bims-micgli 2026-02-22 papers

bims-micgli

Biomed News

on Microglia

Issue of 2026–02–22
nineteen papers selected by
Matheus Garcia Fragas, Universidade de São Paulo

Microglial reactivity and neuroinflammation-driven changes in motivational behaviors are regulated by Orai1 calcium channels.
Lipidome and Proteome of Astrocyte and Microglia ApoE Lipoprotein Reveal Differences Based on Cell Type and ApoE Isoform.
Human microglia in brain assembloids display region-specific diversity and respond to hyperexcitable neurons carrying SCN2A mutation.
Inflammatory stimulus enhances synaptic material uptake by adult APP microglia in a microfluidic neuron-microglia co-culture model.
Microglial Lyn Kinase-TRPV4 axis mediates social deficits in a maternal immune activation model.
Microglia‑mediated neuroinflammation in intracerebral hemorrhage: Pathological mechanisms and implications for therapeutic development (Review).
Astrocyte-microglia crosstalk through Hevin and Toll-like receptor signaling controls developmental thalamocortical synapse refinement.
Stretched to meet the challenge of myelination.
Protective ApoE variants eliminate toxic fats from neurons.
Anatomical and Neuronal Distribution of the G-Coupled Protein Receptor 75 mRNA in the Mouse Central Nervous System.
IFNγ-induced memory in human macrophages is sustained by the durability of cytokine signaling itself.
TMEM106B deficiency exacerbates α-synuclein aggregation in Parkinson's disease.
CDKL5 modulates the plasticity of excitatory synapses via liquid-liquid phase separation.
cGAS-IFN-I responses by extracting nuclear DNA from dying cells via nucleocytosis.
St6gal1-mediated sialylation protects retinal ganglion cells by restraining microglial phagocytosis.
Temporal modulation of microglial repopulation attenuates retinal degeneration in retinitis pigmentosa.
Aurkb deficiency disrupts microglial development, homeostasis and hinders remyelination following cuprizone-induced demyelination.
Structural basis of caveolin-driven membrane bending.
Neuropathologic basis of quantitative susceptibility mapping in the substantia nigra: contributions of tau, pigmented neurons, and iron.

Sci Signal. 2026 Feb 17. 19(925): eady8398

Microglial reactivity and neuroinflammation-driven changes in motivational behaviors are regulated by Orai1 calcium channels.

Kaitlyn E DeMeulenaere, Rogan A Grant, Megan E Martin, Hiam A Valencia, Jelena Radulovic, Michael W Salter, Murali Prakriya.

Microglia are the brain's resident immune cells that respond to injury and disease by transitioning between homeostatic and reactive states. These cell state transitions determine whether microglia promote or resolve inflammation in the central nervous system (CNS). In this study, we explored the role of Ca2+ signaling in regulating broader microglial cell state transitions and identified Orai1 Ca2+ channels as critical regulators of microglial plasticity and neuroinflammatory signaling. Conditional deletion of Orai1 in microglia impaired their ability to adopt reactive, proinflammatory states. Transcriptomic and metabolomic profiling revealed that Orai1 deletion suppressed the expression of proinflammatory genes linked to immunity, inflammation, and cell metabolism. Conversely, Orai1-deficient microglia generated greater amounts of neuroprotective and anti-inflammatory mediators, including BDNF, ARG1, and the mitochondrial metabolite itaconate. In a model of CNS inflammation induced by peripheral lipopolysaccharide (LPS) challenge, microglial Orai1 deletion attenuated microglial and astrocyte reactivity and reduced hippocampal amounts of the proinflammatory cytokines IL-1β and IL-6. Consistent with these cellular changes, microglial Orai1 knockout mice were protected against LPS-induced decreases in motivational behaviors, including impaired reward-seeking and escape behaviors. These findings establish Orai1 channels as key regulators of microglial cell state transitions, linking Ca2+ signaling to neuroinflammation and inflammation-driven behavioral dysfunction.

