Lipid-accumulated reactive astrocytes promote disease progression in epilepsy

Chen, Zhang-Peng; Wang, Suji; Zhao, Xiansen; Fang, Wen; Wang, Zhengge; Ye, Haojie; Wang, Meng-Ju; Ke, Ling; Huang, Tengfei; Lv, Pin; Jiang, Xiaohong; Zhang, Qipeng; Li, Liang; Xie, Shutao; Zhu, Jing-Ning; Hang, Chunhua; Chen, Dijun; Liu, Xiangyu; Yan, Chao

doi:10.1038/s41593-023-01288-6

Cited by 59 publications

(28 citation statements)

References 62 publications

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“…Enhancer-AAV eHGT-390m, on the other hand, did not show a change of expression. This could be due to it being selected based on cell type identity, and most properties of cell types have not been seen to change character dramatically in the context of disease 22,78,79 . Enhancers can also be selected that do not change activity during development, aging, or disease, in a similar way to avoid selecting enhancers predicted to have activity in off-target tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, species-specific features have been described 21 , although the functional significance of these differences is unknown. Glial cell types have also been shown to play critical roles in CNS diseases ranging from epilepsy 22 to neurodegenerative diseases 23 to cancer 24,25 . To understand how glia differ between cell types, regions, species, and disease states, a set of tools is needed to grant targeted genetic access to these specific populations across species.…”

Section: Introductionmentioning

confidence: 99%

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Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species

Mich,

Sunil,

Johansen

et al. 2023

Preprint

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Proper brain function requires the assembly and function of diverse populations of neurons and glia. Single cell gene expression studies have mostly focused on characterization of neuronal cell diversity; however, recent studies have revealed substantial diversity of glial cells, particularly astrocytes. To better understand glial cell types and their roles in neurobiology, we built a new suite of adeno-associated viral (AAV)-based genetic tools to enable genetic access to astrocytes and oligodendrocytes. These oligodendrocyte and astrocyte enhancer-AAVs are highly specific (usually > 95% cell type specificity) with variable expression levels, and our astrocyte enhancer-AAVs show multiple distinct expression patterns reflecting the spatial distribution of astrocyte cell types. To provide the best glial-specific functional tools, several enhancer-AAVs were: optimized for higher expression levels, shown to be functional and specific in rat and macaque, shown to maintain specific activity in epilepsy where traditional promoters changed activity, and used to drive functional transgenes in astrocytes including Cre recombinase and acetylcholine-responsive sensor iAChSnFR. The astrocyte-specific iAChSnFR revealed a clear reward-dependent acetylcholine response in astrocytes of the nucleus accumbens during reinforcement learning. Together, this collection of glial enhancer-AAVs will enable characterization of astrocyte and oligodendrocyte populations and their roles across species, disease states, and behavioral epochs.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species

Mich,

Sunil,

Johansen

et al. 2023

Preprint

View full text Add to dashboard Cite

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“…7 Using 7-tesla-field-strength magnetic resonance spectroscopy, we found Lipid to Creatine ratio in highgrade gliomas is around 1.30 (Figure S2J), higher than the ratio in normal brain tissue around 0.59. 8 Notably, LILRB3 and APOE were expressed higher in the central region (Figure 2G). 9 Abundant expression of APOE in LILRB3 + myeloid cells was observed compared to LILRB3 − cells F I G U R E 1 High LILRB3 localized in monocyte-derived tumour-associated macrophages (MDMs) was an unfavourable prognostic factor in glioma.…”

mentioning

confidence: 93%

LILRB3 suppresses immunity in glioma and is associated with poor prognosis

Zhuang,

Liu,

Wang

et al. 2023

Clinical & Translational Med

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“…In 3xTg-AD mice, modifications in the well-recognized astrocytic marker glial fibrillary acidic protein (GFAP) have been reported for several brain regions (Yeh et al, 2011; González-Molina et al, 2021). Importantly, astrocytes play a crucial role in lipid synthesis, distribution, and storage (Lee et al, 2021; Smolič et al, 2021), and dysregulation of lipid metabolism in astrocytes can contribute to brain diseases and neurodegeneration (Chen et al, 2023; Mi et al, 2023). Astrocytes have also been implicated in the regulation of ECoG activity during different sleep states (Halassa et al 2009; Foley et al, 2017), and a higher expression of activated astrocyte marker genes in the prefrontal cortex was reported to be associated with indications of sleep disturbances and cognitive decline in humans (Wu et al, 2023).…”

Section: Introductionmentioning

confidence: 99%

Electrocorticographic and Astrocytic Signatures of Stearoyl-CoA Desaturase Inhibition in the Triple Transgenic Mouse Model of Alzheimer’s Disease

Hector,

da Costa Caiado,

Leduc

et al. 2024

Preprint

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The symptomatology of Alzheimer's disease (AD) includes cognitive deficits and sleep disturbances. Recent findings suggest the involvement of dysfunctions in lipid metabolism, such as oleic acid build-up, in the brain of AD patients and animal models. In addition, the inhibition of stearoyl-CoA desaturase (SCD), a lipid-converting enzyme, was shown to restore memory in triple transgenic (3xTg)-AD mice. In the brain, astrocytes regulate the synthesis of specific lipids. Alterations in astrocytes and their function were reported in AD patients and animal models, and astrocytes have been implicated in the regulation of sleep. However, the relationship between sleep disturbances, astrocytes and lipid metabolism remains to be explored in AD. This project thus aimed at assessing whether the inhibition of SCD restores sleep in 3xTg-AD mice, and whether this associated with modifications in astrocytic function. Wild-type (WT) and 3xTg-AD female mice (4-months old) received intracerebroventricular infusion of a SCD inhibitor (SCDi) or vehicle for 28 days, and a 24-hour electrocorticographic (ECoG) recording was conducted post-treatment. Post-mortem brain slices were stained for the astrocytic markers glial fibrillary acidic protein (GFAP) and 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) to perform cell counting and/or morphological evaluation in the hippocampus, lateral hypothalamus and thalamus. The results indicate that the reduced time spent awake and increased time spent in slow wave sleep (SWS) in 3xTg-AD mice was not restored by the SCDi treatment. Similar observations were made concerning the increased number of wake and SWS bouts in 3xTg-AD mice. Rhythmic and scale-free ECoG activity were markedly altered in 3xTg-AD mice for all wake/sleep states, and SCDi significantly altered these phenotypes in a different manner in mutant mice in comparison to WT mice. GFAP- and ALDH1L1-positive cell densities were elevated in the hippocampus and lateral hypothalamus/thalamus of 3x-Tg-AD mice, respectively, and SCDi rescued the increase in the CA1 region in particular. Overall, these findings suggest that the multiple wake/sleep alterations in 3xTg-AD mice are not substantially restored by targeting lipid metabolism using SCD inhibition, at least for the targeted age window, but that this treatment can revert hippocampal changes in astrocytes. This work will benefit the understanding of the pathophysiology related to AD and associated sleep disturbances.

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Lipid-accumulated reactive astrocytes promote disease progression in epilepsy

Cited by 59 publications

References 62 publications

Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species

Enhancer-AAVs allow genetic access to oligodendrocytes and diverse populations of astrocytes across species

LILRB3 suppresses immunity in glioma and is associated with poor prognosis

Electrocorticographic and Astrocytic Signatures of Stearoyl-CoA Desaturase Inhibition in the Triple Transgenic Mouse Model of Alzheimer’s Disease

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