bims-micgli 2026-01-18 papers

Cell Rep. 2026 Jan 12. pii: S2211-1247(25)01393-2. [Epub ahead of print] 116621

Angiopoietin-2 aggravates Alzheimer's disease by promoting blood-brain barrier dysfunction and neuroinflammation.

Eunhyeong Lee, Seoyeon Kim, Claire L Zhu, Erica Acquarone, Sungsoo Kim, An Lo, Omar M F Omar, Maraake Taddese, Viviana Gradinaru, Patrick A Murphy, Dritan Agalliu, Ottavio Arancio, Joon-Yong An, Minah Kim.

Disruption of the blood-brain barrier (BBB) increases vascular permeability and promotes neuroinflammation, contributing to Alzheimer's disease (AD) progression. However, the molecular drivers of BBB dysfunction and neuroinflammation in AD remain poorly defined. Here, we identify angiopoietin-2 (ANGPT2) as a central mediator of BBB breakdown and AD progression. Transcriptomic analyses of human AD brains revealed elevated ANGPT2 expression in endothelial cells correlating with disease severity. In 5xFAD mice, endothelial-specific Angpt2 deletion reduced β-amyloid deposition, while Angpt2 overexpression via an adeno-associated viral vector exacerbated the plaque burden. Mechanistically, ANGPT2 suppression of TIE2 signaling increased vascular leakage and fibrin deposition, triggering microglial activation and neuroinflammatory responses that accelerated disease progression. Single-nucleus transcriptomic analyses further revealed Angpt2-driven microglial dysfunction and neuronal impairment consistent with memory deficits observed in behavioral assays. These findings establish ANGPT2 as a critical driver of BBB dysfunction and neuroinflammation in AD and highlight its therapeutic potential.

Keywords: Alzheimer’s disease; CP: neuroscience; angiopoietin-2; blood-brain barrier dysfunction; neuroinflammation; snRNA-seq; spatial memory; β-amyloid

DOI: https://doi.org/10.1016/j.celrep.2025.116621

FEBS Open Bio. 2026 Jan 14.

Microglial dynamics and ferroptosis induction in human iPSC-derived neuron-astrocyte-microglia tri-cultures.

Hongmei Lisa Li, Hiroko Ohmiya, Sou Sakamoto, Masato Yugami, Akiko Oki, Makoto Furusawa, Yan Ling.

The dynamics of microglial activity within neuron-astrocyte-microglia tri-cultures derived from human induced pluripotent stem cells (iPSCs) present a complex interplay and offer an opportunity to obtain new insights into neuron-glia interactions. Iron-laden microglia, correlating with functional changes, represent a key pathological feature of Alzheimer's disease (AD). This study characterized the cellular crosstalk and transcriptional states of microglia in tri-cultures. Complement C3 can be detected in culture media when microglia are cocultured with neurons, and the addition of astrocytes in the coculture led to an increased amount of C3, indicating that the impact of glial interactions can be evaluated in this model system. We compared microglial gene expression profiles comprehensively in monoculture, coculture, and tri-culture settings. Single-cell RNA sequencing (scRNA-seq) revealed various microglial states with gene expression changes associated with endocytosis and neuron-related functions in tri-culture settings, suggesting that microglial behavior is profoundly impacted by the presence of neurons and astrocytes. We assessed microglial responses to iron overload combined with the ferroptosis inducer RSL3 (a GPX4 inhibitor) in tri-cultures. Microglial cell death was accompanied by ferritin heavy-chain expression, indicating microglia ferroptosis. scRNA-seq analyses highlighted alterations in pathways related to ferroptosis, stress response, and autophagy, indicating substantial shifts in microglial profiles upon iron perturbation. These findings underscore the necessity of using tri-cultures as a model to capture certain degrees of complex cellular interactions occurring in vivo. These results offer critical insights for establishing in vitro models for therapeutic development of neurodegenerative diseases, including AD.

Keywords: ferroptosis; iPSC tri‐culture; single‐cell RNA‐seq; transcriptomics

DOI: https://doi.org/10.1002/2211-5463.70182

Immunity. 2026 Jan 13. pii: S1074-7613(25)00560-6. [Epub ahead of print]59(1): 8-10

A head start: Bone channels shape meningeal immunity.