DOI: https://doi.org/10.1126/scisignal.ady8398
J Lipid Res. 2026 Feb 13. pii: S0022-2275(26)00026-X. [Epub ahead of print] 101000

Lipidome and Proteome of Astrocyte and Microglia ApoE Lipoprotein Reveal Differences Based on Cell Type and ApoE Isoform.

Michael R Strickland, Zhen Wang, Lesley R Golden, Hu Wang, Ping Lu, Yingxue Ren, G Travis Tabor, Na Zhao, Jason D Ulrich, Xianlin Han, Junmin Peng, David M Holtzman.

  Apolipoprotein E (ApoE) is the primary, most abundant apolipoprotein of the central nervous system (CNS) and plays an important role in brain metabolism and lipid homeostasis. In the CNS, ApoE is primarily secreted by astrocytes under homeostatic conditions and by microglia in certain disease-related conditions. APOE has three major alleles: APOE2, APOE3, and APOE4. APOE4 is the strongest genetic risk factor for late onset Alzheimer's disease (AD) and APOE2 results in decreased risk relative to APOE3. ApoE derived from astrocytes and microglia have been hypothesized to play different roles in the disease pathogenesis of Alzheimer's disease. In this study, we profiled the lipidome and proteome of ApoE lipoproteins secreted by astrocytes or microglia and found that they differed according to the cellular source of ApoE and ApoE isoform. Lipidomics revealed microglia-derived ApoE lipoproteins were enriched in cholesterol esters whereas astrocyte ApoE lipoproteins were enriched in sphingomyelin. Proteomics revealed astrocyte ApoE lipoproteins were enriched in proteins involved in glucose metabolism and acute phase response. Microglia-secreted lipoproteins were enriched in proteins involved in complement activation, synapse pruning, proteolysis, and the innate immune response. Further comparison of ApoE lipoproteins from APOE4 microglia revealed that ApoE4 lipoproteins were enriched in C1q and Lpl compared to ApoE2 and ApoE3 microglial lipoproteins which were enriched in Ankk1 and ApoC1. These results provide the molecular foundation for better understanding of how ApoE functions as an apolipoprotein with the lipoprotein cargo being dependent on the cellular source and ApoE isoform, ultimately contributing to CNS homeostasis and disease pathogenesis.

Keywords:  Alzheimer’s disease; ApoE; Apolipoproteins; apolipoprotein E; astrocytes; brain lipids; lipidomics; microglia; proteomics

DOI:  https://doi.org/10.1016/j.jlr.2026.101000
Sci Adv. 2026 Feb 20. 12(8): eady2977

Human microglia in brain assembloids display region-specific diversity and respond to hyperexcitable neurons carrying SCN2A mutation.

Jiaxiang Wu, Xiaoling Chen, Jingliang Zhang, Kyle Wettschurack, Morgan Robinson, Weihao Li, Yuanrui Zhao, Ye-Eun Yoo, Brody A Deming, Yue Shu, Akila D Abeyaratna, Zhefu Que, Dongshu Du, Matthew Tegtmeyer, Chongli Yuan, William C Skarnes, Zhong-Yin Zhang, Jean-Christophe Rochet, Long-Jun Wu, Yang Yang.

Microglia critically shape neuronal circuit development and function, yet their region-specific properties and roles in distinct circuits of the human brain remain poorly understood. In this study, we generated region-specific brain organoids (cortical, striatal, and midbrain), each integrated with human microglia, to fill this critical gap. Single-cell RNA sequencing uncovered six distinct microglial subtypes exhibiting unique regional signatures, including a subtype highly enriched for the GABAB receptor gene within striatal organoids. To investigate the contributions of microglia to neural circuitry, we created microglia-incorporated midbrain-striatal assembloids, modeling a core circuit node for many neuropsychiatric disorders, including autism. Using chemogenetics to activate this midbrain-striatal circuit, we observed increased calcium signaling in microglia involving GABAB receptors. Leveraging this model, we examined microglial responses within neural circuits harboring an SCN2A nonsense (C959X) mutation associated with profound autism. Microglia displayed heightened calcium responses to SCN2A mutation-mediated neuronal hyperactivity and engaged in excessive synaptic pruning. These pathological effects were reversed not only by pharmacological inhibition of microglial GABAB receptors but also by knockout of the GABBR1 gene in microglia. Collectively, our findings establish an advanced platform that can be used to dissect human neuroimmune interactions in subcortical regions and to evaluate previously undiscovered therapies, highlighting the important role of microglia in shaping critical circuitry related to neuropsychiatric disorders.

