Biology subjects

Tsartsalis, S.

Publications and source records attributed to Tsartsalis, S..

11 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

Oxytocin release modulates acute neuroinflammation and improves brain development after pediatric traumatic brain injury

Pediatric traumatic brain injury (TBI) is a leading cause of death and disability early in life in infants, and its neurodevelopmental consequences cannot currently be effectively treated. Since TBI is associated with neuroinflammation, modulation of the post-injury neuroinflammatory response is a promising strategy. Oxytocin is thought to have anti-inflammatory properties and appears to play a role in clinical interventions that improve brain development in neonates. However, the underlying mechanisms remain unclear, as does its applicability to acute brain injury. Here we investigate the effects of chemogenetic modulation of endogenous oxytocin on acute neuroinflammation and on long-term brain development after TBI in postnatal day 7 (P7) male mice. We show that oxytocin release attenuates the acute neuroinflammatory response to TBI 24 hours after injury, by reducing the expression of immune- and inflammation-related genes in astrocytes and promoting gene pathways for brain repair and development in microglia. In the long term, oxytocin exposure ameliorates subcortical and cortical white matter damage after TBI, prevents hyperactivity and loss of social behavior, and restores TBI-induced alterations in resting-state functional connectivity of the isocortex. These findings enhance our understanding of the modulation of neuroinflammation and its long-term effects and support intervention related to endogenous oxytocin release as a promising neuroprotective strategy in pediatric TBI.

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↗

bioRxiv2023

Impairment of hippocampal astrocyte-mediated striatal dopamine release and locomotion in Alzheimer's disease

Clinical and translational research has identified deficits in the dopaminergic neurotransmission in the striatum in Alzheimers disease (AD) and this could be related to the pathophysiology of psychiatric symptoms appearing even at early stages of the pathology. We hypothesized that AD pathology in the hippocampus may influence dopaminergic neurotransmission even in the absence of AD-related lesion in the mesostriatal circuit. We thus chemogenetically manipulated the activity of hippocampal neurons and astrocytes in wild-type and hemizygous TgF344-AD (Tg) rats, an animal model of AD pathology. We assessed the brain-wide functional output of this manipulation using in vivo Single Photon Emission Computed Tomography to measure cerebral blood flow and D2/3 receptor binding. We also assessed the effects of the chemogenetic manipulations on astrocytic and microglial capacity to surround and phagocytize A{beta} both locally and in the striatum. Our results show that acute and chronic neuronal and astrocytic stimulation induces widespread effects on the brain regional activation pattern, notably with an inhibition of striatal activation. In the TgF344-AD rats, both these effects were blunted. Chemogenetic stimulation in the hippocampus increased microglial density and its capacity to limit AD pathology, whereas these effects were absent in the striatum perhaps as a consequence of the altered connectivity between the hippocampus and the striatum. Our work suggests that hippocampal AD pathology may alter mesostriatal signalling and induce widespread alterations of brain activity. Neuronal and astrocytic activation may induce a protective, A{beta}-limiting phenotype of microglia, which surrounds A{beta} plaques and limits A{beta} concentration more efficiently.

neuroscience↗

bioRxiv2022

Translocator protein is a marker of activated microglia in rodent models but not human neurodegenerative diseases

Microglial activation plays central roles in neuro-inflammatory and neurodegenerative diseases. Positron emission tomography (PET) targeting 18kDa Translocator Protein (TSPO) is widely used for localising inflammation in vivo, but its quantitative interpretation remains uncertain. We show that TSPO expression increases in activated microglia in mouse brain disease models but does not change in a non-human primate disease model or in common neurodegenerative and neuroinflammatory human diseases. We describe genetic divergence in the TSPO gene promoter, consistent with the hypothesis that the increase in TSPO expression in activated myeloid cells is unique to a subset of species within the Muroidea superfamily of rodents. We show that TSPO is mechanistically linked to classical pro-inflammatory myeloid cell function in rodents but not humans. These data emphasise that TSPO expression in human myeloid cells is related to different phenomena than in mice, and that TSPO PET reflects density of inflammatory cells rather than activation state.

neuroscience↗

bioRxiv2022

Knockout of TSPO delays and reduces amyloid, Tau, astrocytosis and behavioral dysfunctions in Alzheimer's disease.

The 18kDa translocator protein (TSPO) is up-regulated in glial cells in neurodegenerative diseases. In Alzheimers disease (AD) animal models, TSPO is first overexpressed in astrocytes and then in microglia. However, the precise role of TSPO in the onset and progression of pathology and symptoms characteristic of the disease remains unknown. Here, we report that in the absence of TSPO in 3xTgAD mice the expected disease onset is significantly delayed and a reduction is seen in the hippocampal load of poorly and highly aggregated forms of Tau (-44% and -82%, respectively) and A{beta}42 (-25% and -95%, respectively), at 9 months of age. In addition, the astrocyte reactivity was decreased in 3xTgAD.TSPO-/- mice with a reduction in the morphologic complexity and the size of astrocytes in the dorso-dorsal hippocampus and the hilus. Functionally, the absence of TSPO ameliorated the cognitive consequences of adeno-associated virus-induced Tau over-expression in the hippocampus. This suggests that TSPO plays an important role in the active disease progression of AD. TSPO-inhibiting drugs thus merit further exploration as to their potential to reduce the rate of neurodegenerative disease progression.

pathology↗

bioRxiv2021

Single nuclear transcriptional signatures of dysfunctional brain vascular homeostasis in Alzheimer's disease

Brain perfusion and normal blood brain barrier integrity are reduced early in Alzheimers disease (AD). We performed single nucleus RNA sequencing of vascular cells isolated from AD and control brains to characterise pathological transcriptional signatures. We found that endothelial cells (EC) are enriched for expression of genes associated with susceptibility to AD. EC transcriptional signatures identified mechanisms for impaired {beta}-amyloid clearance. Evidence for immune activation was found with upregulation of interferon signalling genes in EC and in pericytes (PC). Transcriptional signatures suggested dysregulation of vascular homeostasis and angiogenesis with upregulation of pro-angiogenic signals (HIF1A) and metabolism in EC, but downregulation of homeostatic growth factor pathways (VEGF, EGF, insulin) in EC and PC and of extracellular matrix genes in fibroblasts (FB). Our genomic dissection of vascular cell risk gene enrichment suggests a potentially causal role for EC and defines transcriptional signatures associated with microvascular dysfunction in AD.

neuroscience↗

bioRxiv2021

Diverse human astrocyte and microglial transcriptional responses to Alzheimer's pathology

To better define roles that astrocytes and microglia play in Alzheimers disease (AD), we used single-nuclei RNA sequencing to comprehensively characterize transcriptomes in astrocyte and microglia nuclei isolated post mortem from neuropathologically-defined AD and control brains with a range of amyloid-beta and phospho-tau (pTau) pathology. Significant differences in glial gene expression (including AD risk genes expressed in astrocytes [CLU, MEF2C, IQCK] and microglia [APOE, MS4A6A, PILRA]) were correlated with tissue amyloid and pTau expression. Astrocytes were enriched for proteostatic, inflammatory and metal ion homeostasis pathways. Pathways for phagocytosis, proteostasis and autophagy were highly enriched in microglia and perivascular macrophages. Gene co-expression analyses revealed potential functional associations of soluble biomarkers of AD in astrocytes (CLU) and microglia (GPNMB). Our work highlights responses of both astrocytes and microglia for pathological protein clearance and inflammation, as well as glial transcriptional diversity in AD.

neuroscience↗