bims-micgli 2026-08-02 papers

bims-micgli

Biomed News

on Microglia

Issue of 2026–08–02
29 papers selected by
Matheus Garcia Fragas, Universidade de São Paulo

Human-specific SRGAP2 paralogs synchronize neotenic microglial maturation and synaptic development.
MicroRNA-223 Enhances Microglia-Dependent Clearance of Amyloid Beta Plaques and Ameliorates Behavioral Deficits in a Mouse Model of Alzheimer's Disease.
A non-canonical androgen signaling pathway drives microglial activation and tau pathology in females.
Transcriptional regulation of disease-relevant microglial activation programs.
Sex differences in somatosensory circuitry are programmed by developmental microglia-astrocyte interaction.
Microglia regulate sleep and thermoregulatory stability.
Microglia extract neuronal proteolytic organelles via skoupocytosis.
Microglia as Double-Edged Players in Ischemic Stroke.
iPSC-Derived Microglia-like Cells Exhibit Protocol-Dependent Transcriptomic Features and Robust Phagocytosis of Glioma Cells.
PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain.
CCR5 drives glucose metabolic reprogramming to control microglial synaptic pruning via histone lactylation in a mouse model of depression.
Oligodendroglial TANGO2 Regulates Lipid Metabolism to Control Motor Coordination.
Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia.
A Microglia-Astrocyte Signaling Axis Regulates Astrocyte Piezo1 Expression and Inflammatory Responses.
Microglial immunometabolic reprogramming in Alzheimer's disease: From mitochondrial dysfunction and redox imbalance to NLRP3 inflammasome-driven neuroinflammation.
NPC1 deficiency engages a lysosome-genome-immune program linked to neurodegeneration and cellular aging signatures.
Retinal proteome changes mirror brain pathology and reveal synaptic and cytoskeletal dysfunction in Alzheimer's disease.
Astrocyte redox imbalance underlies prelimbic neuronal hypoactivity and maladaptive affective behaviors in epilepsy.
APOE4 disrupts the central dogma by arresting neuronal proteome dynamics.
Immunometabolic reprogramming in multiple sclerosis: from pathogenic amplifier to therapeutic target in neuroinflammation and remyelination.
CD4 T lymphocytes shape the development and maturation of the central nervous system.
The Critical Role of Microglia in the Stress Response.
Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.
Obesity-driven microbial GABA depletion promotes metabolic rewiring and colorectal cancer progression.
Lipidomic profiling reveals age-dependent changes in plasma membrane lipids that affect neural stem cell aging.
Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.
Metabolomics atlas of Alzheimer's disease models.
Aquaporin-4 mislocalization from astrocyte endfeet prolongs survival in a prion-cerebral amyloid angiopathy model.
APOE genotype is associated with Ex vivo inflammatory responses in healthy individuals: Potential implications for Alzheimer's disease.

Neuron. 2026 Jul 22. pii: S0896-6273(26)00536-2. [Epub ahead of print]

Human-specific SRGAP2 paralogs synchronize neotenic microglial maturation and synaptic development.

Carlos Diaz-Salazar, JaeYeon Kim, Marine Krzisch, Juyoun Yoo, Patricia R Nano, Aparna Bhaduri, Rudolf Jaenisch, Mercedes Paredes, Franck Polleux.

  The human brain is distinguished by unusually prolonged developmental timing, yet the genetic mechanisms coordinating this neoteny across cell types remain incompletely understood. Here, we show that human cortical microglia undergo neotenic structural and transcriptional maturation relative to mouse microglia. We identify SRGAP2B/C, human-specific paralogs of the ancestral SRGAP2A, as the only human-specific gene duplications expressed in human microglia. Using xenotransplantation of human induced pluripotent stem cell (hiPSC)-derived microglia and mouse genetic models, we demonstrate that human-specific SRGAP2B/C, previously shown to reduce SRGAP2A protein abundance, are both necessary and sufficient to induce neotenic structural microglial maturation. Our results reveal that neotenic microglial maturation modifies the timing of synaptic development, linking microglial developmental programs to the timing of circuit formation. Together with previous evidence for neuronal SRGAP2A function, our results suggest that the human-specific SRGAP2B/C paralogs coordinated the emergence of neotenic synaptic development by acting in both neurons and microglia during human brain evolution.

Keywords:  brain; evolution; human; human-specific gene duplication; microglia; mouse; neoteny; neurons; synapses; xenotransplantation

DOI:  https://doi.org/10.1016/j.neuron.2026.07.007
bioRxiv. 2026 Jul 23. pii: 2026.07.20.738977. [Epub ahead of print]

MicroRNA-223 Enhances Microglia-Dependent Clearance of Amyloid Beta Plaques and Ameliorates Behavioral Deficits in a Mouse Model of Alzheimer's Disease.

Andre Krunic, Nikkitha Umesh Ganesh, Ugur Coskun, William Brennan, Chandani Patel, Ojasi Joshi, Jane Lee, Tori Shiyang Gu, Jaclyn Caruso, Aoife O'Connell, Charles Lisboa, Nicholas Crossland, Margareta Kurkela, Tcw Julia, Abigail Fowler, Tuan Leng Tay, Andre Fischer, Ivana Delalle, Jan K Blusztajn, Tiffany J Mellott.

The Alzheimer's disease (AD) brain is characterized by dysregulated expression of multiple microRNAs (miRNA), positioning them as promising diagnostic and therapeutic targets. The levels of glia-enriched miR-223 are abnormal in the brains and plasma of AD patients and miR-223 is neuroprotective in models of stroke. However, whether miR-223 can be beneficial in AD is not known. Here, we report that intracerebroventricular (ICV) injection of miR-223 oligonucleotide mimic alleviated cognitive impairment, reduced amyloid beta (Aβ) pathology, and ameliorated the defects in synaptic marker expression in App NL-G-F AD model mice. Mechanistically, miR-223 induced microglial clustering around Aβ plaques with a concomitant upregulation of microglial phagocytic receptors AXL, TREM2 and CD11c, while pharmacological microglial depletion abolished the plaque-clearance phenotype. Moreover, in human iPSC-derived microglia miR-223 directly targeted multiple genes in the endo-lysosomal pathway, including AD risk gene SPPL2A , indicating that it acts as a major regulator of microglial phenotype. Lastly, long-term AAV-mediated overexpression of miR-223 recapitulates its beneficial effects on cognition, pathology, and synaptic marker expression. Our study demonstrates a novel approach for the treatment of AD using miR-223 and highlights the potential of RNAi-based therapeutics in neurodegenerative disease.

DOI: https://doi.org/10.64898/2026.07.20.738977
Res Sq. 2026 Jul 16. pii: rs.3.rs-10286730. [Epub ahead of print]

A non-canonical androgen signaling pathway drives microglial activation and tau pathology in females.

Xu Chen, Daniel Munoz-Mayorga, Xinchen Lyu, Suborno Jati, Jibin Zhang, Leigh-Ana Rossitto, Yuren Tao, Shanshan Zhao, Enfu Hui, Alexander Kauffman, Bokai Zhu.

