TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury

Zambusi, Alessandro; Novoselc, Klara Tereza; Hutten, Saskia; Kalpazidou, S.; Koupourtidou, Christina; Schieweck, Rico; Aschenbroich, Sven; Silva, Lara Luíza; Yazgili, Ayse Seda; Bebber, Frauke van; Schmid, Bettina; Möller, Gabriel; Tritscher, Clara; Stigloher, Christian; Delbridge, Claire; Sirko, Swetlana; Günes, Zeynep Irem; Liebscher, Sabine; Schlegel, Jürgen; Aliee, Hananeh; Theis, Fabian J.; Meiners, Silke; Kiebler, Michael A.; Dormann, Dorothee; Ninkovic, Jovica

doi:10.1038/s41593-022-01199-y

Cited by 23 publications

(23 citation statements)

References 96 publications

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“…Experimental TBI also results in the accumulation of lipid-laden microglia (Zambusi et al, 2022). In aged brain tissue in humans and mice, lipid droplet accumulating microglia have a pro-inflammatory activation phenotype that is associated with increased ROS production and reduced phagocytic activity (Marschallinger et al, 2020).…”

Section: Tb I D Is Rup Ts Mi Crog Lial Lipid Me Tabolis M and In Cre ...mentioning

confidence: 99%

“…Notably, the pro-inflammatory state of lipid-laden microglia can be aggravated by CNS injuries, including TBI and stroke (Arbaizar-Rovirosa et al, 2023;Ritzel et al, 2023;Zambusi et al, 2022). Importantly, the lipid-laden pro-inflammatory and dysfunctional metabolic phenotype was reversed by pharmacological depletion and repopulation of microglia using a CSF1R antagonist, PLX5622, not only in aged BALB/c mice (O'Neil et al, 2018) but also in aged C57BL/6 mice subjected to TBI (Ritzel et al, 2023).…”

Section: Tb I D Is Rup Ts Mi Crog Lial Lipid Me Tabolis M and In Cre ...mentioning

confidence: 99%

“…In aged brain tissue in humans and mice, lipid droplet accumulating microglia have a pro‐inflammatory activation phenotype that is associated with increased ROS production and reduced phagocytic activity (Marschallinger et al, 2020). Notably, the pro‐inflammatory state of lipid‐laden microglia can be aggravated by CNS injuries, including TBI and stroke (Arbaizar‐Rovirosa et al, 2023; Ritzel et al, 2023; Zambusi et al, 2022). Importantly, the lipid‐laden pro‐inflammatory and dysfunctional metabolic phenotype was reversed by pharmacological depletion and repopulation of microglia using a CSF1R antagonist, PLX5622, not only in aged BALB/c mice (O'Neil et al, 2018) but also in aged C57BL/6 mice subjected to TBI (Ritzel et al, 2023).…”

Section: Tbi Disrupts Microglial Lipid Metabolism and Increases Keton...mentioning

confidence: 99%

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Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury

Strogulski,

Portela,

Polster

et al. 2023

Journal of Neurochemistry

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Traumatic brain injury (TBI) is a devastating neurological disorder caused by a physical impact to the brain that promotes diffuse damage and chronic neurodegeneration. Key mechanisms believed to support secondary brain injury include mitochondrial dysfunction and chronic neuroinflammation. Microglia and brain‐infiltrating macrophages are responsible for neuroinflammatory cytokine and reactive oxygen species (ROS) production after TBI. Their production is associated with loss of homeostatic microglial functions such as immunosurveillance, phagocytosis, and immune resolution. Beyond providing energy support, mitochondrial metabolic pathways reprogram the pro‐ and anti‐inflammatory machinery in immune cells, providing a critical immunometabolic axis capable of regulating immunologic response to noxious stimuli. In the brain, the capacity to adapt to different environmental stimuli derives, in part, from microglia's ability to recognize and respond to changes in extracellular and intracellular metabolite levels. This capacity is met by an equally plastic metabolism, capable of altering immune function. Microglial pro‐inflammatory activation is associated with decreased mitochondrial respiration, whereas anti‐inflammatory microglial polarization is supported by increased oxidative metabolism. These metabolic adaptations contribute to neuroimmune responses, placing mitochondria as a central regulator of post‐traumatic neuroinflammation. Although it is established that profound neurometabolic changes occur following TBI, key questions related to metabolic shifts in microglia remain unresolved. These include (a) the nature of microglial mitochondrial dysfunction after TBI, (b) the hierarchical positions of different metabolic pathways such as glycolysis, pentose phosphate pathway, glutaminolysis, and lipid oxidation during secondary injury and recovery, and (c) how immunometabolism alters microglial phenotypes, culminating in chronic non‐resolving neuroinflammation. In this basic neurochemistry review article, we describe the contributions of immunometabolism to TBI, detail primary evidence of mitochondrial dysfunction and metabolic impairments in microglia and macrophages, discuss how major metabolic pathways contribute to post‐traumatic neuroinflammation, and set out future directions toward advancing immunometabolic phenotyping in TBI.image