DOI: https://doi.org/10.1126/sciadv.ady2977
J Neuroinflammation. 2026 Feb 19.

Inflammatory stimulus enhances synaptic material uptake by adult APP microglia in a microfluidic neuron-microglia co-culture model.

Dolores Siedlecki-Wullich, Anne-Marie Ayral, Lukas Iohan, Célia Lemeu, Valérie Buiche, Karine Blary, Julien Chapuis, Fanny Eysert, Delphine Beury, Myriam Delacre, David Hot, Takahiro Masuda, Klaus-Peter Knobeloch, Marco Prinz, Jean-Charles Lambert, Devrim Kilinc.



Keywords:  APP mouse model; Alzheimer’s disease; IL-1β; PSD95; microfluidics; microglia; neuroinflammation; synapse

DOI:  https://doi.org/10.1186/s12974-026-03748-9
J Neuroinflammation. 2026 Feb 19.

Microglial Lyn Kinase-TRPV4 axis mediates social deficits in a maternal immune activation model.

Rezwanul Islam, Feng Zhang, Hadi Hasan Choudhary, Jun Yoshida, Ajith J Thomas, Ben Sorum, Khalid A Hanafy.



Keywords:  Autism; Calcium imaging; Lyn kinase; MIA; Microglia; Social deficits; TRPV4

DOI:  https://doi.org/10.1186/s12974-026-03738-x
Int J Mol Med. 2026 Apr;pii: 95. [Epub ahead of print]57(4):

Microglia‑mediated neuroinflammation in intracerebral hemorrhage: Pathological mechanisms and implications for therapeutic development (Review).

Xuehui Fan, Changzhi Pu, Luyi Zhong, Oucheng Wang, Binyi Zhao, Dongyi Liao, Xue Bai, Guiquan Chen, Guoqiang Yang.

  Intracerebral hemorrhage (ICH), a life‑threatening subtype of stroke accounting for 10‑15% of global stroke cases, is characterized by high disability and mortality rates, imposing a heavy socioeconomic burden worldwide. Despite its clinical importance, no effective therapeutic interventions exist for this condition. As the resident immune cells of the central nervous system, microglia play a pivotal role in the pathophysiology of ICH. These cells can be activated to adopt either anti‑inflammatory or pro‑inflammatory phenotypes. Following ICH, pro‑inflammatory mediators derived from microglia act as key drivers of neuroinflammation, thereby exacerbating secondary brain injury. By contrast, promoting the phenotypic shift of microglia toward an anti‑inflammatory state has been shown to mitigate an inflammatory response and facilitate neurological recovery. In the present study, existing evidence was reviewed to propose that post‑ICH brain injury and repair are orchestrated not by isolated cells, but by a highly dynamic neuroimmune network centered on microglia. Elucidating the spatiotemporal dynamics and key communicative nodes within this network represents a critical frontier. Moving beyond the classical M1/M2 dichotomy to target this network contextually offers a promising and precise therapeutic aim for future investigations.

Keywords:  ICH; brain damage; inflammation; microglial polarization; neuroprotection

DOI:  https://doi.org/10.3892/ijmm.2026.5766
Neuron. 2026 Feb 19. pii: S0896-6273(25)00984-5. [Epub ahead of print]

Astrocyte-microglia crosstalk through Hevin and Toll-like receptor signaling controls developmental thalamocortical synapse refinement.

Juan J Ramirez, Evelyn J Hardin, Kristina Sakers, Jinhu Kim, Crystal Colón Ortiz, Justin T Savage, Richa Hanamsagar, Carina L Block, Sandeep K Singh, Staci D Bilbo, Cagla Eroglu.