Alzheimer's disease (AD) disproportionately affects women, who exhibit greater vulnerability to Tau pathology and neuroinflammation. The precise mechanisms underlying this vulnerability remain elusive, although sex hormones are thought to play a pivotal role. Here, we report that supplementation with the non-aromatizable androgen dihydrotestosterone (DHT) exacerbates Tau pathology in female tauopathy models, with microglia as the main driver of this effect. DHT treatment upregulates proinflammatory gene expression in microglia and promotes the disease-associated microglia (DAM) phenotype in a Trem2-dependent manner. Surprisingly, these effects are independent of the canonical androgen receptor (AR) and instead depend on the orphan nuclear receptor TR4, which mediates DHT-driven effects by transcriptionally regulating Trem2 in microglia. Moreover, TR4 protein levels are elevated in postmortem brain tissue from Braak stage 6 female AD patients and correlate with p-Tau levels. Together, our findings uncover a non-canonical DHT-TR4-Trem2 signaling axis in microglia and identify TR4 as a key regulator of neuroinflammation in female neurodegeneration, providing mechanistic insight into female-specific vulnerability to AD.

DOI: https://doi.org/10.21203/rs.3.rs-10286730/v1
Neuron. 2026 Jul 29. pii: S0896-6273(26)00530-1. [Epub ahead of print]

Transcriptional regulation of disease-relevant microglial activation programs.

Amanda McQuade, Reet Mishra, Venus Hagan, Weiwei Liang, Peter J Colias, Vincent Cele Castillo, Bianca Gonzalez, Justin P Lubin, Verena Haage, Victoria Marshe, Masashi Fujita, Thomas Ta, Layla Gomes, Olivia Teter, Xia Han, Nathaniel Robichaud, Sarah E Chasins, Jessica E Rexach, Philip L De Jager, James K Nuñez, Martin Kampmann.

  Microglia, the brain's innate immune cells, can adopt a wide variety of activation states relevant to health and disease. Dysregulation of microglial activation occurs in numerous brain disorders, and driving or inhibiting specific states could be therapeutic. To discover regulators of microglial activation states, we conducted CRISPR interference screens in induced pluripotent stem cell (iPSC)-derived microglia for inhibitors and activators of six microglial states. We characterized 31 regulators at the single-cell transcriptomic and cell-surface proteome level in two distinct iPSC-derived microglia models, uncovering protein markers of relevant states. We functionally characterized several multi-state regulators. ZNF532 and PRDM1 knockdown drive disease-associated, lipid-rich signatures and enhance phagocytosis while showing opposing effects on antigen-presentation signatures. DNMT1 knockdown results in widespread loss of DNA methylation, activating negative regulators of interferon signaling. These findings provide a framework to direct microglial activation to selectively enrich microglial activation states, define their functional outputs, and inform future therapies.

Keywords:  CRISPR; DNMT1; PRDM1; STAT2; ZNF532; disease-associated microglia; interferon; microglia; microglial activation; phagocytosis

DOI:  https://doi.org/10.1016/j.neuron.2026.07.001
Cell Rep. 2026 Jul 25. pii: S2211-1247(26)00787-4. [Epub ahead of print]45(8): 117709

Sex differences in somatosensory circuitry are programmed by developmental microglia-astrocyte interaction.

Abigayle Duffy, Leigh Ellen Fremuth, Madison Doceti, JaQuinta Thomas, Charlotte Buswell, Osaretin Lawani, John R Lukens, Ukpong B Eyo.

  Men possess a greater density of cortical synapses in the adult brain relative to women, but the underlying mechanism and functional significance of this sex difference is unclear. Here, we identify a greater density of excitatory synapses in the male mouse somatosensory cortex (S1) which emerges during development and persists into the adult brain. We show that increased phagocytic activity in microglia of female mice causes a greater engulfment of astrocytes in the female S1 in a MERTK-dependent manner during a discrete developmental window, regulated at least in part by estrogen signaling. The resulting greater astrocyte density in males corresponds with an increase in astrocyte-derived synaptogenic factors, hevin and thrombospondin-2, which we propose leads to the observed sex difference in S1 synapse density. Moreover, we demonstrate that this sex difference in synapse density correlates with an increase in neuronal activity in the male S1 both in development and adulthood.

Keywords:  CP: neuroscience; astrocytes; glia; microglia; neurodevelopment; phagocytosis; sex differences

DOI:  https://doi.org/10.1016/j.celrep.2026.117709
Brain Behav Immun. 2026 Jul 30. pii: S0889-1591(26)00685-9. [Epub ahead of print] 106937

Microglia regulate sleep and thermoregulatory stability.

Nikolaas Steele, Grant S Mannino, Tabitha R F Green, Lindsey L Beauregard, Madison Szewczak, Sean M Murphy, Mark R Opp, Rachel K Rowe.

  Sleep fragmentation disrupts physiological homeostasis, including thermoregulation, metabolism, and immune signaling; however, cellular mechanisms that stabilize core body temperature and sleep architecture during disrupted sleep remain poorly understood. Microglia are the resident immune cells of the central nervous system and play a central role in integrating neuroimmune signaling with hypothalamic regulation of thermoregulation and sleep-wake control. We tested the hypothesis that microglia are required to maintain both thermoregulatory and sleep stability during physiological sleep and when sleep is disrupted. Male and female C57BL/6J mice (n = 128) were implanted with telemetry devices for continuous core body temperature monitoring and maintained on either a control diet or diet containing the CSF1R-inhibitor PLX5622 (PLX) to pharmacologically deplete microglia. Body temperature and sleep-wake behavior were assessed across a two-week depletion period and during a subsequent 7-day sleep fragmentation paradigm. Hierarchical models were used to quantify the effects of microglial depletion (via diet), sex, and time-of-day (light/dark period). Microglial depletion produced sex- and diet-dependent alterations in both thermoregulation and sleep measures. PLX increased body temperature in females early during the depletion period, after which body temperature normalized and subsequently declined to pre-PLX baseline values. In contrast, PLX minimally influenced outcome metrics in males. During sleep fragmentation, microglial depletion induced time-of-day-specific hypothermia in males and females during the dark and light periods, respectively. Notably, microglial depletion dissociated components of sleep in a sex-dependent manner: Total sleep time increased in females, whereas males exhibited reduced sleep-wake transitions, suggesting increased sleep consolidation and therefore distinct regulation of sleep quantity versus stability. Across experimental conditions, body temperature was a strong nonlinear predictor of sleep, with higher temperatures (>35°C) associated with substantially reduced total sleep time (5-10 min reduction for every 1℃ increase), particularly during the dark (active) period. These findings collectively suggest that microglia contribute to thermoregulatory processes and sleep stability in a sex-dependent manner, supporting a role for microglia in coordinating physiological homeostasis. Together, our results support a neuroimmune framework in which microglia may help coordinate thermoregulation and sleep, as microglial depletion was associated with dysregulation of both processes.