Jasmin Herz, Jonathan Kipnis.

Immune cells from the skull marrow reach the meninges through bone channels. In this issue of Immunity, Eme-Scolan and colleagues show that these channels form neonatally and can be remodeled to alter immune access to the brain's borders. Their work suggests that the skull is a developmental checkpoint for neuroimmune defense, potentially shaping vulnerability or resilience across the lifespan.

DOI: https://doi.org/10.1016/j.immuni.2025.12.004

Am J Physiol Regul Integr Comp Physiol. 2026 Jan 12.

Microglial Activation and RAS Signaling: A Dual-Edged Sword in Neuroinflammation.

Uma-Priya Priya Mohan, Catalin M Filipeanu, Eric Lazartigues.

Microglia, the resident immune cells of the central nervous system (CNS), play a pivotal role in monitoring neuronal activity, maintaining tissue homeostasis, and orchestrating immune responses. Under physiological conditions, microglia support neuronal survival and synaptic remodeling, in part through anti-inflammatory mechanisms and clearance of cellular debris. However, dysregulated microglial activation is implicated in a wide variety of pathologic states, including neurodegenerative diseases, stroke, and hypertension, largely through the induction of chronic neuroinflammation. Emerging evidence highlights the renin-angiotensin system (RAS) as a critical modulator of microglial activity. Microglia express most RAS components, including angiotensinogen, ACE, ACE2, AT1R, AT2R, and Mas1R, enabling local generation of angiotensin peptides and autocrine/paracrine signaling. Activation of AT1R leads toward pro-inflammatory reactive microglial phenotypes, characterized by elevated release of cytokines and reactive oxygen species, whereas AT2R and Mas1R signaling transitions toward more homeostatic anti-inflammatory phenotypes, supporting tissue repair and neuronal protection. Dysregulation of this balance contributes to chronic neuroinflammation and may impact autonomic nervous system activity, linking microglial RAS signaling to systemic homeostatic alterations. Here, we review current literature into the expression, regulation, and functional consequences of RAS components in microglia, highlighting each element expression and signaling as regulators of neuroimmune activity while attempting to move away from the outdated M1/M2 nomenclature. We also discuss the therapeutic potential of pharmacologically targeting microglial RAS to shift reactive microglia toward a more homeostatic state, offering a promising strategy to mitigate neuroinflammation and protect against neurodegenerative and cardiovascular pathologies. Collectively, understanding the microglial RAS provides new avenues for intervention in CNS diseases associated with chronic inflammation.

Keywords: Microglia; Renin-Angiotensin System; homeostasis; neuroinflammation

DOI: https://doi.org/10.1152/ajpregu.00268.2025

bioRxiv. 2026 Jan 06. pii: 2026.01.06.697996. [Epub ahead of print]

Microglial Lag3 Drives α-Synuclein-induced Neurotoxic Activated (A1) Astrocytes and Neurodegeneration.