  Synapse formation and elimination are two crucial processes that occur concurrently in the developing brain. Astrocytes and microglia control both processes, yet how these two major glial cell types of the central nervous system (CNS) communicate to balance synapse formation and elimination is unknown. Astrocytes secrete the synaptogenic protein Hevin/SPARCL1, which induces the formation and plasticity of thalamocortical synapses in the mouse visual cortex. Here, we found that, in addition to this synaptogenic function, Hevin directly signals to microglia by interacting with Toll-like receptor 4 (TLR4). This signaling occurs when Hevin is proteolytically cleaved, producing a C-terminal fragment that is no longer synaptogenic. We found that Hevin, through TLR4, induces a distinct microglial state defined by increased TLR2 expression and phago-lysosomal content in vitro and in vivo. Microglial TLR4 signaling is required for the proper elimination of thalamocortical synapses during early postnatal development.

Keywords:  Hevin/Sparcl1; TLR4; astrocyte; microglia; thalamocortical synapse

DOI:  https://doi.org/10.1016/j.neuron.2025.12.028
Neuron. 2026 Feb 18. pii: S0896-6273(26)00041-3. [Epub ahead of print]114(4): 559-561

Stretched to meet the challenge of myelination.

Wenlong Xia, Stephen P J Fancy.

Myelin thickness and internode length are matched to axon caliber in the central nervous system (CNS), critical for optimal axonal action potential conduction. Dereddi et al.1 show that mechanotransduction channel TMEM63A in oligodendrocytes couples membrane stretch to Ca2+ signaling to refine myelin architecture.

DOI: https://doi.org/10.1016/j.neuron.2026.01.015
Neuron. 2026 Feb 18. pii: S0896-6273(26)00010-3. [Epub ahead of print]114(4): 556-558

Protective ApoE variants eliminate toxic fats from neurons.

Catherine M Heffner, Gilbert Di Paolo.

Ralhan et al.1 describe how lipidated particles of apolipoprotein E (ApoE) isoforms ApoE2 and ApoE3-Christchurch protect neurons from oxidative stress through the efflux of unsaturated and oxidized lipids via ABCA7. This mechanism ameliorated multiple dysfunctions observed in ApoE4 models.

DOI: https://doi.org/10.1016/j.neuron.2026.01.010
Eur J Neurosci. 2026 Feb;63(4): e70441

Anatomical and Neuronal Distribution of the G-Coupled Protein Receptor 75 mRNA in the Mouse Central Nervous System.

Melanie K Becher, Tessa Knox, Kaela Wilson, Lawrence F Kromer, Italo Mocchetti.

  G-protein coupled receptor (GPCR) 75 (GPR75) is a 540 amino acid member of the Gαq class of GPCRs, with no homology with other classic GPCRs. The current focus on GPR75 has centred on its potential role in metabolic disorders and cancer. GPR75 expression is abundant in the central nervous system (CNS) more so than in the peripheral tissues; however, much remains unknown about the distribution and role of this receptor throughout the CNS. In this study, we quantified GPR75 mRNA expression in the mouse CNS using RNAscope fluorescent in situ hybridization (FISH) technology, combined with immunohistochemistry (IHC) to detect GPR75 transcripts in specific neuronal cell types. GPR75 knockout (KO) mice were used as controls and specificity of hybridization. Our results show that GPR75 mRNA expression occurs in several neuronal populations including GABAergic and glutamatergic neurons. In select areas, such as the substantia nigra/ventral tegmental area, locus coeruleus and raphe nucleus, GPR75 mRNA is also highly expressed in monoaminergic neurons. Moreover, we found high expression of GPR75 mRNA in the cerebellum, in both GABAergic and glutamatergic neurons, suggesting a potential role for this receptor in motor/equilibrium activity. Indeed, GPR75 KO mice perform significantly better than wild-type littermates on the rotarod test. Our data suggest that this receptor may play an important role in brain physiology and function.