Keywords:  Core body temperature; Microglia; Neuroimmune signaling; Physiological stress; Sex differences; Sleep disruption; Sleep fragmentation; Thermoregulation

DOI:  https://doi.org/10.1016/j.bbi.2026.106937
bioRxiv. 2026 Jul 24. pii: 2026.07.22.740182. [Epub ahead of print]

Microglia extract neuronal proteolytic organelles via skoupocytosis.

Renee Pepper, Jacqueline M Griswold, Frances Middleton-Davis, Sarah Syed, Yuuta Imoto, Lani Tran, Eunbin Park, Yu Kang T Xu, Dwight Bergles, JoAnn Buchanan, Shigeki Watanabe.

Neurons face unique challenges in maintaining protein homeostasis due to their tortuous morphology and extended processes. Proteolytic organelles are typically transported retrogradely towards their soma for degradation where lysosomes are enriched, but some organelles are larger than these neuronal processes, questioning how these organelles are degraded. Here we show that microglia, the resident immune cells of the brain, extract proteolytic organelles from neurons both in vitro and in vivo . Microglia make transient contact with neuronal membranes where proteolytic organelles are stationed beneath. At these sites of interaction, microglia pinch off a small portion of the neuronal process containing the organelle, leaving the rest of the process intact. We term this process 'skoupocytosis' after the Greek word for garbage. Phosphatidylserine (PS) lipase ABHD16a accumulates near these proteolytic organelles and converts PS into lyso-PS to initiate microglial skoupocytosis. Skoupocytosis bypasses the need for retrograde organelle transport, providing homeostatic advantages for neurons that must maintain function in processes that extend extraordinarily long distances from the cell soma.

DOI: https://doi.org/10.64898/2026.07.22.740182
J Integr Neurosci. 2026 Jul 23. 25(7): 49507

Microglia as Double-Edged Players in Ischemic Stroke.

Shiyuan Lin, Zejing Lin, Ying Chen, Xingyong Chen.

  Stroke has long been a leading cause of death and long-term disability worldwide. In recent years, more and more research has revealed that microglial responses to ischemic injury are highly heterogeneous and exhibit dynamic evolution over time, across brain regions, and under different metabolic states. This endows microglia with a dual regulatory role in both neurotoxicity and neuroprotection after ischemia: on one hand, they drive inflammatory responses, exacerbating secondary neuronal damage, blood-brain barrier disruption, and synaptic loss; on the other hand, they orchestrate debris clearance, vascular rebuilding, and neural repair. The traditional pro-inflammatory versus anti-inflammatory dichotomy is no longer sufficient to fully describe their complex functions. In this review we summarize recent advances in understanding the dual regulatory roles of microglia after ischemic stroke, with a focus on key mechanisms such as metabolic reprogramming, lipid metabolism regulation, inflammasome activation, and epigenetic modification. Furthermore, emerging therapeutic strategies targeting microglia and the challenges they face are discussed.

Keywords:  ischemic stroke; metabolic reprogramming; microglia; neuroinflammation

DOI:  https://doi.org/10.31083/JIN49507
bioRxiv. 2026 Jul 22. pii: 2026.07.21.739939. [Epub ahead of print]

iPSC-Derived Microglia-like Cells Exhibit Protocol-Dependent Transcriptomic Features and Robust Phagocytosis of Glioma Cells.

Maya N Walker, Hui Tang, Caylee Silvers, Sasha Roth, Deanna Tiek, Bo Hu, Shi-Yuan Cheng, Xiao Song.

Microglia are the brain-resident macrophages and key regulators of the brain tumor microenvironment. Although induced pluripotent stem cell-derived microglia (iMG) provide a valuable model for studying human microglial, systematic comparisons of differentiation protocols are limited, and their utility for modeling microglia-tumor cell interactions remains underexplored. Here, we analyzed 54 public RNA-seq datasets representing 22 iMG differentiation protocols, including embryoid body (EB)-based, two-dimensional (2D), transcription factor-induced, and coculture-based approaches. Most iMG closely resembled primary human microglia, although substantial protocol-dependent differences were observed. iMG generated using EB-based protocols showed higher TMEM119 expression, whereas those generated using 2D-based protocols showed higher P2RY12 expression. A widely adopted EB-based protocol showed the highest phagocytosis gene signature. Using this protocol, we generated iMG that efficiently phagocytosed patient-derived glioma stem-like cells and upregulated inflammatory and immunoregulatory genes following phagocytosis. These findings provide a transcriptomic benchmark for current iMG models and support their use in investigating microglia-glioma interactions.

DOI: https://doi.org/10.64898/2026.07.21.739939
bioRxiv. 2026 Jul 14. pii: 2026.07.13.738356. [Epub ahead of print]

PLCγ2 deficiency compromises systemic immune tolerance and erodes myelin homeostasis while enhancing oxidative metabolism in the mouse brain.

Eduardo Gutierrez-Kuri, Juliet Lynn Marie Garcia-Rogers, Jaid Perez, Sabrina Smith, Matthew R Kenwood, Kahealani S Archuleta, Yangming Xiao, Gabriela Campos, Savannah Barannikov, Hu Wang, Sammy Pardo, Trevor B Romsdahl, Henry Miller, Ann M Stowe, Russell William, Mark Goldberg, Xianlin Han, Kevin F Bieniek, Susan T Weintraub, Ann V Griffith, Sarah C Hopp, Juan Pablo Palavicini.

   Background: Phospholipase C gamma-2 (PLCγ2) catalyzes the hydrolysis of the membrane phosphatidylinositol-4,5-bisphosphate (PIP2) to form diacylglycerol (DAG) and inositol trisphosphate (IP3), feeding into diverse downstream signaling pathways. PLCG2 polymorphisms have been associated with reduced and/or increased risk of Alzheimer's disease (AD) and related dementias, longevity, autoinflammation, and immune disorders. In the brain, PLCγ2 is expressed in microglia, and other neuroimmune and vascular interface populations, yet its role in brain homeostasis remains incompletely defined.
Methods: We analyzed the brains of three-month-old Plcg2 wild-type (WT), heterozygous (Het KO) and homozygous knockout (Homo KO) littermate mice modeling human PLCG2 loss-of-function risk alleles linked to AD risk using a multiomic approach that included lipidomics, metabolomics, proteomics, and transcriptomics, together with immunofluorescence, as well as flow-cytometric profiling of peripheral and brain-draining immune compartments.
Results: Plcg2 deficiency substantially impaired early survival and produced splenomegaly without increasing total spleen cellularity, instead shifting spleen composition toward myeloid/innate-enriched cells and away from B cells, with expansion of age-associated B-cell (ABC-like) subsets and parallel reductions in CD4 and CD8 regulatory T cells in spleen and cervical lymph nodes. Brain lipidomics revealed selective depletion of PIP2, despite very low bulk PLCγ2 protein abundance relative to other PLC family members. PLCγ2 loss led to significant reductions in myelin-enriched lipid classes and myelin/paranode-associated proteins, accompanied by compensatory upregulation of oligodendrocyte/myelin genes, and modest shifts in microglial, lysosomal, complement, and oxidative metabolism pathways by NanoString and DIA-MS. Targeted acylcarnitine profiling demonstrated reprogramming of brain oxidative metabolism, with increased short-, medium-, and long-chain acylcarnitines and enrichment of mitochondrial matrix fatty-acid and amino-acid catabolic enzymes in Homo KO brains.
Conclusions: Loss of PLCγ2 installs a coordinated program that compromises systemic immune tolerance and subtly erodes central myelin and phosphoinositide homeostasis while enhancing brain oxidative metabolism, effects that extend beyond microglial phagocytic signaling and may underlie increased vulnerability to AD pathology and aging, providing a mechanistic framework for how PLCG2 variation may link systemic immune regulation, white-matter integrity, and neurodegenerative risk.
Limitations: Because constitutive Plcg2 Homo KO mice display high early mortality and intestinal vascular abnormalities, observed phenotypes may reflect developmental compensation and may not fully recapitulate protective human PLCG2 variants.