Background: Neuroinflammation and pathologic α-synuclein (α-syn) aggregation cooperate to drive dopaminergic neurodegeneration in Parkinson's disease, but the glial receptors that couple extracellular α-syn to inflammatory cascades remain incompletely defined. Microglia express higher levels of lymphocyte activation gene 3 (Lag3) than neurons, yet the contribution of microglial Lag3 to α-syn recognition, glial crosstalk, and neurodegeneration is unknown.
Methods: Biochemical binding assays, live-cell imaging, cytokine profiling, and neuron-microglia-astrocyte co-culture paradigms were used to define Lag3-dependent α-syn preformed fibril (PFF) binding, uptake, and microglial activation. To interrogate in vivo function, microglia-specific Lag3 conditional knockout mice (Lag3 L/L -Cx3cr1 CreER ) and littermate controls received unilateral intrastriatal α-syn PFF injections, followed by histological, biochemical, and behavioral assessments of α-syn pathology, gliosis, nigrostriatal integrity, and motor performance.
Results: α-syn PFFs bound microglial Lag3 with high specificity and nanomolar affinity and required Lag3 for efficient fibril internalization and induction of proinflammatory cytokines. Microglial Lag3 deficiency markedly blunted α-syn PFF-evoked microglial activation, prevented cytokine-driven conversion of astrocytes into neurotoxic reactive A1 astrocytes, and abolished astrocyte-dependent neuronal death in vitro. In vivo, microglia-specific Lag3 deletion reduced cortical, striatal, and substantia nigra pS129 α-syn pathology, suppressed microgliosis and A1 astrocyte induction, preserved substantia nigra dopaminergic neurons and striatal dopamine transporter/tyrosine hydroxylase expression, and ameliorated α-syn PFF-induced motor deficits.
Conclusions: This study identifies microglial Lag3 as a key receptor linking extracellular α-syn PFF recognition to inflammatory amplification, neurotoxic reactive A1 astrocyte conversion, and dopaminergic neurodegeneration. Together with prior work on neuronal Lag3, these findings support a cell-type-specific dual-axis model in which neuronal Lag3 mediates α-syn propagation while microglial Lag3 drives glia-dependent neurotoxicity, positioning Lag3 as a promising precision therapeutic target in α-synucleinopathies.

DOI: https://doi.org/10.64898/2026.01.06.697996

bioRxiv. 2025 Sep 28. pii: 2025.09.26.678370. [Epub ahead of print]

Parkinson's disease LRRK2 mutations dysregulate iron homeostasis and promote oxidative stress and ferroptosis in human neurons and astrocytes.

Adamantios Mamais, Richard D Batchelor, Aravindraja Chairmandurai, Nitya Subrahmanian, Nunziata Maio, Christopher D Vulpe, Matthew J LaVoie.

Background: Iron accumulation is a hallmark of sporadic and familial Parkinson's disease (PD) pathology and correlates with clinical motor symptom severity. The biochemical mechanisms driving iron dyshomeostasis in PD brain and whether these are early or late event in the neurodegenerative process remain unknown. Elevated nigral iron levels have been reported in LRRK2 mutation carriers, both in PD patients compared to idiopathic PD and in asymptomatic carriers relative to controls, suggesting that iron accumulation precedes clinical onset in LRRK2-associated PD. However, the precise consequence of pathogenic LRRK2 mutations on cellular iron handling within neurons and glial cells remains unclear.
Methods: Here, we investigated different readouts of iron homeostasis in iPSCs and iPSC-derived neurons and astrocytes from PD patients harboring G2019S or R1441C/G LRRK2 mutations or healthy controls, as well as an isogenic iPSC panel with the same variants. By using high-content and super-resolution microscopy of iron-specific probes, we assayed iron content and distribution in cells and examined the downstream effects of iron dyshomeostasis on ferroptosis signaling.
Results: We show that heterozygous LRRK2 mutations dysregulate cellular iron across iPSCs, neurons and astrocytes, in a kinase-dependent manner. Lysosomal ferrous iron storage was consistently elevated across iPSCs, iPSC-derived neurons and astrocytes carrying LRRK2 mutations. LRRK2 regulates Rab GTPase function through their direct phosphorylation, and our prior work revealed significant but divergent lysosomal phenotypes between Rab8a and Rab10 knockout models. Here, we report that Rab8a knockout recapitulates key aspects of LRRK2 mutation phenotypes on intracellular iron and ferritin levels, although with differences in magnitude and specificity. By contrast, Rab10 deficiency showed opposing effects, suggesting distinct roles for these well-established LRRK2 substrates in iron homeostasis. Finally, we show that basal lipid peroxidation and ROS levels are elevated in isogenic LRRK2 mutant neurons, while iron chelation was sufficient to reduce LRRK2-dependent ROS.
Conclusions: Together, our findings demonstrate that LRRK2 mutations disrupt iron homeostasis across disease-relevant cell types and establish a discrete biochemical pathway linking LRRK2 signaling and vulnerability to ferroptosis. Ongoing work aims to further dissect the roles of Rab substrates in these pathways.

DOI: https://doi.org/10.1101/2025.09.26.678370