bims-microg 2024-12-29 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2024–12–29
twenty papers selected by
Marcus Karlstetter, Universität zu Köln

A neurodegenerative cellular stress response linked to dark microglia and toxic lipid secretion.
Microglia heterogeneity during neuroinflammation and neurodegeneration in the mouse retina.
Accumulated BCAAs and BCKAs contribute to the HFD-induced deterioration of Alzheimer's disease via a dysfunctional TREM2-related reduction in microglial β-amyloid clearance.
Higher CSF sTREM2 attenuates APOE ε4-related risk for amyloid pathology in cognitively intact adults: The CABLE study.
Amelioration of signaling deficits underlying metabolic shortfall in TREM2R47H human iPSC-derived microglia.
Partial microglial depletion and repopulation exert subtle but differential effects on amyloid pathology at different disease stages.
Deep Proteome Coverage of Microglia Using a Streamlined Data-Independent Acquisition-Based Proteomic Workflow: Method Consideration for a Phenotypically Diverse Cell Type.
Microglial Activation and Hypothalamic Structural Plasticity in HFD Obesity: Insights from Semaglutide and Minocycline.
3-Dimensional morphological characterization of neuroretinal microglia in Alzheimer's disease via machine learning.
The unanticipated contribution of Zap70 in retinal degeneration: implications for microglial inflammatory activation.
Potentiating microglial efferocytosis by MFG-E8 improves survival and neurological outcome after successful cardiopulmonary resuscitation in mice.
A Self-Reinforced "Microglia Energy Modulator" for Synergistic Amyloid-β Clearance in Alzheimer's Disease Model.
Microglial Nrf2-mediated lipid and iron metabolism reprogramming promotes remyelination during white matter ischemia.
Therapeutic potential of microglial SMEK1 in regulating H3K9 lactylation in cerebral ischemia-reperfusion.
Microglia internalize tau monomers and fibrils using distinct receptors but similar mechanisms.
Human pluripotent stem cell-derived microglia shape neuronal morphology and enhance network activity in vitro.
Microglial Depletion, a New Tool in Neuroinflammatory Disorders: Comparison of Pharmacological Inhibitors of the CSF-1R.
Molecular intersections of traumatic brain injury and Alzheimer's disease: the role of ADMSC-derived exosomes and hub genes in microglial polarization.
Olfactory bulb microglia activation mediates neuronal pyroptosis in ozone-exposed mice with olfactory and cognitive dysfunction.
Resveratrol ameliorates postoperative cognitive dysfunction in aged mice by regulating microglial polarization through CX3CL1/CX3CR1 signaling axis.

Neuron. 2024 Dec 19. pii: S0896-6273(24)00875-4. [Epub ahead of print]

A neurodegenerative cellular stress response linked to dark microglia and toxic lipid secretion.

Anna Flury, Leen Aljayousi, Hye-Jin Park, Mohammadparsa Khakpour, Jack Mechler, Siaresh Aziz, Jackson D McGrath, Pragney Deme, Colby Sandberg, Fernando González Ibáñez, Olivia Braniff, Thi Ngo, Simira Smith, Matthew Velez, Denice Moran Ramirez, Dvir Avnon-Klein, John W Murray, Jia Liu, Martin Parent, Susana Mingote, Norman J Haughey, Sebastian Werneburg, Marie-Ève Tremblay, Pinar Ayata.

  The brain's primary immune cells, microglia, are a leading causal cell type in Alzheimer's disease (AD). Yet, the mechanisms by which microglia can drive neurodegeneration remain unresolved. Here, we discover that a conserved stress signaling pathway, the integrated stress response (ISR), characterizes a microglia subset with neurodegenerative outcomes. Autonomous activation of ISR in microglia is sufficient to induce early features of the ultrastructurally distinct "dark microglia" linked to pathological synapse loss. In AD models, microglial ISR activation exacerbates neurodegenerative pathologies and synapse loss while its inhibition ameliorates them. Mechanistically, we present evidence that ISR activation promotes the secretion of toxic lipids by microglia, impairing neuron homeostasis and survival in vitro. Accordingly, pharmacological inhibition of ISR or lipid synthesis mitigates synapse loss in AD models. Our results demonstrate that microglial ISR activation represents a neurodegenerative phenotype, which may be sustained, at least in part, by the secretion of toxic lipids.