Keywords:  GABA; GPR75; cerebellum; glutamate; monoamines; rotarod

DOI:  https://doi.org/10.1111/ejn.70441
J Exp Med. 2026 Apr 06. pii: e20250976. [Epub ahead of print]223(4):

IFNγ-induced memory in human macrophages is sustained by the durability of cytokine signaling itself.

Aleksandr Gorin, Siyue Niu, Noa Harriott, Vyas Koduvayur, Quen J Cheng, Alexander Hoffmann.

Macrophages, as key sentinel cells of the innate immune system, can retain memory of prior stimulus exposure. IFNγ plays a central role in maintaining trained immunity in vivo and can induce potent memory in macrophages. Such memory is associated with the formation of de novo enhancers that alter gene expression responses to subsequent stimuli. However, how such enhancers are maintained after cytokine exposure remains unclear. We report that the mechanism underlying durable IFNγ-induced enhancers is not cell intrinsic. IFNγ-treated macrophages continue to exhibit JAK/STAT signaling days after cytokine removal. Blocking IFNγ signaling with a JAK inhibitor or anti-IFNγ neutralizing antibodies after cytokine removal is sufficient to reverse IFNγ-induced enhancers and erase the potentiated state of the treated macrophages. Our findings suggest that epigenetic changes in macrophages do not inherently encode innate immune memory or a "potentiated" macrophage state, but in fact are themselves dependent on ongoing signaling from cytokines sequestered at the cell surface.

DOI: https://doi.org/10.1084/jem.20250976
Brain. 2026 Feb 17. pii: awag065. [Epub ahead of print]

TMEM106B deficiency exacerbates α-synuclein aggregation in Parkinson's disease.

Lanxia Meng, Congcong Liu, Meihui Li, Huangchuan Gong, Xiaoling Gu, Wenxuan Zou, Han Liu, Hanying Teng, Jing Xiong, Zhentao Zhang.

  Parkinson's disease is an age-related neurodegenerative disease that is characterized by the deposition of α-synuclein aggregates in the brain. Nevertheless, the molecular mechanisms that regulate α-synuclein aggregation have not yet been fully identified. TMEM106B is a lysosomal transmembrane protein that has been reported to be associated with brain aging and neurodegenerative diseases including Parkinson's disease. Here we show that TMEM106B is reduced in the brains of patients with Parkinson's disease. Knockdown of TMEM106B increases the formation of α-synuclein aggregates in primary neurons and mouse brains. TMEM106B deficiency results in impaired lysosomal acidification, lipid metabolism disorders, and lipid droplet deposition in neurons. Interestingly, lipid droplets promote α-synuclein aggregation, resulting in the formation of α-synuclein fibrils with enhanced seeding activity and neurotoxicity compared with α-synuclein fibrils formed in the absence of lipid droplets. TMEM106B deficiency also leads to retardation of α-synuclein degradation by reducing the enzymatic activity of the lysosomal protease cathepsin D. Taken together, these results indicate that TMEM106B deficiency contributes to Parkinson's disease pathogenesis by accelerating α-synuclein aggregation and halting α-synuclein degradation.

Keywords:  Parkinson’s disease; lipid metabolism; neurodegenerative diseases; transmembrane protein 106B (TMEM106B)

DOI:  https://doi.org/10.1093/brain/awag065
Proc Natl Acad Sci U S A. 2026 Feb 24. 123(8): e2511123123

CDKL5 modulates the plasticity of excitatory synapses via liquid-liquid phase separation.

Mingjie Li, Ziai Zhu, Dan Li, Jinchao Wang, Mingjie Zhang, Qi-Wu Xu, Yu-Xian Zhang, Yongchuan Zhu, Jinwei Zhu, Zhi-Qi Xiong.