Keywords:  Alzheimer’s disease; PLCG2; RNA profiling; lipidomics; microglia; oligodendrocytes; proteomics

DOI:  https://doi.org/10.64898/2026.07.13.738356
Cell Rep. 2026 Jul 29. pii: S2211-1247(26)00827-2. [Epub ahead of print]45(8): 117749

CCR5 drives glucose metabolic reprogramming to control microglial synaptic pruning via histone lactylation in a mouse model of depression.

Ying-Ying Jiao, Zhu Zhu, Rui-An Wang, Ben-Yu He, Hang Yao, Zhi-Yong Zhou, Yun-Fan Shi, Cong Wang, Lei Cao, Yang Liu, Gang Hu, Ren-Hong Du, Ming Lu.

  Depression is linked to microglial activation, but the precise triggers and downstream pathways remain elusive. Through single-cell RNA sequencing of human blood samples, we find upregulation of the CCL5-CCR5 axis in patients with major depressive disorder. Using a chronic social defeat stress mouse model, we show that CCR5 is specifically elevated in activated hippocampal microglia. Microglia-specific deletion of CCR5 alleviates depressive-like behaviors and prevents microglial activation. Mechanistically, CCR5 binding to VHL stabilizes HIF-1α, redirecting microglial metabolism toward aerobic glycolysis. This metabolic shift results in lactate accumulation, which drives histone H4 lysine 12 lactylation (H4K12la). Genome-wide profiling reveals that H4K12la enrichment at complement gene promoters facilitates their transcription, ultimately leading to excessive microglial engulfment of neuronal spines and synaptic loss. Importantly, either inhibiting glycolysis or exogenous lactate supplementation can respectively rescue or mimic the pathological synaptic pruning and depressive-like behaviors. Our findings indicate a CCR5-driven immune-metabolic-transcriptional axis in microglia that underlies synaptic deficits in depressive-like behaviors, offering potential targets for therapeutic intervention.

Keywords:  CCR5; CP: neuroscience; depression; histone lactylation; metabolic reprogramming; metabolism; microglia; synaptic pruning

DOI:  https://doi.org/10.1016/j.celrep.2026.117749
FASEB J. 2026 Aug 15. 40(15): e72155

Oligodendroglial TANGO2 Regulates Lipid Metabolism to Control Motor Coordination.

Jiewen Chen, Zhili Liu, Fengling Chen, Yongfei Cui, Liming Qin, Mengdi Wang, Xiangbin Zhu, Na Li, Can Huang, Bo Zhang, Kunfu Ouyang.

  TANGO2 deficiency disorder (TDD) is a rare genetic disease caused by mutations in the TANGO2 gene, characterized by prominent neurological symptoms. However, the pathological mechanisms underlying TANGO2 loss-of-function in neurologic symptoms remain unknown. Here, we generated constitutive and cell-type-specific Tango2 knockout mouse models to examine TANGO2's role in the central nervous system (CNS). Behavioral analyses revealed that both constitutive and oligodendrocyte-specific deletion of Tango2 recapitulate the motor deficits associated with individuals with TDD. Morphological quantifications further showed that Tango2 deletion led to robust cerebellar myelin loss and an increase in synapse number in the cerebellar cortex. In addition, transcriptional analysis and lipidomic profiling demonstrated that Tango2 deletion downregulated key processes involved in phospholipid metabolism. Significantly, vitamin B5 supplementation alleviated motor deficits and cerebellar myelin defects in Tango2 knockout mice. Overall, our findings establish that TANGO2 is essential for maintaining normal motor behaviors by regulating lipid metabolism in oligodendroglia.

Keywords:  TANGO2 deficiency disorder; lipid metabolism; motor deficits; myelin; oligodendrocyte

DOI:  https://doi.org/10.1096/fj.202601407RR
Sci Adv. 2026 Jul 31. 12(31): eadz6517

Corticosterone-linked microglial activity underpins sexually dimorphic neuroplasticity after ketamine anesthesia.

Alessandro Venturino, MohammadAmin Alamalhoda, Thomas Negrello, Kelly Jin, Cindy T J van Velthoven, Ryan John A Cubero, Jake Yeung, Peter Koppensteiner, Bosiljka Tasic, Sandra Siegert.

Anesthesia recovery is critical for resuming normal physiological and neuronal functions; however, the mechanisms involved remain elusive. Here, we identify a female-selective corticosterone-mediated microglia-neuron interaction during ketamine anesthesia recovery, absent in males. This microglia-neuron interaction induces plastic and functional neuronal changes, as evidenced by increased mEPSC frequency, which was occluded upon microglia depletion. We showed that this process is driven through up-regulation of the stress-responsive co-chaperone Fkbp5 mRNA and its protein, Fkbp51, in female microglia. Fkbp5/Fkbp51 is a key intermediary in a corticosteroid-induced stress response, and its involvement points toward a critical interface between endocrine signaling and microglia. To counteract the observed ketamine anesthesia-mediated increase in blood corticosterone during recovery, we removed the primary source of corticosterone by adrenalectomy. Close microglia-neuron interaction was reduced and increased again following corticosterone injection. Our findings identify a sex-specific microglia-mediated mechanism of neuronal plasticity during anesthesia recovery, driven by corticosterone, thereby enhancing our understanding of sex differences in brain function.

DOI: https://doi.org/10.1126/sciadv.adz6517
Glia. 2026 Sep;74(9): e70199

A Microglia-Astrocyte Signaling Axis Regulates Astrocyte Piezo1 Expression and Inflammatory Responses.

Yanyang Bai, Hyun B Choi, Stefan Wendt, Morgan Towriss, Ada J Lin, Christopher J Groten, Ivy Cui, Haakon B Nygaard, Brian A MacVicar.