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Section: Tb I D Is Rup Ts Mi Crog Lial Lipid Me Tabolis M and In Cre ...mentioning

confidence: 99%

Section: Tb I D Is Rup Ts Mi Crog Lial Lipid Me Tabolis M and In Cre ...mentioning

confidence: 99%

Section: Tbi Disrupts Microglial Lipid Metabolism and Increases Keton...mentioning

confidence: 99%

See 1 more Smart Citation

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury

Strogulski,

Portela,

Polster

et al. 2023

Journal of Neurochemistry

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“…29 In the context of traumatic injury models, it has been observed that TDP-43 induction contributes to the activation of microglial cells, leading to the upregulation of Gal-3. 30 Like in AD, the role of neuroinflammation and immune-mediated mechanisms in the development of FTD is well established. 10 Indeed, a causal role of neuroinflammation has been proposed, as evidenced by increased microglial activation in the frontal and temporal cortices, astrogliosis, and abnormal expression of pro-and anti-inflammatory factors in CSF and blood.…”

Section: Introductionmentioning

confidence: 99%

“…In the context of traumatic injury models, it has been observed that TDP‐43 induction contributes to the activation of microglial cells, leading to the upregulation of Gal‐3 30 . Like in AD, the role of neuroinflammation and immune‐mediated mechanisms in the development of FTD is well established 10 .…”

Section: Introductionmentioning

confidence: 99%

Galectin‐3 is upregulated in frontotemporal dementia patients with subtype specificity

Borrego–Écija,

Pérez‐Millan,

Antonell

et al. 2023

Alzheimer's & Dementia

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INTRODUCTIONNeuroinflammation is a major contributor to the progression of frontotemporal dementia (FTD). Galectin‐3 (Gal‐3), a microglial activation regulator, holds promise as a therapeutic target and potential biomarker. Our study aimed to investigate Gal‐3 levels in patients with FTD and assess its diagnostic potential.METHODSWe examined Gal‐3 levels in brain, serum, and cerebrospinal fluid (CSF) samples of patients with FTD and controls. Multiple linear regressions between Gal‐3 levels and other FTD markers were explored.RESULTSGal‐3 levels were increased significantly in patients with FTD, mainly across brain tissue and CSF, compared to controls. Remarkably, Gal‐3 levels were higher in cases with tau pathology than TAR‐DNA Binding Protein 43 (TDP‐43) pathology. Only MAPT mutation carriers displayed increased Gal‐3 levels in CSF samples, which correlated with total tau and 14‐3‐3.DISCUSSIONOur findings underscore the potential of Gal‐3 as a diagnostic marker for FTD, particularly in MAPT cases, and highlights the relation of Gal‐3 with neuronal injury markers.

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Microglia Lipid Droplets in Physiology and Neurodegeneration

West,

Glass

2023

Phase Separation in Living Cells

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TDP-43 condensates and lipid droplets regulate the reactivity of microglia and regeneration after traumatic brain injury

Cited by 23 publications

References 96 publications

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury

Fundamental Neurochemistry Review: Microglial immunometabolism in traumatic brain injury

Galectin‐3 is upregulated in frontotemporal dementia patients with subtype specificity

Microglia Lipid Droplets in Physiology and Neurodegeneration

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