  Activity-dependent synaptic remodeling, essential for neural circuit plasticity, is orchestrated by central organizers within the postsynaptic density (PSD), including the scaffolding protein PSD95. However, the molecular mechanisms driving this process remain incompletely understood. Here, we identify cyclin-dependent kinase-like 5 (CDKL5), a protein associated with a severe neurodevelopmental condition known as CDKL5 deficiency disorder (CDD), as a critical regulator of structural plasticity at excitatory synapses. We show that CDKL5 undergoes liquid-liquid phase separation (LLPS) in vitro and in cultured neurons, forming cocondensates with PSD95. This LLPS-driven process spatially organizes synaptic components, specifically enabling the synaptic recruitment of Kalirin7 to promote dendritic spine enlargement. Pathogenic mutations disrupt condensate formation by impairing the LLPS capacity of CDKL5, directly linking phase separation defects to the pathogenesis of CDD. Our findings reveal a crucial role for CDKL5 in synaptic plasticity and establish LLPS as a fundamental mechanism by which CDKL5 coordinates molecular events to reorganize PSD architecture during synaptic remodeling.

Keywords:  CDKL5; dendritic spine; liquid–liquid phase separation; postsynaptic density; synaptic plasticity

DOI:  https://doi.org/10.1073/pnas.2511123123
Nat Commun. 2026 Feb 18. 17(1): 1658

cGAS-IFN-I responses by extracting nuclear DNA from dying cells via nucleocytosis.

Hideo Negishi, Yusuke Wada, Yoshitaka Shirasaki, Tomoya Hayashi, Yuji Kubota, Tomio Iwasaki, Mina Kurosawa, Tatsuma Ban, Daisuke Muto, Yusuke Suenaga, Taichi Kojima, Yuzuki Matsuda, Sean Lord Irish, Kosuke Dodo, Toru Suzuki, Mai Yamagishi, Burcu Temizoz, Atsushi Yoshimori, Chisato Kanai, Yoji Nagasaki, Masaki Ohmuraya, Tomohiko Tamura, Atsushi Iwama, Toshifumi Inada, Etsushi Kuroda, Kouji Kobiyama, Noriko Toyama-Sorimachi, Mutsuhiro Takekawa, Cevayir Coban, Ken J Ishii.

Self-DNA triggers cGAS-STING-mediated type I interferon (IFN-I) to induce both protective and pathogenic immune responses; however, how self-DNA activates the cytosolic cGAS-STING pathway remains unclear. Here we show that the cGAS/STING/IFN-I axis is activated by self-DNA via a process termed 'nucleocytosis', in which nuclear DNA is extracted from dying cells by macrophages. Mechanistically, lysosomal malfunction, via both proton loss and palmitoyl-protein thioesterase 1 (PPT1) inhibition, triggers cell death and calreticulin accumulation in the nuclei. Live-cell imaging of secretion activity reveals that macrophages access the calreticulin-enriched nuclei of dying cells and extract DNA for cGAS-STING activation. Consistent with these findings, PPT1-targeting cationic amphiphilic drugs induce a cGAS-STING-dependent IFN-I response in vitro and in vivo. Our findings thus identify nucleocytosis as a macrophage function for nuclear DNA extraction and induction of the cGAS/IFN-I axis, and suggest that nucleocytosis-inducing cell death could be a druggable target for treating self-DNA-related inflammatory diseases.

DOI: https://doi.org/10.1038/s41467-026-68839-w
J Neuroinflammation. 2026 Feb 18.

St6gal1-mediated sialylation protects retinal ganglion cells by restraining microglial phagocytosis.

Liyan Liu, Jiahui Tang, Qi Zhang, Zhe Liu, Yuxuan Qiu, Bing Zhang, Yidan Liu, Yehong Zhuo, Yiqing Li.



Keywords:  Microglia; Optic nerve injury; Retinal ganglion cells; ST6Gal1; Sialylation

DOI:  https://doi.org/10.1186/s12974-026-03736-z
Neurobiol Dis. 2026 Feb 12. pii: S0969-9961(26)00039-2. [Epub ahead of print]221 107295

Temporal modulation of microglial repopulation attenuates retinal degeneration in retinitis pigmentosa.

Weitao Zhang, Baishijiao Bian, Chunge Ren, Min Chen, Yajie Fang, Yixiao Zhou, Hongjia Zhang, Bowen Li, Hongling Liu, Xue Zhang, Yong Liu, Jianxin Jiang.

