of Tau condensates may induce the formation of seeding-competent Tau and lead to distinct cellular Tau accumulations.

molecular biology↗

bioRxiv2017

Local Nucleation Of Microtubule Bundles Through Tubulin Concentration Into A Condensed Tau Phase

Non-centrosomal microtubule bundles play important roles in cellular organization and function. Although many diverse proteins are known that can bundle microtubules, biochemical mechanisms by which cells could locally control the nucleation and formation of microtubule bundles are understudied. Here, we demonstrate that concentration of tubulin into a condensed, liquid-like compartment composed of the unstructured neuronal protein tau is sufficient to nucleate microtubule bundles. We show that under conditions of macro-molecular crowding, tau forms liquid drops. Tubulin partitions into these drops, efficiently increasing tubulin concentration and driving the nucleation of microtubules. These growing microtubules form bundles enclosed in a liquid sheath of tau. Our data suggest that condensed compartments of microtubule bundling proteins could promote the local formation of microtubule bundles in neurons by acting as non-centrosomal microtubule nucleation centers, and that liquid-like tau encapsulation could provide both stability and plasticity to long axonal microtubule bundles.

cell biology↗