  Structural tissue alterations in numerous brain disorders can initiate mechanosensory signaling pathways and influence neuropathology. Astrocytes are highly mechanosensitive cells that play essential roles in maintaining brain homeostasis; however, the molecular mechanisms underlying astrocyte mechanosensation during pathological conditions remain largely unexplored. In this study, we investigated how the expression of the mechanosensitive ion channel Piezo1 in astrocytes is modulated by inflammatory triggers. We found that direct exposure of primary astrocyte cultures to inflammatory stimuli, including lipopolysaccharide (LPS) or oligomeric amyloid-β (oAβ), had minimal impact on astrocytic Piezo1 expression. In contrast, when LPS or oAβ were applied to primary microglia cultures, Piezo1 expression was increased in microglia, and conditioned media from these microglia cultures significantly upregulated Piezo1 expression in astrocytes. We further identified that microglia released pro-inflammatory cytokines (IL-1α, IL-1β, and TNF-α) that can directly enhance Piezo1 expression and Piezo1-mediated Ca2+ signaling in both rodent and human astrocytes. Microglial depletion in 5xFAD mice consistently and substantially reduced astrocytic Piezo1 expression in vivo, supporting the physiological relevance of this microglia-astrocyte signaling axis during pathology. Activation of Piezo1 with Yoda2 did not alter astrocytic inflammatory gene expression under basal conditions but reduced TNF-α, CCL2, and C3 expression following cytokine pretreatment. Conversely, Piezo1 knockdown increased GFAP expression at baseline and enhanced pro-inflammatory gene expression under cytokine stimulation, indirectly promoting microglial activation. These findings demonstrate that astrocytic Piezo1 expression is regulated by microglia-derived inflammatory signals and plays a context-dependent role in modulating astrocyte reactivity and neuroinflammatory responses.

Keywords:  Ca2+ activity in astrocytes; Piezo1; microglia depletion in 5xFAD mice; microglia‐astrocyte crosstalk; neuroinflammation; proinflammatory cytokines

DOI:  https://doi.org/10.1002/glia.70199
J Alzheimers Dis. 2026 Jul 31. 13872877261469862

Microglial immunometabolic reprogramming in Alzheimer's disease: From mitochondrial dysfunction and redox imbalance to NLRP3 inflammasome-driven neuroinflammation.

Siyu Li, Juntao Jin, Yingying Liu, Jing Yuan, Yuhan Dong, Ziyi Wang, Lu Li, Yamin Zhang.

  Alzheimer's disease (AD) is increasingly recognized as a disorder in which amyloid-β deposition and tau pathology interact with neuroinflammation and metabolic dysregulation. Although mitochondrial dysfunction, redox imbalance, and NLRP3 inflammasome activation have each been implicated in AD pathogenesis, their mechanistic continuity within microglial immunometabolic reprogramming remains insufficiently defined. This narrative review integrates mechanistic, preclinical, and human-relevant evidence to propose a stage-dependent mitochondrial dysfunction-redox imbalance-NLRP3 inflammasome axis. We discuss how AD-related stimuli shift microglia toward a pro-inflammatory metabolic phenotype; how impaired mitochondrial quality control promotes reactive oxygen species generation and oxidized mitochondrial DNA release; and how these signals facilitate NLRP3 inflammasome activation and sustained inflammatory amplification. We further summarize therapeutic strategies targeting upstream mitochondrial homeostasis, intermediate metabolic-redox coupling, and downstream NLRP3 signaling, while emphasizing the translational limitations and biomarker needs. We conclude that this proposed axis provides a testable stage-dependent framework for interpreting chronic, self-amplifying neuroinflammation in AD and may inform biomarker-guided, combinatorial therapeutic strategies.

Keywords:  Alzheimer's disease; NLRP3 inflammasome; immunometabolic reprogramming; microglia; mitochondrial dysfunction; neuroinflammation; redox imbalance

DOI:  https://doi.org/10.1177/13872877261469862
bioRxiv. 2026 Jul 13. pii: 2026.07.12.738054. [Epub ahead of print]

NPC1 deficiency engages a lysosome-genome-immune program linked to neurodegeneration and cellular aging signatures.

Morteza Abyadeh, Masoumeh Zarei Kheirabadi, Pei-Chi Hou, Vedat Sari, Kyubin Lee, Rohil Hameed, Bushra Mehkri, Elizabeth Malaugh, Jason Newton, Tomasz Kordula, Yuh-Hwa Wang, Alaattin Kaya.

Lysosomal dysfunction is a prominent feature of neurodegeneration and aging, yet how primary defects in lysosomal trafficking are converted into progressive cellular decline remains poorly understood. Niemann Pick disease type C (NPC), caused by impaired NPC1 dependent cholesterol export, provides a genetically defined model to address this question. Here, we show that NPC1 deficiency activates a lysosome, genome, immune axis linking cholesterol trafficking failure to neurodegeneration and hallmarks of cellular aging. In Npc1 mutant mice, NPC1 loss triggered DNA damage, neuroinflammation, microglial and astrocytic activation, Purkinje neuron degeneration, and motor dysfunction. Consistently, NPC patient-derived fibroblasts exhibited mitochondrial abnormalities and widespread DNA double-strand breaks. Genome-wide DNA break mapping and transcriptomic analyses revealed extensive genomic instability at regulatory regions, including enrichment of DNA breaks at transcription start sites and G quadruplex associated loci, accompanied by widespread transcriptional reprogramming, activation of innate immune pathways, disruption of fibroblast identity, and induction of cellular aging signatures. We further identify Fingolimod, an FDA approved sphingosine - 1 phosphate receptor modulator, as a potent modifier of this disease network. Fingolimod improved lysosomal cholesterol trafficking, increased LAMP1 abundance, attenuated STING associated inflammatory signaling, normalized mitochondrial function, reduced neuroinflammatory and neurodegenerative phenotypes in Npc1 mutant mice, and broadly shifted disease-associated transcriptional programs toward a healthier state. Extending these findings beyond NPC, Fingolimod improved age-associated phenotypes in C. elegans and prolonged lifespan in aged male mice. Together, these findings identify genome instability and chronic innate immune activation as major downstream consequences of lysosomal cholesterol trafficking failure and establish Fingolimod as a clinically actionable modulator of lysosomal dysfunction, neurodegeneration, and aging-related decline.

DOI: https://doi.org/10.64898/2026.07.12.738054
Acta Neuropathol. 2026 Jul 29. pii: 12. [Epub ahead of print]152(1):

Retinal proteome changes mirror brain pathology and reveal synaptic and cytoskeletal dysfunction in Alzheimer's disease.

Netherlands Brain Bank

  Visual dysfunction is increasingly recognized as an important feature of Alzheimer's disease, and substantial retinal changes have been documented across multiple studies. Yet the molecular changes underlying retinal neurodegeneration and which retinal protein signatures best track cerebral pathology remain incompletely defined. Here, we performed comprehensive mass spectrometry-based proteomics on paired retinal and hippocampal tissue from the same postmortem donors (8 AD, 8 non-demented controls) to identify disease-associated molecular signatures and assess their overlap between these tissues. Using a sequential dual-extraction protocol, we identified 372 differentially abundant retinal proteins in AD, including established APP-processing regulators (SORL1, BACE1) and synaptic proteins. Retinal proteomes clearly separated AD from controls in principal component analysis, indicating robust AD-related molecular differences in the retina. Notably, 87% of proteins were detected in both retina and hippocampus, with 64 differentially abundant proteins shared between tissues, some of which showed strong cross-tissue correlation. Several retinal proteins also correlated with neuropathological disease stage. Functional enrichment analysis revealed convergent alterations in synaptic organization, cytoskeletal dynamics, mitochondrial function, cell adhesion, and APP metabolism in both tissues. Cell-type mapping using single-cell retinal reference data indicated that most proteomic changes were broadly distributed across cell types, though some proteins showed enrichment in specific populations, such as SORL1 in microglia and EYS in photoreceptors. The molecular changes identified here offer a potential basis for the retinal alterations previously documented through in vivo imaging and histological studies. Their similarities with brain pathology further support the retina as a promising window for assessing cerebral disease.