  Retinitis pigmentosa (RP) is an inherited retinal degenerative disorder characterized by the progressive loss of retinal pigment epithelial cells and rod and cone photoreceptors and irreversible vision loss, with no effective therapies currently available. Microglia, the resident immune cells in the retina, are known to aggravate neurodegeneration when chronically activated. Here, we investigated the impact of temporally controlled microglial depletion and repopulation on retinal degeneration in rd10 mice. Using the CSF1R inhibitor PLX5622, we achieved efficient microglial depletion during the peak of degeneration (P21), followed by spontaneous microglial repopulation. Short-term-repopulated microglia displayed a ramified morphology and homeostatic transcriptomic signatures, including the downregulation of disease-associated microglia (DAM) genes and suppression of neurodegeneration-related pathways, effects that were correlated with preserved visual function and photoreceptor survival. However, long-term repopulated microglia progressively exhibited DAM phenotypes, which coincided with diminished therapeutic efficacy and exacerbated neurodegeneration. Single-cell RNA sequencing confirmed the dynamic transcriptional transitions of repopulated microglia, their altered regulon activity, and their functional association with other immune cells. To counteract microglial reactivation, we developed a sequential 2-round depletion-repopulation strategy, which restored microglial homeostasis, reduced the expression of the proinflammatory cytokine IL-1β, preserved outer nuclear layer thickness, and sustained visual function. Our findings highlight the time-dependent plasticity of microglial phenotypes and suggest that temporally optimized microglial modulation is a promising therapeutic strategy for retinal neurodegeneration in RP.

Keywords:  Depletion; Macrophages; Microglia; Neuroinflammation; PLX5622; Repopulation; Retinitis pigmentosa

DOI:  https://doi.org/10.1016/j.nbd.2026.107295
iScience. 2026 Feb 20. 29(2): 114718

Aurkb deficiency disrupts microglial development, homeostasis and hinders remyelination following cuprizone-induced demyelination.

Weixing Yan, Dong Xiang, Li Du, Di Zhu, Qi Jia, Yuting Liu, Siyu Wang, Li Liu, Haihao Guan, Yelin Zhao, Guan Jiang, Sijia Gao, Hui Wang.

  Microglia are crucial for phagocytic clearance of myelin debris, which hinders remyelination and leads to neurological decline during aging and in multiple sclerosis (MS). However, the molecular mechanism enabling microglia to expand and function effectively in remyelination remains elusive. Here, we identified that mitotic kinase Aurkb was upregulated in microglia during early development and in MS. Neonatal deletion of Aurkb disrupted cell density, morphology, and proliferation, which is attributed to stalled mitosis. Inducible Aurkb ablation in adulthood led to microglial dystrophy and disrupted homeostasis. Aurkb deficiency compromised microglial activation in response to LPS-induced inflammation. Critically, Aurkb-deficient mice exhibited accumulated myelin debris and impaired oligodendrocyte regeneration and remyelination in the CPZ-induced demyelination model. Additionally, Aurkb deletion inhibited microglial clearance of myelin debris, independent of reduced microglia numbers. This defect was associated with diminished autophagy. Together, these findings establish Aurkb as a key regulator of microglial development, homeostasis, and responses to remyelination.

Keywords:  Cell biology; Neuroscience

DOI:  https://doi.org/10.1016/j.isci.2026.114718
bioRxiv. 2026 Feb 17. pii: 2026.02.05.703862. [Epub ahead of print]

Structural basis of caveolin-driven membrane bending.

Sarah M Connelly, Leon Bergner, Ajit Tiwari, Tyler S Brant, Samatha Medford, Siddanth Ramesh, Elizabeth D Tidwell, Youngki Yoo, Ke Xiao, J Gentry, Louise Chang, Bing Han, Padmini Rangamani, Milka Doktorova, Anne K Kenworthy, Shyamal Mosalaganti, Melanie D Ohi.

