investigating-glycolysis-primary-microglia-using-extracellular-flux

Investigating Glycolysis in Primary Microglia Using Extracellular Flux Assay

Microglia, the resident macrophage cells of the central nervous system, dynamically alter their metabolic programs in response to physiological and ...

Memorial University of Newfoundland

Editorial: Age-Related Neuroimmunology of Degeneration and Repair.

Multiple sclerosis (MS) is a neurodegenerative condition of the central nervous system (CNS). It is associated with blood-brain barrier (BBB) breakdown and intravasation of leukocytes, particularly monocyte-derived macrophages, into the CNS. Pericytes are mural cells that are encased within the basement membrane of vasculature, and they contribute functionally to the neurovascular unit. These cells play an important role in maintaining BBB integrity and CNS homeostasis. However, the critical role of pericytes in mediating inflammation in MS or its models is unclear. Whether pericytes infiltrate into the CNS parenchyma in MS also needs clarification.

Pericytes as mediators of infiltration of macrophages in multiple sclerosis.

Multiple sclerosis (MS) is a devastating autoimmune disease that leads to profound disability. This disability arises from the stochastic, regional loss of myelin-the insulating sheath surrounding neurons-in the central nervous system (CNS). The demyelinated regions are dominated by the brain's resident macrophages: microglia. Microglia perform a variety of functions in MS and are thought to initiate and perpetuate demyelination through their interactions with peripheral immune cells that traffic into the brain. However, microglia are also likely essential for recruiting and promoting the differentiation of cells that can restore lost myelin in a process known as remyelination. Given these seemingly opposing functions, an overarching beneficial or detrimental role is yet to be ascribed to these immune cells. In this chapter, we will discuss microglia dynamics throughout the MS disease course and probe the apparent dichotomy of microglia as the drivers of both demyelination and remyelination.

Microglia and Multiple Sclerosis.

Microglia, the resident immune cells of the central nervous system, emerge in the brain during early embryonic development and persist throughout life. They play essential roles in brain homeostasis, and their dysfunction contributes to neuroinflammation and the progression of neurodegenerative diseases. Recent studies have uncovered an intricate relationship between microglia functions and metabolic processes, offering fresh perspectives on disease mechanisms and possible treatments. Despite these advancements, there are still significant gaps in our understanding of how metabolic dysregulation affects microglial phenotypes in these disorders. This review aims to address these gaps, laying the groundwork for future research on the topic. We specifically examine how metabolic shifts in microglia, such as the transition from oxidative phosphorylation and mitochondrial metabolism to heightened glycolysis during proinflammatory states, impact the disease progression in Alzheimer's disease, multiple sclerosis, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease. Additionally, we explore the role of iron, fatty and amino acid metabolism in microglial homeostasis and repair. Identifying both distinct and shared metabolic adaptations in microglia across neurodegenerative diseases could reveal common therapeutic targets and provide a deeper understanding of disease-specific mechanisms underlying multiple CNS disorders.

Fueling neurodegeneration: metabolic insights into microglia functions.

Oxidized phosphatidylcholines (OxPCs) are neurotoxic byproducts of oxidative stress elevated in the central nervous system (CNS) during progressive multiple sclerosis (P-MS). How OxPCs contribute to the pathophysiology of P-MS is unclear. Here we show that stereotactic OxPC deposition in the CNS of mice induces a chronic compartmentalized lesion with pathological features similar to chronic active lesions found in P-MS. Using this model, we found that although microglia protected the CNS from chronic neurodegeneration, they were also replaced by monocyte-derived macrophages in chronic OxPC lesions. Aging, a risk factor for P-MS, altered microglial composition and exacerbated neurodegeneration in chronic OxPC lesions. Amelioration of disease pathology in Casp1/Casp4-deficient mice and by blockade of IL-1R1 indicate that IL-1β signaling contributes to chronic OxPC accumulation and neurodegeneration. These results highlight OxPCs and IL-1β as potential drivers of chronic neurodegeneration in MS and suggest that their neutralization could be effective for treating P-MS.

Oxidized phosphatidylcholines deposition drives chronic neurodegeneration in a mouse model of progressive multiple sclerosis via IL-1β signaling.