Keywords:  Alzheimer’s disease; Proteomics; Retina

DOI:  https://doi.org/10.1007/s00401-026-03054-x
Sci Adv. 2026 Jul 31. 12(31): eaef6777

Astrocyte redox imbalance underlies prelimbic neuronal hypoactivity and maladaptive affective behaviors in epilepsy.

Travis E Faust, Atsushi Saito, Shoichi Ishikawa, Kun Yang, Wendy Xin, Ho Namkung, Amit Agarwal, Adriana Ramos, Brian J Lee, Lindsay Hayes, Rupali Srivastava, Sunday Adelakun, Sneha Saha, Trexy Palen, Tyler Cash-Padgett, Daniel J Wood, Elisa Carloni, Ryosuke Yusa, Hanna Jaaro-Peled, Jed W Fahey, Dwight E Bergles, Koko Ishizuka, Akira Sawa.

A fundamental but unanswered question in neuropsychiatry is whether the psychiatric symptoms of epilepsy are caused by the same or a separate pathophysiology as seizures. To address this question, we investigated a monogenic form of epilepsy (pyridoxine-dependent epilepsy) caused by aldehyde dehydrogenase 7 family member A1 (ALDH7A1) mutations. ALDH7A1 global knockout mice exhibited both seizure-associated and maladaptive affective behavioral phenotypes. However, seizure phenotypes were caused by ALDH7A1 deletion in hepatocytes whereas maladaptive affective behaviors were caused by ALDH7A1 deletion in astrocytes. Deletion in astrocytes disrupted astrocyte redox homeostasis, impairing regulation of extracellular ion concentrations and reducing neuronal activity in the prelimbic cortex. Sulforaphane, which activates the NRF2 antioxidant pathway, restored prelimbic neuronal activity and rescued maladaptive affective behaviors in ALDH7A1 knockout mice but did not prevent seizures. These studies implicate astrocyte redox homeostasis and prelimbic hypoactivity in maladaptive affective behavioral phenotypes in a congenital form of epilepsy, which are mechanistically and therapeutically dissociable from seizure pathophysiology.

DOI: https://doi.org/10.1126/sciadv.aef6777
bioRxiv. 2026 Jul 22. pii: 2026.07.15.738801. [Epub ahead of print]

APOE4 disrupts the central dogma by arresting neuronal proteome dynamics.

Einar K Krogsaeter, Justin McKetney, Lishi Li, Isabelle Liu, Alicia L Richards, Vishvak Subramanyam, Keyi Yin, Martin Gordon, Pedro Belio Mairal, Erica J Stevenson, Houzhen Qian, Yadong Huang, Hani Goodarzi, Nevan J Krogan, Danielle L Swaney.

Apolipoprotein E4 (APOE4) is the strongest genetic risk factor for late-onset Alzheimer's disease and promotes neuronal dysfunction through incompletely understood mechanisms. Here, we integrated transcriptomic, translatomic, and proteomic profiling of isogenic APOE3 and APOE4 human iPSC-derived neurons and found that APOE4 fundamentally impairs neuronal proteome renewal. Although transcriptional changes were modest, APOE4 disrupted ribosome occupancy, altered translational dynamics, and uncoupled protein abundance from transcript levels. Proteome-wide turnover measurements revealed a global extension of protein half-lives and widespread accumulation of long-lived proteins. Functional proteomic analyses demonstrated concurrent lysosomal and proteasomal impairments associated with reduced proteasome activity and increased association of APOE with neuronal proteasomes. Longitudinal proteomics further showed that protein accumulation emerges during neuronal maturation and precedes a senescence-like cellular stress state. Together, these findings identify impaired proteome renewal as a central mechanism underlying neuronal vulnerability to APOE4 and establish defective proteostasis as an early pathogenic event in Alzheimer's disease.

DOI: https://doi.org/10.64898/2026.07.15.738801
Inflammopharmacology. 2026 Jul 28.

Immunometabolic reprogramming in multiple sclerosis: from pathogenic amplifier to therapeutic target in neuroinflammation and remyelination.

Ghada A Badawi, Rehab M El-Sayed, Mohamed N Fawzy.

  Multiple sclerosis (MS) has conventionally been considered a prototypical autoimmune disorder. While modern immunotherapies effectively control relapsing conditions, they fail to avert progressive neuroinflammation, neurodegeneration, and remyelination failure. This review offers an evidence-based recontextualization. The pathogenesis of multiple sclerosis is multifactorial, resulting from the interaction of genetic predisposition (especially HLA alleles), environmental factors (particularly Epstein-Barr virus infection), B-cell-mediated autoimmunity, and localized CNS inflammation. In this intricate environment, cellular metabolic dysregulation is a notable factor and potentially adjustable enhancer of disease progression, functioning within the extensive multifactorial pathogenic context, where the bioenergetic programming of immune and neural cells determines inflammatory or protective responses. Proinflammatory Th17 cells and M1 microglia depend on aerobic glycolysis and glutaminolysis regulated by mTOR and HIF-1α, whereas regulatory T cells, M2 microglia, and neurons require fatty acid oxidation and oxidative phosphorylation via AMPK. In multiple sclerosis, glycolysis disrupts metabolic equilibrium, sustaining chronic neuroinflammation and obstructing repair processes. Established multiple sclerosis therapies, dimethyl fumarate and teriflunomide, exhibit direct, previously unrecognized metabolic effects, validating this pathway as therapeutically viable. Emerging strategies intentionally target these vulnerabilities: glutaminase inhibitors to counteract pathogenic Th17 cells, AMPK activators such as metformin to enhance remyelination, mTOR inhibitors to restore immune tolerance, and NAD + precursors to rejuvenate mitochondrial function. Transitioning from broad immunosuppression to specific metabolic reprogramming offers remarkable opportunities for tackling chronic neuroinflammation and correcting remyelination deficits in progressive multiple sclerosis. Immuno-metabolic pharmacology is a promising field; however, its clinical application necessitates stringent validation via meticulously designed trials and dependable biomarkers.

Keywords:  AMPK; Drug repurposing; Immunometabolism; Multiple Sclerosis; Neuroinflammation; mTOR signaling

DOI:  https://doi.org/10.1007/s10787-026-02350-y
Brain Res Bull. 2026 Jul 25. pii: S0361-9230(26)00345-X. [Epub ahead of print]244 112058

CD4 T lymphocytes shape the development and maturation of the central nervous system.

