Biology subjects

Abjean, L.

Publications and source records attributed to Abjean, L..

6 recordsLinked to original sources

bioRxiv2026

Carbonyl stress primes the metastable aging brain for Alzheimer's disease

Alzheimers disease (AD) is defined by amyloid-{beta} (A{beta}) plaques and tau tangles, yet the inflammation that comes with it is only partly localized where those lesions accumulate. Using spatial transcriptomics on 16 human hippocampal sections containing adjacent cortex, we found that plaques concentrated in grey matter, especially cortex. In contrast, the strongest inflammatory response occupied white matter and increased with distance from A{beta}-positive spots. This inflammatory signature increased with Braak stage in an independent 31-subject hippocampal bulk proteomic cohort. The white-matter environment revealed a distinct chemistry, with lipidomics showing cortical white matter gaining cholesteryl esters, lysosomal storage lipids and peroxidation-prone polyunsaturated species while losing myelin lipids, alongside carbonyl, glycation and iron-handling signatures. In an external single-nucleus cohort, an oligodendrocyte lipid-droplet program tracked cognitive decline after adjustment for amyloid and tangles, and the same reactive-glia chemistry recurred above expression-matched nulls across seven neurodegenerative datasets. We propose that this lipid-rich glial environment is a metastable, primed state, and that A{beta} and tau act as catalysts that tip it toward a self-sustaining inflammatory reaction. HighlightsO_LIPlaques concentrate in grey matter, whereas inflammatory programs increase with distance and peak in glial/myelin-rich white matter. C_LIO_LIThe white-matter response strengthens with Braak stage and is characterized by carbonyl stress, lipid storage, and myelin loss. C_LIO_LIAn oligodendrocyte lipid-droplet program tracks cognitive decline after adjustment for A{beta} and tau. C_LIO_LIA lipid-droplet reactive-glial state recurs across neurodegenerative diseases with distinct triggers and vulnerable cells. C_LIO_LIA{beta} and pTau may tip a metastable tissue environment already primed by lipid and carbonyl stress. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=188 SRC="FIGDIR/small/740487v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@127708borg.highwire.dtl.DTLVardef@4dc7b4org.highwire.dtl.DTLVardef@72350corg.highwire.dtl.DTLVardef@1f8d016_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Minute- and second-scale hippocampal network dysfunctions in the 3xTgAD mouse model of Alzheimer's disease are prevented by TSPO knockout

The 18kDa translocator protein (TSPO) is widely recognized as a biomarker of neuroinflammation, but recent evidence suggests that it may also play a direct role in the pathophysiology of neurological conditions with an inflammatory component such as Alzheimers disease (AD). In this study, we leveraged functional ultrasound imaging (fUSi) to assess how TSPO knockout influences brain activity and connectivity in the 3xTgAD mouse model of AD. Resting-state scans were performed in 16-month-old male and female mice across four genotypes: WT, TSPO-/-, 3xTgAD or 3xTgAD.TSPO-/-. Using a data-driven approach, we identified key functional networks, including a bilateral hippocampal-amygdala limbic network. Dual regression analysis revealed increased engagement of the ventral hippocampus within the limbic network and elevated hemodynamic variance in 3xTgAD mice compared to WT. Moreover, co-activation patterns (CAPs) analysis showed abnormal activation/deactivation cycles involving the dorsal hippocampus, both of which were prevented by TSPO knockout without affecting amyloid or tau burden. Our findings highlight a functional role for TSPO in shaping network dynamics and suggest that its deletion can mitigate brain dysfunction in AD models.

neuroscience↗

bioRxiv2025

Non-linear microglial, inflammatory and oligodendrocyte dynamics across stages of Alzheimer's disease

Alzheimers disease (AD) is characterized by cognitive decline and neuropathological hallmarks including A{beta} plaques and Tau tangles. Emerging evidence indicates oligodendrocyte (OL) dysfunction and demyelination also contribute to disease progression. Here, we analyzed OL markers and inflammatory gene expression in human hippocampal samples at early and late AD stages. In early AD, we observed OL and myelinating pathways downregulation, alongside microglial and astrocytic activation, as well as upregulated chemokine CCL2 and peripheral immune infiltration markers. In late stages, expression of OL-related genes and myelination pathways increase, with a higher NG2/MBP ratio, coinciding with decreased microglial coverage and peripheral immune markers. These findings indicate that early neuroinflammation may impair OL function, while attenuated immune activity in late AD allows partial OL recovery. This study provides insights into stage-specific inflammatory and myelin-related changes in AD, supporting the relevance of understanding oligodendrocyte dynamics and potential regenerative responses for future therapeutic strategies. HighlightsO_LIEarly AD: heightened microglial activation and peripheral infiltration. C_LIO_LILate AD: reduced microglial presence and oligodendrocyte partial recovery. C_LIO_LINeuroinflammation shifts toward remyelination-supporting conditions. C_LI Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=190 HEIGHT=200 SRC="FIGDIR/small/645240v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@eb5f3forg.highwire.dtl.DTLVardef@ba239eorg.highwire.dtl.DTLVardef@7897feorg.highwire.dtl.DTLVardef@142a6fd_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2024

