Biology subjects

Amosse, Q.

Publications and source records attributed to Amosse, Q..

5 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

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↗

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

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↗