Glial cells maintain the brain’s lipid and energy balance, and their breakdown is increasingly recognized as a causal contributor to Alzheimer’s disease (AD). While this concept is established, no approach has directly shown how glial homeostatic failure manifests across brain regions and microenvironments or how it links local pathology, such as plaques, to global metabolic imbalance. To address this gap, we developed iMIST, an integrated platform that combines MALDI-based metabolite imaging, histology, and spatial transcriptomics within a single tissue section to align molecular and anatomical information. Using a mouse model of late-onset AD that recapitulates both amyloid deposition and metabolic vulnerability, iMIST revealed that glial lipid dysregulation is widespread but spatially specialized. In gray matter, plaque-associated microglia were associated with upregulated glycerophospholipid-remodeling in cortico-thalamic areas indicating metabolic stress around local pathology. In contrast, white matter tracts rich in lipid-producing oligodendrocytes show plaque-independent deficits in galactosylceramide metabolism reflecting their high myelin demand. Both processes intensify with age, transforming adaptive glial responses into persistent metabolic dysfunction. Together, these findings demonstrate the spatial interplay between global glial metabolic imbalance and local microenvironmental stressors associated with AD pathology. By integrating transcriptomic and metabolomic information in situ , iMIST provides a framework for uncovering how regional glial vulnerability shapes the pathogenesis of neurodegenerative diseases. ### Competing Interest Statement The authors have declared no competing interest. NIH, R01NS130876, R01AI178795, R01AI149699, R42GM143989, P01AG002132, R01AG082141

Oligodendrocytes form myelin sheaths around axons to enable rapid signaling within neural circuits. The generation of new oligodendrocytes through differentiation of oligodendrocyte precursor cells (O...

Brain myeloid cells accumulate neutral lipids in multiple human neurodegenerative disorders and relevant mouse models. These lipids are often assumed …

Obesity is a worldwide health crisis, with unhealthy diet as a major contributor. Comorbid neuropsychiatric conditions such as depression and anxiety are associated with obesity. Since obesity is a pro-inflammatory state, chronic neuroinflammation may mediate obesity and neuropsychiatric comorbidity. We used RNA-seq to provide a single-cell resolution transcriptome of brain immune cells using long-term high-fat diet (HFD) to model obesity in male mice. HFD mice exhibited depression and anxiety-like behavior. We observed a shift towards increased proportions of lipid droplet-accumulating microglia (LDAM) in the long-term HFD brain. By in-depth characterization of the transcriptional signature of LDAM, we identified that ACSL1, a key regulator of lipid droplet biogenesis, was highly expressed in LDAM induced by HFD. Finally, we demonstrated that ACSL1 inhibition reduced lipid droplets deposition in microglia exposed to free fatty acids (FFA). Our findings provide a comprehensive view of the molecular changes in brain immune cells associated with HFD, suggesting a link between microglial lipid droplet accumulation and neurological comorbidities induced by obesity.

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This postdoc uncovers how glial dysfunction drives neurodegeneration in a rare movement disorder.

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A tri-omic atlas of the mouse brain from postnatal day 0 to P21 reveals that layer-specific projection neurons have a role in coordinating axonogenesis and myelination.

Persistent microglial activation upon ischaemic injury leads to the formation of stroke-associated foamy microglia, perpetuating long-term inflammation, white matter damage and functional impairments....

Brain functions require a constant supply of glucose. However, the brain energy stores are unclear. Here, the authors show that oligodendroglial fatty acid metabolism can be an energy reserve for whit...

Myelin damage in multiple sclerosis can be detected up to 7 years before symptoms, with early immune pathway activation and a 21-protein panel showing promise for presymptomatic diagnosis.