Repeated low-intensity focused ultrasound led to microglial profile changes at long term in TgF344-AD rats

Alzheimers disease (AD), the most common cause of dementia, represents one of the main clinical challenges of the century as the number of patients is predicted to triple by 2050. Despite the recent approval of three monoclonal antibodies targeting Amyloid {beta} (A{beta}) aggregates by the Food and Drug Administration (FDA), immunotherapies still face challenges due to the difficulty of antibodies crossing the blood-brain barrier (BBB). This necessitates administering large doses of drugs to achieve their therapeutic effects, which is associated with significant side effects. In this context, low-intensity focused ultrasound (LiFUS) appears as an innovative and non-invasive method which, in association with intravenous injection of microbubbles (MB), leads to a transient BBB opening. This innovative strategy has been extensively studied in different preclinical models and more recently in human clinical trials, particularly in the context of AD. LiFUS+MB increases the inflammatory response at short-term, but the time course of this response is not consistent between studies, certainly due to the discrepancy between LiFUS protocols used. Moreover, the impact at longer term is understudied and the mechanisms underlying this effect are still not well understood. In our study, we therefore used the TgF344-AD rat model of AD to investigate the effect of a single or multiple exposures to LiFUS+MB in a large volume of the brain on inflammatory response, tauopathy and amyloid load, at both early and advanced stages. The ultrasound attenuation through the skull was corrected to apply a peak negative acoustic pressure of 450 kPa in all treated animals. At an advanced disease stage, single LiFUS+MB exposure induces a slight astrocyte and microglial response 24 hours post-treatment whereas chronic LiFUS treatment is associated with a transient inflammatory response predominantly affecting microglial cells, which is no longer detectable 6 weeks post-treatment. At an early stage of pathology, LiFUS seems to induce microglial reprogramming, leading to the adaptation of gene expression related to key functions such as inflammatory response, mitochondrial and energetic metabolism. In our rat model and LiFUS+MB protocol conditions, a single LiFUS exposure reduced significantly highly aggregated A{beta}42 peptide concentration. Surprisingly, multiple exposures had this opposite effect at short-term but not at longer term.

neuroscience↗

bioRxiv2023

Altered astrocytic and microglial homeostasis characterizes a decreased proinflammatory state in bipolar disorder

Multiple lines of evidence point to peripheral immune alterations in bipolar disorder (BD) although the activity of brain immune mechanisms remain largely unexplored. To identify the cell type-specific immune alterations in the BD brain, we performed a proteomic and single nuclear transcriptomic analysis of postmortem cingulate cortex samples from BD and control subjects. Our results showed that genes associated to the genetic risk for BD are enriched in microglia and astrocytes. Transcriptomic alterations in microglia point to a reduced proinflammatory phenotype, associated to reduced resistance to oxidative stress and apoptosis, which was confirmed with immunohistochemical quantification of IBA1 density. Astrocytes show transcriptomic evidence of an imbalance of multiple metabolic pathways, extracellular matrix composition and downregulated immune signalling. These alterations are associated to ADCY2 and NCAN, two GWAS genes upregulated in astrocytes. Finally, cell-cell communication analysis prioritized upregulated SPP1-CD44 signalling to astrocytes as a potential regulator of the transcriptomic alterations in BD. Our results indicate that microglia and astrocytes are characterized by downregulated immune responses associated to a dysfunction of core mechanisms via which these cells contribute to brain homeostasis.

neuroscience↗

bioRxiv2021

The JAK2-STAT3 pathway controls a beneficial proteostasis response of reactive astrocytes in Huntington disease

Huntingtons disease is a fatal neurodegenerative disease characterized by striatal neurodegeneration, aggregation of mutant Huntingtin and the presence of reactive astrocytes. Astrocytes are important partners for neurons and engage in a specific reactive response in Huntingtons disease that involves morphological, molecular and functional changes. How reactive astrocytes contribute to Huntingtons disease is still an open question, especially because their reactive state is poorly reproduced in experimental mouse models. Here, we show that the JAK2-STAT3 pathway, a central cascade controlling astrocyte reactive response, is activated in the putamen of Huntingtons disease patients. Selective activation of this cascade in astrocytes through viral gene transfer reduces the number and size of mutant Huntingtin aggregates in neurons and improves neuronal defects in two complementary mouse models of Huntingtons disease. It also reduces striatal atrophy and increases glutamate levels, two central clinical outcomes measured by non-invasive magnetic resonance imaging. Moreover, astrocyte-specific transcriptomic analysis shows that activation of the JAK2-STAT3 pathway in astrocytes coordinates a transcriptional program that increases their intrinsic proteolytic capacity, through the lysosomal and ubiquitin-proteasome degradation systems. This pathway also enhances their production and exosomal release of the co-chaperone DNAJB1, which contributes to mutant Huntingtin clearance in neurons. Together, our results show that the JAK2-STAT3 pathway controls a beneficial proteostasis response in reactive astrocytes in Huntingtons disease, which involves bi-directional signalling with neurons to reduce mutant Huntingtin aggregation, eventually improving disease outcomes.

neuroscience↗