Caveolins are monotopic membrane proteins essential for caveolae formation and play a key role in signaling and lipid regulation. Recent structural studies show that caveolins assemble into amphipathic disc-shaped oligomers with a central β-barrel, an architecture conserved across species and distinct from other membrane-remodeling proteins. These discs embed in the membrane by displacing lipids from a single leaflet, inducing membrane curvature. However, the mechanism of disc-driven bending remains unresolved. Using cryo-electron tomography, structure-guided mutagenesis, and mammalian cell studies, we show that evolutionarily distinct caveolins differ dramatically in their ability to induce membrane curvature despite sharing a conserved global architecture. Through computational and theoretical analyses, we further demonstrate that patterning of hydrophobic residues along the outer rim of the disc of human Caveolin-1 induces the deformation of the surrounding leaflet, which, in turn, dictates membrane bending. Finally, we determine a 4.1 A resolution structure of human Caveolin-1 within heterologous caveolae in situ, revealing that the disc adopts a funnel-like conformation, further shaping membrane architecture. Together, these findings reveal fundamental structural principles that empower caveolins to sculpt and remodel cellular membranes.

DOI: https://doi.org/10.64898/2026.02.05.703862
Acta Neuropathol. 2026 Feb 18. 151(1): 17

Neuropathologic basis of quantitative susceptibility mapping in the substantia nigra: contributions of tau, pigmented neurons, and iron.

Daisuke Ono, Sravya Kondrakunta, Elijah Mak, Scott A Przybelski, Angela J Fought, Christopher G Schwarz, Melissa E Murray, Aivi Nguyen, Ross R Reichard, Matthew L Senjem, Jeffrey L Gunter, Clifford R Jack, Toji Miyagawa, Leah K Forsberg, Julie A Fields, Rodolfo Savica, Vijay K Ramanan, David T Jones, Hugo Botha, Erik K St Louis, David S Knopman, Neill R Graff-Radford, Gregory S Day, Tanis J Ferman, Walter K Kremers, Val J Lowe, Ronald C Petersen, Bradley F Boeve, Dennis W Dickson, Kejal Kantarci.

  Quantitative susceptibility mapping (QSM) on MRI quantifies tissue magnetic susceptibility, which increases with iron accumulation, myelin loss, and neuroinflammation. Elevated QSM in the substantia nigra (SN) has been reported in Lewy body disease and other parkinsonian disorders, but from existing literature it remains unclear whether these findings are driven by neurodegeneration-related iron deposition or other neuropathologic features. We studied 59 autopsied participants who underwent antemortem 3 T MRI with QSM (median age at death, 78.5 years; MRI-to-death interval, 2.0 years), including clinical diagnoses of 18 with Alzheimer's-type dementia, 15 cognitively unimpaired, 9 with mild cognitive impairment, and 9 with dementia with Lewy bodies. A machine learning-incorporated digital histopathology pipeline quantified tau burden, iron deposition, and neuronal densities. The SN was divided into geometric quadrants, and QSM values were analyzed in relation to corresponding neuropathologic measures within each quadrant. Iron deposition correlated with QSM in all quadrants (ρ = 0.41-0.56, all P < 0.005). Tau burden correlated with QSM in the ventromedial (VM) quadrant (ρ = 0.45, P = 0.002), whereas lower pigmented neuron density was associated with higher QSM in the dorsomedial quadrant (ρ = - 0.35, P = 0.007). Rank regression analysis confirmed iron as the strongest predictor of QSM across all quadrants (β = 0.35-1.06, P ≤ 0.026), with tau independently associated with QSM in the VM (β = 0.45, P = 0.015). Mediation analysis demonstrated that tau exerted direct (0.45, P = 0.018) and indirect effects via iron (0.12, P = 0.046) on QSM in the VM, with 80% of the effect being direct. These findings underscore the contributions of tau pathology, pigmented neuron density, and iron deposition to nigral magnetic susceptibility and highlight the potential for QSM to serve as a sensitive biomarker for diverse neuropathologies.

Keywords:  Alzheimer’s disease; Artificial intelligence; Lewy body disease; Machine learning; Quantitative susceptibility mapping

DOI:  https://doi.org/10.1007/s00401-026-02991-x