Although increased maternal androgens, such as those in polycystic ovary syndrome (PCOS), are associated with a higher incidence of autism spectrum disorder (ASD) in offspring, a causal link has yet to be established. We assessed whether perinatal hyperandrogenization in a murine model recapitulates core ASD traits and compared this model to the maternal immune activation (MIA) model of ASD. Both models produced ASD-like phenotypes, yet they exhibited distinct behavioral subtypes and neurodevelopmental trajectories. Hyperandrogenized offspring showed greater reductions in social communication (neonatal USVs, d = 0.633-0.773; juvenile USVs, d = 1.103-1.216; social preference, d = 0.715), whereas only MIA offspring showed increased repetitive behaviors (d = 0.599). Ex vivo magnetic resonance imaging revealed volume increases in specific cortical regions in both models, with MIA additionally showing absolute cingulate cortex enlargement, and hyperandrogenized mice displaying focal increases in sexually dimorphic regions, despite a 36% reduction in overall brain volume (FDR 10%). Placentas from both groups showed reduced LIX (CXCL5), but distinct immune shifts also emerged: MIA placentas exhibited elevated IL-4 and IL-1β, whereas hyperandrogenized placentas showed increased TNFα. In neonatal brains, both conditions were associated with reduced IL-2, with MIA additionally decreasing IL-17A and IL-12p70, suggesting suppression of Th1/Th17-type cytokine signaling that normally supports proinflammatory and immune-neural interactions. DRD2 and BDNF protein were upregulated in hyperandrogenized fetal brains but downregulated with MIA. These results suggest that hyperandrogenization and MIA act through distinct mechanisms, producing subtle neurodevelopmental and behavioral differences consistent with human ASD subtypes.

Perinatal hyperandrogenization and immune activation in rodents model subtypes of autism.

Maternal immune activation (MIA) contributes to neurodevelopmental disorders with male-biased prevalence. To disentangle the contributions of sex chromosomes (XX vs. XY) and gonads (ovaries vs. testes) in shaping fetal responses to MIA, we used the four-core genotypes (FCG) mouse model. Offspring representing all combinations of sex chromosome and gonadal status were generated and exposed to poly(I:C) or saline at embryonic day (E)12.5. We assessed maternal serum, fetal placentas, and fetal brain cytokines at E13.5; at E17.5, fetal development was evaluated via microultrasound and CT imaging. MIA induced a robust maternal inflammatory response, elevating IL-6, MCP-1 (CCL2), and TNF-α, which disrupted placental function and fetal development. Compared to all other genotypes, XX gonadal females exhibited a distinct placental proinflammatory signature that appeared largely independent of MIA exposure, along with greater umbilical artery blood flow and relatively little fetal brain inflammation, suggesting a placental buffering effect. In contrast, gonadal males demonstrated greater susceptibility to MIA-related impairments than gonadal females in umbilical artery diameter and blood flow, while XY gonadal females displayed the greatest neural inflammation following MIA. A pilot study using CT imaging suggests concurrent underdevelopment of the fetal thymus, trachea, heart ventricles, and clavicle in MIA-exposed XX gonadal males relative to gonadal females, indicating that the presence of testes/Sry in an XX chromosomal context may exacerbate MIA effects for these structures. These findings reveal that sex chromosomes and gonadal hormones both contribute to fetal resilience to MIA, offering insight into sex-specific developmental trajectories and informing strategies to protect fetal neurodevelopment.

Article	Year
Editorial: Age-Related Neuroimmunology of Degeneration and Repair. Frontiers in aging neuroscience\| PubMed ID: 34489687	2021
Pericytes as mediators of infiltration of macrophages in multiple sclerosis. Journal of neuroinflammation\| PubMed ID: 34952601	2021
Microglia and Multiple Sclerosis. Advances in neurobiology\| PubMed ID: 39207707	2024
Fueling neurodegeneration: metabolic insights into microglia functions. Journal of neuroinflammation\| PubMed ID: 39551788	2024
Oxidized phosphatidylcholines deposition drives chronic neurodegeneration in a mouse model of progressive multiple sclerosis via IL-1β signaling. Nature neuroscience\| PubMed ID: 41326786	2026
Perinatal hyperandrogenization and immune activation in rodents model subtypes of autism. Translational psychiatry\| PubMed ID: 41611658	2026
Fetal developmental trajectories following maternal immune activation are shaped by sex chromosome-gonadal interactions. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 41849388	2026

Deepak K. Kaushik

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