Keywords:  Alzheimer’s disease; ISR; dark microglia; integrated stress response; lipid secretion; lipotoxicity; microglia; neurodegeneration; neurotoxic microglia; non-cell-autonomous stress

DOI:  https://doi.org/10.1016/j.neuron.2024.11.018
Brain Struct Funct. 2024 Dec 25. 230(1): 19

Microglia heterogeneity during neuroinflammation and neurodegeneration in the mouse retina.

Bilin Rao, Xiaoqing Liu, Jiayi Xiao, Xiaotian Wu, Fang He, Qingwen Yang, Wenna Zhao, Xin Lin, Jun Zhang.

  Microglia play important roles in maintaining homeostasis and immunoreactive defense in the central nervous system including retina. To accomplish such a wide range of functions, microglia are highly heterogeneous. Dark microglia (DM) were recently identified by electron microscopy (EM). However, the specific correlation between microglial morphological phenotypes, including DM, and physiological or pathological conditions remains poorly understood. We established acute and chronic neuroinflammatory models by Lipopolysaccharide (LPS) and light-induced photoreceptor neurodegeneration model to explore these questions in the mouse retina. Immunofluorescence and EM were used to detect microglia in these models. Our light microscopy (LM) results reveal that the withdrawal phenotype is predominant in acute neuroinflammation models, both in vitro and in vivo, while the dystrophic microglia are the major phenotype in chronic neuroinflammation and neurodegeneration models in vivo. Ultrastructurally, acute models exhibit high electron dense processes, but not somas, while chronic models show high electron dense somas and processes. Given the consistency between LM and EM, we propose that DM-like somas and processes likely indicate a dystrophic population. It's important to note, however, that DM may not represent a single specific microglia phenotype, but rather a dynamic transformation of gradually activated microglia. Finally, we provide evidence for the presence of DM in mouse retinas in the neuroinflammatory model and the neurodegenerative model. This research provides valuable insights into investigating microglia phenotypes through both LM and EM.

Keywords:  Dark microglia; Dynamics; Electron microscopy; Heterogeneity; Light microscopy; Microglia

DOI:  https://doi.org/10.1007/s00429-024-02875-4
J Neuroinflammation. 2024 Dec 23. 21(1): 327

Accumulated BCAAs and BCKAs contribute to the HFD-induced deterioration of Alzheimer's disease via a dysfunctional TREM2-related reduction in microglial β-amyloid clearance.

Yang Yang, Guanjin Shi, Yanyan Ge, Shanshan Huang, Ningning Cui, Le Tan, Rui Liu, Xuefeng Yang.

  A high-fat diet (HFD) induces obesity and insulin resistance, which may exacerbate amyloid-β peptide (Aβ) pathology during Alzheimer's disease (AD) progression. Branched-chain amino acids (BCAAs) accumulate in obese or insulin-resistant patients and animal models. However, roles of accumulated BCAAs and their metabolites, branched-chain keto acids (BCKAs), in the HFD-induced deterioration of AD and the underlying mechanisms remains largely unclear. In this study, APPswe/PSEN1dE9 (APP/PS1) transgenic mice were fed a HFD for 6 months, and the BCAAs content of the HFD was adjusted to 200% or 50% to determine the effects of BCAAs. The HFD-fed APP/PS1 mice accumulated BCAAs and BCKAs in the serum and cortex, which was accompanied by more severe cognitive deficits and AD-related pathology. The additional or restricted intake of BCAAs aggravated or reversed these phenomena. Importantly, BCAAs and BCKAs repressed microglial phagocytosis of Aβ in vivo and in BV2 cells, which might be relevant for triggering receptor expressed on myeloid cells 2 (TREM2) dysfunction and autophagy deficiency. We found that BCAAs and BCKAs could bind to TREM2 in silico, in pure protein solutions and in the cellular environment. These molecules competed with Aβ for binding to TREM2 so that the response of TREM2 to Aβ was impaired. Moreover, BCAAs and BCKAs decreased TREM2 recycling in an mTOR-independent manner, which might also lead to TREM2 dysfunction. Our findings suggest that accumulated BCAAs and BCKAs contribute to the HFD-induced acceleration of AD progression through hypofunctional TREM2-mediated disturbances in Aβ clearance in microglia. Lowering BCAAs and BCKAs levels may become a potential dietary intervention for AD.