Poliana Capucho Sandre de Carvalho, Felipe Henrique da Cunha Xavier, Eriane Cerqueira Santos, Letícia Barros de Souza, Pedro Henrique Oliveira Vianna, Áquila Rodrigues Costa Santos, Rômulo Gonçalves Agostinho Galvani, Wilson Savino, Rudimar Luiz Frozza, Adriana Cesar Bonomo.

  For decades, the central nervous system (CNS) was considered largely isolated from the peripheral immune system. However, growing evidence indicates that adaptive immune cells contribute to neurodevelopment and brain homeostasis. T lymphocytes are present in healthy brain parenchyma and have been implicated in microglial maturation and behavioral regulation, although their precise roles remain incompletely understood. Here, we aimed to identify and localize T lymphocytes in the brain parenchyma across developmental stages and to evaluate the contribution of CD4⁺ T cell subpopulations to mouse behavior. We detected T lymphocytes in multiple brain regions at different ages, with a predominance of CD4⁺ over CD8⁺ T lymphocytes from postnatal day 7 through 20 months. During the neonatal period, naïve T cells were more prevalent, whereas effector memory T cells increased progressively with age. Behavioral assessment of immunodeficient neonates and adults revealed neuromotor and cognitive alterations. Together, these findings indicate that T lymphocytes are associated with brain maturation and cognitive-related outcomes, highlighting a potential influence of adaptive immunity on neural development.

Keywords:  CD4 T lymphocyte; CNS maturation; Cognition; Neurodevelopment

DOI:  https://doi.org/10.1016/j.brainresbull.2026.112058
Neurosci Biobehav Rev. 2026 Jul 31. pii: S0149-7634(26)00351-9. [Epub ahead of print] 106894

The Critical Role of Microglia in the Stress Response.

Ke Chen, Zong-Yuan Xuan, Bao-Yi Sun, Guan-Ning Zhong, Xiao-Lei Sun, Jun Yan.

  Microglia are the principal resident innate immune cells of the central nervous system (CNS). Beyond maintaining brain homeostasis via cytokine secretion and phagocytic clearance, they fulfill essential roles in synaptic pruning, oligodendrocyte maturation, and higher-order functions including learning and memory. In response to stress exposure, microglia undergo robust activation, characterized by morphological remodeling, altered phagocytic activity, and dysregulated inflammatory signaling, positioning them as active mediators of the integrated systemic stress response. This review systematically synthesizes preclinical and clinical evidence regarding the multifaceted contributions of microglia to stress processing, their mechanistic involvement in the pathogenesis of major stress-related disorders-including post-traumatic stress disorder (PTSD), major depressive disorder (MDD), Alzheimer's disease (AD), and Parkinson's disease (PD)-and summarizes emerging microglia-targeted therapeutic strategies. We underscore the substantial mechanistic and translational value of microglial research for advancing our understanding of stress adaptation and associated brain pathologies.

Keywords:  Alzheimer’s disease; Major depressive disorder; Microglia; Parkinson’s disease; Post-traumatic stress disorder; Stress

DOI:  https://doi.org/10.1016/j.neubiorev.2026.106894
Science. 2026 Jul 30. 393(6810): eady0832

Atlas of lysosomal aging reveals a metabolite signature shared with lysosomal storage disorders.

Anna M Puszynska, Thao P Nguyen, Andrew L Cangelosi, Andrea Armani, Justin M Roberts, Kristin A Singh, James C Cameron, Tenzin Tseyang, Grace Y Liu, Steven Lai, Hans-Georg Sprenger, Jason Yang, William N Colgan, Jibril F Kedir, Kathrin M Kajderowicz, Theodore K Esantsi, Yuancheng Ryan Lu, Millenia Waite, Tenzin Kunchok, Caroline A Lewis, Fabian Schulte, George W Bell, David M Sabatini, Jonathan S Weissman.

Lysosomal dysfunction is a well-recognized feature of aging. Here, we used a suite of tools for rapid lysosomal isolation to construct a multitissue atlas of the metabolite changes lysosomes undergo during aging. Aged lysosomes in brain, heart, muscle, and white adipose tissue accumulated glycerophosphodiesters and cystine, metabolites that are causally linked to juvenile lysosomal storage disorders, Batten disease, and cystinosis. Levels of these metabolites increased linearly with age, preceding organismal decline. Caloric restriction, a lifespan-extending intervention, mitigated these changes in the heart and muscle but not the brain. Our findings link lysosomal storage disorders to aging-related dysfunction and open avenues for the mechanistic investigation of how lysosomal functions deteriorate during aging and in age-associated diseases.

DOI: https://doi.org/10.1126/science.ady0832
Nat Commun. 2026 07 27. pii: 7404. [Epub ahead of print]17(1):

Obesity-driven microbial GABA depletion promotes metabolic rewiring and colorectal cancer progression.

Wei Guo, Kaiyue Sun, Xia Wang, Mengmeng Li, Zheng Li, Xizan Yue, Yi Yin, Tengfei Ma, Yikun Li, Xiaoning Xu, Jianbo Liu, Jiahao Zhang, Cuiyu Zhang, Panpan Feng, Ruijie Ma, Jiayi Ren, Jie Liu, Changan Liu, Xiang Gao, Dawei Chen, Jingxin Li.

Obesity is a major risk factor for colorectal cancer (CRC), yet the mechanisms linking obesity-associated gut dysbiosis to tumor progression remain unclear. Here, we show that a high-fat diet and fecal microbiota from patients with obesity-associated CRC deplete the GABA-producing commensal Bacteroides ovatus, resulting in reduced luminal GABA and accelerated tumorigenesis. Microbial GABA activates epithelial GABAB receptor signaling and induces TPI1 through the PI3K-HIF1α pathway. Increased TPI1-derived glyceraldehyde-3-phosphate inhibits PPP1CA, maintains YAP phosphorylation, restricts nuclear YAP activity, and suppresses pentose phosphate pathway flux, thereby limiting tumor growth. Consistently, obesity-associated CRC exhibits reduced fecal GABA, decreased TPI1 expression, and metabolic rewiring. A GABA-deficient B. ovatus mutant fails to restore GABA or suppress tumors despite normal colonization, whereas oral GABA supplementation or recolonization with wild-type B. ovatus markedly reduces tumor burden. These findings identify a microbiota-neurotransmitter-metabolism axis linking obesity to CRC and suggest microbiota-based GABA restoration as a potential preventive strategy.

DOI: https://doi.org/10.1038/s41467-026-76079-1
Sci Adv. 2026 Jul 31. 12(31): eaeh9771

Lipidomic profiling reveals age-dependent changes in plasma membrane lipids that affect neural stem cell aging.

Xiaoai Zhao, Ryan M Feitzinger, Jeeyoon Na, Xin Yan, Andrew Erickson, Kévin Contrepois, Olivia Y Zhou, Francesco Vallania, Mathew Ellenberger, Chloe M Kashiwagi, Stephanie D Gagnon, Cynthia J Siebrand, Matias Cabruja, Gavin M Traber, Andrew McKay, Daniel Hornburg, Purvesh Khatri, Michael P Snyder, Richard N Zare, Anne Brunet.

