Biology subjects

Paitre, E.

Publications and source records attributed to Paitre, E..

4 recordsLinked to original sources

bioRxiv2026

Mitochondrial dysfunction as a hallmark of brain senescence in telomerase-deficient mice

Neurodegenerative diseases, including Alzheimer's disease (AD), are strongly associated with aging. However, the molecular mechanisms underlying pathological brain aging remain incompletely understood. In this study, we used a mouse model of telomere attrition, a major driver of cellular senescence, to perform an unbiased analysis of how telomere-driven senescence affects cellular physiology and contributes to processes relevant to neurodegenerative conditions. After validating the presence of senescence hallmarks in telomerase-deficient brains, we characterized their transcriptomic and proteomic profiles. Mitochondrial function and associated energy metabolism emerged as the major dysregulated pathways, driven predominantly by proteomic rather than transcriptomic changes. Functional biochemical analyses on isolated brain mitochondria demonstrated impaired electron transport chain (ETC) complex activity and reduced energetic status, despite preserved ETC complex integrity and mitochondrial content. Further analyses in senescent primary neurons indicated an accumulation of dysfunctional mitochondria, characterized by increased reactive oxygen species (ROS) production and reduced ATP levels, although basal cellular respiration was maintained. At the tissue level, these alterations were associated with moderate reductions in neuronal density in the subiculum and cortical layer V, indicating region-specific vulnerability rather than widespread neurodegeneration. We propose that a major consequence of telomere dysfunction associated with pathological brain aging is the downregulation of mitochondrial activity, which contributes to the selective vulnerability of specific brain regions. These findings highlight mitochondrial pathways as attractive targets for interventions aimed at preserving brain health during aging.

neuroscience↗

bioRxiv2025

An Early Olfactory Transcriptomic Signature of Tauopathy: Gbp2b Emerges as a Candidate Biomarker of Tau-Driven Neuroinflammation

Olfactory dysfunction is increasingly recognized as an early feature of neurodegenerative diseases such as Alzheimers disease. PS19 mice, a well-established tauopathy model, exhibit hallmarks of tau pathology--including hyperphosphorylated tau and pretangle formations--in various regions of the olfactory system. Notably, very recent data demonstrated that aberrantly hyperphosphorylated tau (pTau) was detected as early as 1.5 months of age in the olfactory epithelium (OE). This region contains olfactory sensory neurons projecting to the olfactory bulb (OB), where similar pTau pattern was also observed at this early stage. By 6 months, tau pretangles were evidenced in higher olfactory areas such as the piriform and entorhinal cortices. Given the early involvement of the OE and OB in tau pathology, we performed transcriptomic analyses at 3, 6, and 9 months to investigate the molecular pathways underlying tau pathology in these olfactory regions. Due to the OEs peripheral location and anatomical accessibility, we also aimed in that respect to identify potential early biomarkers of tauopathy. The hippocampus, a key brain region affected in Alzheimers disease and related disorders, was included in the analysis as a comparative reference due to its known vulnerability and clinical relevance. Our analyses revealed region- and age-specific gene expression changes in PS19 mice. Functional enrichment analyses indicated a temporal progression of molecular alterations associated with tau pathology. We identified a subset of genes differentially expressed across different time points and/or regions. Among these, Gbp2b emerged as a particularly promising early biomarker candidate for tauopathy in the OE, showing consistent upregulation across tau pathological stages and brain regions. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=152 SRC="FIGDIR/small/662324v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@17148c1org.highwire.dtl.DTLVardef@5fa7dborg.highwire.dtl.DTLVardef@51e21org.highwire.dtl.DTLVardef@1fd4302_HPS_FORMAT_FIGEXP M_FIG Created in BioRender. Kienlen-Campard, P. (2025) https://BioRender.com/k7xoypd C_FIG

neuroscience↗

bioRxiv2025

Telomere-driven senescence accelerates tau pathology, neuroinflammation and neurodegeneration in a tauopathy mouse model

BackgroundAlthough the connection between aging and neurodegenerative pathologies like Alzheimers disease (AD) has long been recognized, the underlying pathological mechanisms remain largely unknown. Senescent brain cells build up in the brains of AD patients and a causal link has been established between senescence and AD-related tauopathy. MethodsTo investigate the role of cellular senescence in tau-mediated neuropathology, we crossed the Terc knockout (Terc-/-) senescent mouse model with the P301S tauopathy model (PS19 line). Using brain sections and protein extracts, we employed Western blot and immunostaining analyses to investigate the expression of tau-related neuropathological features within a senescent context. ResultsWe found that the brains of 6-and 9-month-old Terc-/- mice exhibit significant telomere attrition and signs of cellular senescence. Introducing a senescent phenotype in a tauopathy mouse model resulted in increased tau phosphorylation at key residues, particularly in the hippocampus. Over time, this was associated with enhanced tau truncation and aggregation. These pathological changes were accompanied by exacerbated astrocyte and microglial activation, as well as selective neuronal loss in vulnerable brain regions. ConclusionsOverall, our findings place senescence as a key upstream regulator of tau pathology, suggesting that targeting senescent cells and their detrimental effects may offer promising therapeutic strategies for AD and other related tauopathies.

neuroscience↗

bioRxiv2025

The Olfactory Epithelium: A Critical Gateway for Pathological Tau Propagation and a Target for Mitigating Tauopathy in the Central Nervous System

Olfactory impairment is a recognized early indicator of neurodegenerative diseases (NDs), such as Alzheimers disease (AD). Intracellular aggregates of hyperphosphorylated tau protein, referred to as neurofibrillary tangles (NFTs), are a hallmark of AD. NFTs are found in the olfactory bulb (OB) and entorhinal cortex (EC), both crucial for processing olfactory information. We explored the hypothesis that typical tau lesions could appear early and progress along olfactory regions to reach connected areas critically affected in AD (e.g. EC and hippocampal formation). To that end, we used transgenic PS19 mice expressing mutated human tau protein (1N4R isoform, P301S mutation). They recapitulate major phenotypes of AD, such as accumulation of NFTs, synaptic dysfunction, cognitive impairment, and neuronal loss. The presence of pathological hyperphosphorylated human tau protein (pTau) was monitored in olfactory regions: olfactory epithelium (OE), OB, piriform cortex (PC), and in connected regions of the hippocampal formation (hippocampus and EC). pTau was detected in the OEs middle stratum and in the OBs olfactory nerve layer (ONL) at 1.5 months. At 6 months of age, tau accumulations were found in the PC and EC, along with the CA3 region and dentate gyrus of the hippocampus. We found that olfactory function remained unaffected in PS19 mice, despite the presence of tau pathology in key regions of the olfactory system. Complete stripping of the OE by intranasal administration of ZnSO4 led to a significant reduction in pretangle-like tau pathology within the PC, amygdala, and EC of 6-month-old PS19 mice. Finally, we observed in human post-mortem samples that pTau signal was present in the olfactory regions (OE and OB) of patients at early Braak stages (I/II). Based on these observations, we propose that pTau could appear, due to ageing or environmental agents, in the OE and subsequently spread in a prion-like manner to the hippocampal formation along neuroanatomical connections. These findings also indicate the interest of the OE as a target for intervention aimed at mitigating the progression of tauopathy in the CNS.

neuroscience↗