Keywords:  Alzheimer’s disease; Amyloid-β; BCAAs; BCKAs; HFD; Insulin resistance; Microglia; TREM2

DOI:  https://doi.org/10.1186/s12974-024-03314-1
J Neurochem. 2025 Jan;169(1): e16273

Higher CSF sTREM2 attenuates APOE ε4-related risk for amyloid pathology in cognitively intact adults: The CABLE study.

Yong-Chang Wang, Liang-Yu Huang, Hai-Hua Guo, Min Liu, Yu-Ying Zhang, Zi-Qi Zhang, Quan Hao, Chen-Chen Tan, Lan Tan.

  The triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane protein found in microglia within the brain, and its soluble form (sTREM2) has been shown to reduce amyloid deposition. Whether elevated TREM2-mediated microglial activity decreases the risk of Alzheimer's disease (AD) is unclear. The aim of this study was to assess whether high cerebrospinal fluid (CSF) levels of sTREM2 attenuate the risk of APOE ε4-associated amyloid pathology. We included 877 cognitively intact subjects from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) study, including APOE ε4 carriers (n = 136) and non-carriers (n = 741). The linear regression was used to examine the interaction effect between CSF sTREM2 levels and APOE ε4 status on CSF Aβ42 levels. Additionally, subgroup analyses stratified by sex and age were conducted. Our main finding was that higher concentrations of CSF sTREM2 attenuated the effect of APOE ε4 carriage (i.e., the sTREM2 × APOE ε4 interaction) on amyloid deposition (β = -2.701e-05, p = 0.023). Subgroup analyses showed that the effect of interaction was still significant only in male (p = 0.041) and mid-life (p = 0.013) subgroups. Our study suggested that in cognitively intact individuals, changes in sTREM2 levels are associated with biomarkers of AD, and higher concentrations of CSF sTREM2 attenuated the risk of APOE ε4-related amyloid pathology. The identified role of the sTREM2 × APOE ε4 interaction in amyloid pathology offers new insights into potential strategies for AD prevention in APOE ε4 carriers.

Keywords:   APOE ε4 ; Alzheimer's disease; amyloid deposition; microglial activation; sTREM2

DOI:  https://doi.org/10.1111/jnc.16273
FEBS J. 2024 Dec 26.

Amelioration of signaling deficits underlying metabolic shortfall in TREM2R47H human iPSC-derived microglia.

Foteini Vasilopoulou, Thomas M Piers, Jingzhang Wei, John Hardy, Jennifer M Pocock.