The aging brain exhibits a decline in the regenerative populations of neural stem cells (NSCs). While mechanisms that restore old NSC function have started to be identified, the role of lipids-especially complex lipids-in NSC aging remains largely unclear. Using lipidomic profiling by mass spectrometry, we identify age-related changes in complex lipids in quiescent NSCs in vitro and in vivo. Moreover, several polyunsaturated fatty acids increase across lipid classes in quiescent NSCs during aging. Using spatial lipidomics, we find that some of the changes in complex lipids are also observed in situ. Several age-related changes in complex lipids and side chain composition are occurring at the plasma membrane, as revealed by lipidomic profiling of isolated plasma membrane vesicles. Experimentally, we show that aging is accompanied by a decrease in plasma membrane order, a key membrane biophysical property, in old quiescent NSCs in vitro and in vivo. To determine the functional role of plasma membrane lipids in aging NSCs, we performed genetic and supplementation studies. Knocking out the phospholipid acyltransferase MBOAT2 exacerbates age-related lipidomic changes in old quiescent NSCs and impedes their ability to activate. Mboat2 overexpression reverses age-related lipidomic changes in old quiescent NSCs and boosts their ability to activate in vitro and in vivo. Moreover, supplementation of plasma membrane lipids from young NSCs improves the ability of old quiescent NSCs to activate. Our work could lead to lipid-based strategies for restoring the regenerative potential of NSCs, which has important implications for countering brain decline during aging.

DOI: https://doi.org/10.1126/sciadv.aeh9771
Sci Adv. 2026 Jul 31. 12(31): eaef0140

Mitochondrial control of amino acid catabolism by a fasting-inducible mitochondrial carrier.

Satoshi Oikawa, Tadashi Yamamuro, Hiroshi Nishida, Daisuke Katoh, Dandan Wang, Masanori Fujimoto, Shingo Kajimura.

Metabolic adaptation to nutrient deprivation requires coordinated control of mitochondrial anaplerosis and cataplerosis; however, how metabolite flux across the mitochondrial membrane is regulated during fasting remains less defined. Here, we report SLC25A34 as a fasting-inducible mitochondrial carrier that is highly expressed in oxidative skeletal muscle. Using bacterial reconstitution, proteo-liposomes, and tracer studies, we showed that SLC25A34 mediates the import of phosphoenolpyruvate (PEP) into the mitochondrial matrix. Loss of SLC25A34 impaired glutamine-supported anaplerosis under nutrient-deprived conditions, while glucose and pyruvate utilization remained largely intact. Muscle-specific deletion of Slc25a34 resulted in reduced fasting-induced amino acid catabolism and the accumulation of amino acids, leading to activation of mTORC1 signaling even under fasted conditions. Consequently, SLC25A34-deficient soleus muscle exhibited hypertrophy and myopathic features, accompanied by mTORC1-dependent increase in protein synthesis. Together, these results highlight a unique biological role for the inducible mitochondrial carrier SLC25A34, which couples PEP import to amino acid catabolism and proteostasis to preserve skeletal muscle integrity in response to metabolic stress.

DOI: https://doi.org/10.1126/sciadv.aef0140
Lab Anim (NY). 2026 Aug;55(8): 283

Metabolomics atlas of Alzheimer's disease models.

Alexandra Le Bras.

DOI: https://doi.org/10.1038/s41684-026-01782-x
bioRxiv. 2026 Jul 17. pii: 2026.07.13.732468. [Epub ahead of print]

Aquaporin-4 mislocalization from astrocyte endfeet prolongs survival in a prion-cerebral amyloid angiopathy model.

Samantha Flores, Amanda Wilpitz, Daniel Ojeda-Juarez, Jin Wang, Garrett Danque, Paige Sumowski, Gail Funk, Adela Malik, Don Pizzo, Emily Richards, Jeffrey J Iliff, Christina J Sigurdson.

Aquaporin 4 (AQP4) water channels are polarized to astrocytic endfeet at blood vessel interfaces, and lose polarity in vascular diseases, including stroke, chronic traumatic encephalopathy, and Alzheimer's disease. AQP4 modulates water influx and efflux in the interstitial fluid, yet how AQP4 localization impacts cerebral amyloid angiopathy (CAA) remains poorly understood. Here we show that astrocytic end feet and AQP4 are displaced from amyloid-bearing vessels in a prion-CAA mouse model that expresses GPI-anchorless PrP C . Displacing AQP4 genetically through deleting alpha-syntrophin ( Snta1 -/- ) led to a marked prolongation in survival, together with reduced microglial inflammation and C1q, in prion-CAA-affected mice. Additionally, synaptic structural proteins were better maintained. Finally, the level and distribution of prion aggregates were similar among the mice, indicating that prion conversion and spread was not affected. These results suggest that reducing AQP4 water channel function slows the decline in a vascular amyloid disease by reducing neuroinflammation.

DOI: https://doi.org/10.64898/2026.07.13.732468
Brain Behav Immun Health. 2026 Oct;56 101307

APOE genotype is associated with Ex vivo inflammatory responses in healthy individuals: Potential implications for Alzheimer's disease.

Joan Y Song, Liane E Hunter, Yun Freudenberg-Hua, Naomi Lubin, Shanshan Hu, Kenny Ye, Richard B Lipton, Christopher G Engeland, Michael L Lipton.

Background: Apolipoprotein E (APOE) genotype and inflammation are each linked to Alzheimer's disease (AD) risk. The APOE-ε4 (APOE4) allele is associated with increased AD risk, while the APOE-ε2 (APOE2) allele is protective. The mechanisms behind these associations remain unclear, particularly regarding the role of inflammation. This study examined the association between APOE genotype and different measures of inflammation, including mitogen-stimulated cytokine production (ex vivo) which provides a stable measure of immune response traits.
Methods: We examined basal and lipopolysaccharide (LPS)-stimulated cytokine levels (interleukin (IL)-1β, IL-4, IL-6, IL-8, IL-10, tumor necrosis factor-alpha (TNF-α), granulocyte-macrophage colony-stimulating factor (GM-CSF)) and C-reactive protein (CRP) in blood samples from 91 healthy individuals (ages 18-51) of varying APOE genotypes.
Results: APOE4 carriers exhibited higher LPS-stimulated inflammatory responses (IL-1β, TNF-α) in peripheral whole blood compared to non-carriers, while APOE2 carriers showed a hypo-inflammatory profile (lower stimulated IL-1β) compared to APOE3 individuals.
Conclusion: Distinct inflammatory phenotypes were associated with APOE genotypes, with APOE4 carriers exhibiting a hyper-inflammatory response and APOE2 carriers exhibiting a hypo-inflammatory response. These profiles may contribute to differential AD risk, highlighting the potential involvement of inflammation in APOE-associated AD susceptibility.

DOI: https://doi.org/10.1016/j.bbih.2026.101307