Novel App knock-in mouse model shows key features of amyloid pathology and reveals profound metabolic dysregulation of microglia

Molecular Neurodegeneration, Год журнала: 2022, Номер 17(1)

Опубликована: Июнь 11, 2022

Genetic mutations underlying familial Alzheimer's disease (AD) were identified decades ago, but the field is still in search of transformative therapies for patients. While mouse models based on overexpression mutated transgenes have yielded key insights mechanisms disease, those are subject to artifacts, including random genetic integration transgene, ectopic expression and non-physiological protein levels. The engineering novel using knock-in approaches addresses some limitations. With mounting evidence role played by microglia AD, high-dimensional phenotype critical refine our understanding immune response brain.We engineered a App model (AppSAA) homologous recombination introduce three disease-causing coding (Swedish, Arctic Austrian) gene. Amyloid-β pathology, neurodegeneration, glial responses, brain metabolism behavioral phenotypes characterized heterozygous homozygous AppSAA mice at different ages and/ or biofluids. Wild type littermate used as experimental controls. We situ imaging technologies define whole-brain distribution amyloid plaques compare it other AD human pathology. To further explore microglial relevant we isolated with fibrillar Aβ content from performed transcriptomics metabolomics analyses vivo measure energy response. Finally, also various assays.Leveraging multi-omics approaches, discovered profound alteration diverse lipids metabolites well an exacerbated disease-associated transcriptomic high intracellular content. recapitulates pathological features such progressive accumulation parenchymal vascular deposits, altered astroglial responses elevation CSF markers neurodegeneration. Those observations associated increased TSPO FDG-PET signals hyperactivity animals aged.Our findings demonstrate that lipid dyshomeostasis consistent lysosomal dysfunction foam cell immuno-metabolic perturbations, opening new avenues investigate metabolic pathways play responding AD-relevant pathogenesis. in-depth characterization hallmarks this open-access should serve resource scientific community disease-relevant biology.

Язык: Английский

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Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro

Nature Immunology, Год журнала: 2023, Номер 24(8), С. 1382 - 1390

Опубликована: Июль 27, 2023

Abstract Microglia, the macrophages of brain parenchyma, are key players in neurodegenerative diseases such as Alzheimer’s disease. These cells adopt distinct transcriptional subtypes known states. Understanding state function, especially human microglia, has been elusive owing to a lack tools model and manipulate these cells. Here, we developed platform for modeling microglia states vitro. We found that exposure stem-cell-differentiated synaptosomes, myelin debris, apoptotic neurons or synthetic amyloid-beta fibrils generated diversity mapped gene signatures identified including disease-associated enriched diseases. Using new lentiviral approach, demonstrated transcription factor MITF drives signature highly phagocytic state. Together, enable manipulation functional interrogation microglial both homeostatic disease-relevant contexts.

Язык: Английский

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Single-cell immunology: Past, present, and future

Immunity, Год журнала: 2022, Номер 55(3), С. 393 - 404

Опубликована: Март 1, 2022

Язык: Английский

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Cell-autonomous effects of APOE4 in restricting microglial response in brain homeostasis and Alzheimer’s disease

Nature Immunology, Год журнала: 2023, Номер 24(11), С. 1854 - 1866

Опубликована: Окт. 19, 2023

Язык: Английский

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Microglia regulation of central nervous system myelin health and regeneration

Nature reviews. Immunology, Год журнала: 2023, Номер 24(1), С. 49 - 63

Опубликована: Июль 14, 2023

Язык: Английский

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Brain macrophage development, diversity and dysregulation in health and disease

Cellular and Molecular Immunology, Год журнала: 2023, Номер 20(11), С. 1277 - 1289

Опубликована: Июнь 26, 2023

Abstract Brain macrophages include microglia in the parenchyma, border-associated meningeal-choroid plexus-perivascular space, and monocyte-derived that infiltrate brain under various disease conditions. The vast heterogeneity of these cells has been elucidated over last decade using revolutionary multiomics technologies. As such, we can now start to define macrophage populations according their ontogeny diverse functional programs during development, homeostasis pathogenesis. In this review, first outline critical roles played by development healthy aging. We then discuss how might undergo reprogramming contribute neurodegenerative disorders, autoimmune diseases, glioma. Finally, speculate about most recent ongoing discoveries are prompting translational attempts leverage as prognostic markers or therapeutic targets for diseases affect brain.

Язык: Английский

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Cell type specific transcriptomic differences in depression show similar patterns between males and females but implicate distinct cell types and genes

Nature Communications, Год журнала: 2023, Номер 14(1)

Опубликована: Май 22, 2023

Abstract Major depressive disorder (MDD) is a common, heterogenous, and potentially serious psychiatric illness. Diverse brain cell types have been implicated in MDD etiology. Significant sexual differences exist clinical presentation outcome, recent evidence suggests different molecular bases for male female MDD. We evaluated over 160,000 nuclei from 71 donors, leveraging new pre-existing single-nucleus RNA-sequencing data the dorsolateral prefrontal cortex. Cell type specific transcriptome-wide threshold-free MDD-associated gene expression patterns were similar between sexes, but significant differentially expressed genes (DEGs) diverged. Among 7 broad 41 clusters evaluated, microglia parvalbumin interneurons contributed most DEGs females, while deep layer excitatory neurons, astrocytes, oligodendrocyte precursors major contributors males. Further, Mic1 cluster with 38% of ExN10_L46 53% DEGs, stood out meta-analysis both sexes.

Язык: Английский

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Aging microglia

Cellular and Molecular Life Sciences, Год журнала: 2023, Номер 80(5)

Опубликована: Апрель 21, 2023

Abstract Microglia are the tissue-resident macrophage population of brain, specialized in supporting CNS environment and protecting it from endogenous exogenous insults. Nonetheless, their function declines with age, ways that remain to be fully elucidated. Given critical role played by microglia neurodegenerative diseases, a better understanding aging phenotype is an essential prerequisite designing preventive therapeutic strategies. In this review, we discuss most recent literature on aging, comparing findings rodent models human subjects.

Язык: Английский

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APOE3ch alters microglial response and suppresses Aβ-induced tau seeding and spread

Cell, Год журнала: 2023, Номер 187(2), С. 428 - 445.e20

Опубликована: Дек. 11, 2023

Язык: Английский

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TGF-β1 signalling in Alzheimer’s pathology and cytoskeletal reorganization: a specialized Tau perspective

Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)

Опубликована: Март 13, 2023

Microtubule-associated protein, Tau has been implicated in Alzheimer's disease for its detachment from microtubules and formation of insoluble intracellular aggregates within the neurons. Recent findings have suggested expulsion seeds extracellular domain their prion-like propagation between Transforming Growth Factor-β1 (TGF-β1) is a ubiquitously occurring cytokine reported to carry out immunomodulation neuroprotection brain. TGF-β-mediated regulation occurs at level neuronal survival differentiation, glial activation (astrocyte microglia), amyloid production-distribution-clearance neurofibrillary tangle formation, all which contributes pathophysiology. Its role reorganization cytoskeletal architecture remodelling matrix facilitate cellular migration well-documented. Microglia are resident immune sentinels brain responsible surveying local microenvironment, migrating towards beacon pertinent damage phagocytosing debris or patho-protein deposits site insult. Channelizing microglia target could be good strategy combat transmission seeding problem disease. The current review focuses on reaffirming TGF-β1 signalling pathology considers utilizing approach TGF-β-triggered microglia-mediated targeting patho-protein, Tau, as possible potential

Язык: Английский

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