  The microglial triggering receptor expressed on myeloid cells 2 (TREM2) is required for diverse microglia responses in neurodegeneration, including immunometabolic plasticity, phagocytosis, and survival. We previously identified that patient iPSC-derived microglia (iPS-Mg) harboring the Alzheimer's disease (AD) TREM2R47H hypomorph display several functional deficits linked to metabolism. To investigate whether these deficits are associated with disruptions in metabolite signaling, we generated common variant, TREM2R47H and TREM2-/- variant human iPS-Mg. We assessed the ability of supplementation with citrate or succinate, key metabolites and cell cycle breaking points upon microglia activation, to overcome these functional deficits with potential impact on neurons. Succinate supplementation was more effective than citrate at overcoming mitochondrial deficits in OXPHOS and did not promote a glycolytic switch. Citrate enhanced the lipid content of TREM2R47H iPS-Mg and was more effective at overcoming Αβ phagocytic deficits, whereas succinate increased lipid content and phagocytic capacity in TREM2-/- iPS-Mg. Microglia cytokine secretion upon pro-inflammatory activation was moderately affected by citrate or succinate showing a condition-dependent increasing trend. Neither metabolite altered basal levels of soluble TREM2 shedding. In addition, neither citrate nor succinate enhanced glycolysis; instead, drove their effects through oxidative phosphorylation. IPS-neurons exposed to conditioned medium from TREM2 variant iPS-Mg showed changes in oxidative phosphorylation, which could be ameliorated when iPS-Mg were first treated with citrate or succinate. Our data point to discrete pathway linkage between microglial metabolism and functional outcomes with implications for AD pathogenesis and treatments.

Keywords:  Alzheimer's disease; R47H TREM2 variant; TCA‐metabolites; human microglia; metabolism; neurodegeneration

DOI:  https://doi.org/10.1111/febs.17353
Sci Rep. 2024 Dec 28. 14(1): 30912

Partial microglial depletion and repopulation exert subtle but differential effects on amyloid pathology at different disease stages.

L H D Le, M K O'Banion, A K Majewska.

Colony-stimulating factor-1-receptor (CSF1R) inhibitors have been widely used to rapidly deplete microglia from the brain, allowing the remaining microglia population to self-renew and repopulate. These new-born microglia are thought to be "rejuvenated" and have been shown to be beneficial in several disease contexts and in normal aging. Their role in Alzheimer's disease (AD) is thus of great interest as they represent a potential disease-modifying therapy. Here, we explored the differential effects of microglial depletion and repopulation during amyloid pathology progression using 5xFAD mice. We utilized the CSF1R inhibitor PLX3397 to induce microglial self-renewal and tracked microglia-plaque dynamics with in vivo imaging. We observed transient improvement in plaque burden on different timescales depending on the animal's age. While the improvement in plaque burden did not persist in any age group, renewing microglia during mid- to late-pathology might still be beneficial as we observed a potential improvement in microglial sensitivity to noradrenergic signaling. Altogether, our findings provide further insights into the therapeutic potential of microglial renewal in AD.

DOI: https://doi.org/10.1038/s41598-024-81910-0
Proteomes. 2024 Nov 27. pii: 35. [Epub ahead of print]12(4):

Deep Proteome Coverage of Microglia Using a Streamlined Data-Independent Acquisition-Based Proteomic Workflow: Method Consideration for a Phenotypically Diverse Cell Type.

Jessica Wohlfahrt, Jennifer Guergues, Stanley M Stevens.

  As the primary innate immune cells of the brain, microglia play a key role in various homeostatic and disease-related processes. To carry out their numerous functions, microglia adopt a wide range of phenotypic states. The proteomic landscape represents a more accurate molecular representation of these phenotypes; however, microglia present unique challenges for proteomic analysis. This study implemented a streamlined liquid- and gas-phase fractionation method with data-dependent acquisition (DDA) and parallel accumulation-serial fragmentation (PASEF) analysis on a TIMS-TOF instrument to compile a comprehensive protein library obtained from adult-derived, immortalized mouse microglia with low starting material (10 µg). The empirical library consisted of 9140 microglial proteins and was utilized to identify an average of 7264 proteins/run from single-shot, data-independent acquisition (DIA)-based analysis microglial cell lysate digest (200 ng). Additionally, a predicted library facilitated the identification of 7519 average proteins/run from the same DIA data, revealing complementary coverage compared with the empirical library and collectively increasing coverage to approximately 8000 proteins. Importantly, several microglia-relevant pathways were uniquely identified with the empirical library approach. Overall, we report a simplified, reproducible approach to address the proteome complexity of microglia using low sample input and show the importance of library optimization for this phenotypically diverse cell type.

