bims-micgli 2026-01-25 papers

PLoS Biol. 2026 Jan;24(1): e3003538

Microglial activity during postnatal development is required for infantile amnesia in mice.

Erika Stewart, Louisa G Zielke, Antje R de Boer, Gabrielle Guillaume Boulaire, Sarah D Power, Tomás J Ryan.

Infantile amnesia, the inability to recall episodic memories formed during early childhood, is a hallmark of postnatal brain development. Yet the underlying mechanisms remain poorly understood. This work aimed to gain a better mechanistic understanding of infantile amnesia. Microglia, specialized macrophages of the central nervous system, are known to play an important role in synaptic refinement during postnatal development and have recently been implicated in memory-related functions. Using mouse models, we identified microglia as key regulators of memory accessibility in infancy. We profiled dynamic changes in microglial morphology across the postnatal window that paralleled the onset of infantile forgetting. We found that pharmacological inhibition of microglial activity during a specific postnatal window prevents infantile amnesia for a contextual fear memory, implicating microglia as active modulators of infant memory persistence. Using activity-dependent tagging of infant encoded engram cells, we demonstrated that microglial inhibition alters engram size and engram reactivation in the amygdala and results in changes in microglia-engram cell interactions. Furthermore, we characterized a relationship between microglial dysfunction and the lack of infantile amnesia in maternal immune activation offspring. Together, these findings reveal a novel role for microglia in regulating infant memory retrieval in mice and suggest that microglial dysfunction may contribute to altered memory trajectories in neurodevelopmental disorders.

DOI: https://doi.org/10.1371/journal.pbio.3003538

Neuron. 2026 Jan 21. pii: S0896-6273(25)00997-3. [Epub ahead of print]114(2): 193-195

The TREM2 T96K paradox: Stronger signaling in vitro, weaker microglia in vivo.

Silvia Penati, Marco Colonna.

Pilat, Le, and colleagues1 reveal that the Alzheimer's-linked TREM2 T96K variant, previously labeled gain of function based on in vitro assays, unexpectedly weakens microglial activation and disease-associated microglial responses in female mice in vivo, prompting a reassessment of what "functional gain" means for TREM2 in neurodegeneration.

DOI: https://doi.org/10.1016/j.neuron.2025.12.041

Mol Neurobiol. 2026 Jan 23. 63(1): 391

Targeting HMGB1 in Microglia Alleviates Neuroinflammation and Modulates the Pro-/Anti-inflammatory Balance of Microglia/Macrophages in Experimental Autoimmune Encephalomyelitis.

Yuzhen Li, Ke Lei, Haoyu Wang, Siyu Yang, E Du, Jiapei Dai, Fang Zheng, Jiawen Lei, Huoying Chen, Yan Sun.

High-mobility group box 1 (HMGB1) undergoes dynamic expression, release, and subcellular localization changes, and exerts distinct functions in the central nervous system, playing a crucial role in neuroinflammation and exacerbating autoimmune diseases. Although microglia exhibit elevated HMGB1 expression during experimental autoimmune encephalomyelitis (EAE), the precise roles of microglial-derived HMGB1 in the pathogenesis and progression of EAE remain largely unknown. In this study, we generated conditional knockout mice lacking HMGB1 in microglia to assess the role of HMGB1 in EAE progression. We found that depletion of microglial HMGB1 decreased morbidity, delayed the onset of symptoms, and reduced the severity of demyelination in EAE. Furthermore, EAE mice with a conditional knockout of HMGB1 in microglia exhibited decreased expression of CD3+ T cells and HMGB1-positive cells in the spinal cord. This resulted in a marked reduction in the number of activated microglia and an alteration in their morphology, thereby restoring the pro-/anti-inflammatory balance of microglia/macrophages; these effects were accompanied by the regulation of inflammatory factor expression and neuronal damage in EAE. Together, these results suggest that HMGB1 derived from microglia breaks the pro-/anti-inflammatory balance and aggravates neuroinflammation in EAE. We propose that targeting microglial HMGB1 could be an effective way to reduce neuroinflammation.

Keywords: Experimental autoimmune encephalomyelitis; HMGB1; Microglia; Neuroinflammation; Pro-/anti-inflammatory polarization

DOI: https://doi.org/10.1007/s12035-026-05706-1

Cell Rep. 2026 Jan 16. pii: S2211-1247(25)01613-4. [Epub ahead of print]45(1): 116841

Inducible deletion of DGAT1 and 2 from microglia exacerbates neurodegeneration and endolysosomal lipid accumulation in male PS19 mice.

Brain myeloid cells accumulate neutral lipids in multiple human neurodegenerative disorders and relevant mouse models. These lipids are often assumed to be contained in lipid droplets (LDs). While studies have been performed in cell culture and Drosophila models to characterize glial LDs, the roles of microglial LD biogenesis in mammalian tauopathy are unclear. To address this issue, we induced the deletion of diacylglycerol acyltransferases (DGATs) 1 and 2, enzymes critical for LD formation, from microglia in the PS19 mouse model of tauopathy. Microglial DGAT double knockout (KO) exacerbated neurodegeneration and increased the abundance of brain cholesteryl esters in male PS19 mice. Myeloid cell lipid accumulations appeared to largely localize to endosomes/lysosomes, not LDs, at baseline and were exacerbated upon DGAT KO. Our results suggest that microglial DGAT-dependent TAG/LD biogenesis is adaptive in advanced tauopathy. Most lipid accumulation in brain myeloid cells does not appear to correspond to LDs in this tauopathy model, which has implications for the development of lipid-modulating therapies for neurodegenerative diseases.

Keywords: CD68; CP: metabolism; CP: neuroscience; PS19; cholesteryl ester; diacylglycerol acyltransferase; lipid droplet; lysosome; microglia; neurodegeneration; tauopathy; triglyceride

DOI: https://doi.org/10.1016/j.celrep.2025.116841

Elife. 2026 Jan 19. pii: e110158. [Epub ahead of print]15

Linking neuron-glia interactions and longevity.

Michael Pokrass, Nan Hao.

Proteomics experiments on Drosophila reveal sex-specific effects in aging, and an important role for a protein called DIP-β.

Keywords: D. melanogaster; DIP-β; aging; cell surface proteome; glia; intercellular signaling; neuroscience; sex-specific regulators

DOI: https://doi.org/10.7554/eLife.110158