Biology subjects

Buee-Scherrer, V.

Publications and source records attributed to Buee-Scherrer, V..

3 recordsLinked to original sources

bioRxiv2026

A proline-rich-domain-binding single domain antibody selectively inhibits RNA-induced liquid-liquid phase separation of tau

Liquid-liquid phase separation (LLPS) mediates the formation of biomolecular condensates, which organize cellular processes such as synaptic plasticity and stress response. The neuronal microtubule-associated protein tau undergoes LLPS under specific conditions, regulating synaptic vesicle clustering and microtubule dynamics. In vitro, tau LLPS is induced by cofactors such as polyethylene glycol (PEG) or RNA, mainly via weak multivalent electrostatic interactions. However, the molecular mechanisms governing the formation of tau LLPS, including domain specific contribution, remain unclear. In this study, we used eight single-domain antibodies (VHHs), targeting six distinct short sequences of tau, to explore the mechanisms of tau LLPS in vitro. By combining several biophysical methods, we evaluated the effect of each anti-tau VHH on tau LLPS with two main LLPS inducers, PEG (molecular crowding) and RNA (complex coacervation). With PEG as an inducer, all VHHs targeting tau enhanced tau LLPS formation, regardless of their affinity for tau. With RNA as an inducer, the effect of the VHHs was mixed: VHHs targeting the C-terminal domain promoted condensation, while VHH B1-1, which binds the proline-rich domain (PRD; including residues (221REPKKVAVVRTP232), abolished droplet formation. NMR and surface plasmon resonance confirmed 1 to 1 binding of VHH B1-1 to the PRD, and competition assays with a PRD peptide restored LLPS, demonstrating mechanistic specificity. This result underscores the importance of this region in tau LLPS formation. Our findings provide domain-resolved insights into the regulation of tau LLPS and demonstrate the potential of VHHs as tools to selectively modulate biomolecular condensates in physiological and pathological contexts.

biochemistry↗

bioRxiv2025

N-terminally acetylated Met11-Tau: a new pathological truncated Tau species with functional relevance in Alzheimer Disease

Neurodegenerative diseases like Alzheimers disease (AD) are characterized by progressive accumulation of pathological Tau proteins. Among the diverse Tau species, truncated variants are emerging as key contributors, yet their identity remains elusive, particularly for the N-terminal truncated ones. The present study identifies and characterizes a novel N-terminally truncated and N-alpha-acetylated form of the Tau protein. Using a newly developed antibody specifically targeting this truncated variant, we demonstrate that this species accumulates early in degenerating neurons in both transgenic mouse models of AD-related Tau pathology and post-mortem brain tissues from AD patients. Importantly, in vivo functional experiments reveal that expression of this truncated Tau species exacerbates Tau pathology, whereas targeted immunotherapeutic with the specific antibody significantly reduces pathological Tau accumulation and prevents associated memory impairments. These findings position this newly identified Tau variant as both a marker of neurofibrillary degeneration and a pathogenic driver of neurodegeneration and supports its potential as a therapeutic target in Tau-related disorders, notably AD.

neuroscience↗

bioRxiv2024

Hampered AMPK-ULK1 cascade in Alzheimer disease (AD) instigates mitochondria dysfunctions and AD-related alterations that are alleviated by metformin

BackgroundMitochondrial structure and function alterations are key pathological features in Alzheimers disease (AD) brains. The adenosine monophosphate-activated protein kinase (AMPK) and its downstream effector Unc-51 like autophagy activating kinase 1 (ULK1) represent a key node controlling mitochondria health, the alteration of which likely contribute to AD development. MethodsWe designed this study to investigate AMPK-ULK1 activation state in post-mortem human sporadic AD brains, in 3xTgAD mice that recapitulate most of human AD features, and in neuronal cells expressing the amyloid precursor protein with the familial Swedish mutation (APPswe). We examined the impact of the pharmacological and genetic modulation of AMPK-ULK1 cascade on mitochondria structure and functions in APPswe cells. We evaluated the potential beneficial impact of AMPK-ULK1 activation by Metformin (Met) on mitochondria defects, as well as on early- and late-stage AD-related alterations in vivo and ex vivo. ResultsAt first, we show that AMPK-ULK1 cascade is defective in murine and human AD brains as well as in APPswe cells. We then report that Met administration to 3xTgAD mice alleviates the alterations of neuronal mitochondria structure and function and we consolidate these results in cells using both pharmacological and genetic tools to modulate AMPK-ULK1 cascade. In mice brains, Met reduces the early accumulation of APP C-terminal fragments (APP-CTFs) as well as the amyloid beta (A{beta}) burden present in aged mice. Mechanistically, we show that Met increases the localization of APP-CTFs within cathepsin D-positive lysosomal compartments in vivo and enhances cathepsin D activity in vitro. The reduction of A{beta} load by Met occurs through an increased recruitment of Iba1+ cells to A{beta} plaques and an enhancement of the phagocytic activity of microglia. Accordingly, in symptomatic 3xTgAD mice, Met alleviates microgliosis and astrogliosis, modulates microglia morphology, reduces peripheral proinflammatory cytokines levels, and regulates the expression of a set of inflammatory genes. In addition, Met normalizes dendritic spines shape in organotypic hippocampal slice cultures modeling AD and improves learning performance of 3xTgAD mice. ConclusionsOur study demonstrates potential therapeutic benefits of targeting AMPK-ULK1 cascade to reverse both early and late AD-related alterations, deserving further investigation in fundamental research and in human clinical studies.

neuroscience↗