Keywords:  DDA library generation; DIA methods development; DIA-PASEF; deep proteomics; microglia

DOI:  https://doi.org/10.3390/proteomes12040035
J Lipid Res. 2024 Dec 24. pii: S0022-2275(24)00241-4. [Epub ahead of print] 100736

Microglial Activation and Hypothalamic Structural Plasticity in HFD Obesity: Insights from Semaglutide and Minocycline.

Xi Rong, Fang Wei, Yuqi Jiang, Qintao Ma, Dongmei Wang, Jie Shen.

  High-fat diet (HFD) -induced microglial activation contributes to hypothalamic inflammation and obesity, but the mechanisms linking microglia to structural changes remain unclear. This study explored the role of microglia in impairing hypothalamic synaptic plasticity in diet-induced obesity (DIO) mice and evaluated the therapeutic potential of semaglutide (Sema) and minocycline (MI). Six-week-old C57BL/6J mice were divided into low-fat diet (LFD) and HFD groups. At week 30, the HFD-fed mice were treated daily with Sema or MI for six weeks. Confocal microscopy assessed hypothalamic dendritic spines, synaptic organization, and microglia-synapse interactions. We also analyzed microglial morphology, CD68/CD11b colocalization with Iba-1, synaptic marker expression, and phagocytosis-related pathways (C1q, C3, CD11b). BV2 microglia were used to examine the direct effects of MI and Sema on microglia and validate the in vivo findings. HFD feeding induced microglial activation, as indicated by increased colocalization of CD68 or synaptophysin and CD11b with Iba-1, along with elevated C1q, C3, and CD11b expression, signaling enhanced synaptic phagocytosis. This was accompanied by reduced hypothalamic dendritic spines, decreased synaptic marker expression, and disrupted excitatory/inhibitory synaptic organization in the melanocortin system, as well as impaired glucose metabolism, disrupted leptin-ghrelin balance, and increased food intake and body weight. Sema and MI treatments reversed the pathological changes of microglial activation and restored hypothalamic synaptic structure, although their effects on synaptic organization and metabolic outcomes differed. Our findings highlight the key role of microglial activation in hypothalamic synaptic impairment in DIO models, with Sema and MI possibly offering distinct therapeutic pathways to mitigate these impairments.

Keywords:  High-fat diet obesity; Hypothalamic structural plasticity; Microglial activation; Minocycline; Semaglutide

DOI:  https://doi.org/10.1016/j.jlr.2024.100736
Acta Neuropathol Commun. 2024 Dec 24. 12(1): 202

3-Dimensional morphological characterization of neuroretinal microglia in Alzheimer's disease via machine learning.

Wissam B Nassrallah, Hao Ran Li, Lyden Irani, Printha Wijesinghe, Peter William Hogg, Lucy Hui, Jean Oh, Ian R Mackenzie, Veronica Hirsch-Reinshagen, Ging-Yuek Robin Hsiung, Wellington Pham, Sieun Lee, Joanne A Matsubara.

  Alzheimer's Disease (AD) is a debilitating neurodegenerative disease that affects 47.5 million people worldwide. AD is characterised by the formation of plaques containing extracellular amyloid-β (Aβ) and neurofibrillary tangles composed of hyper-phosphorylated tau proteins (pTau). Aβ gradually accumulates in the brain up to 20 years before the clinical onset of dementia, making it a compelling candidate for early detection of AD. It has been shown that there is increased deposition of Aβs in AD patients' retinas. However, little is known about microglia's ability to function and clear Aβ within the retina of AD and control eyes. We labelled microglia with ionised calcium-binding adaptor molecule 1 (IBA-1) in AD and age-matched control donor retinas. We then used interactive machine learning to segment individual microglia in 3D. In the temporal mid-peripheral region, we found that the number of microglia was significantly lower in AD retinas compared to controls. Unexpectedly, the size of the microglia was significantly larger in the AD retinas compared to controls. We also labelled retinal microglia for Cluster of Differentiation 68 (CD68), a transmembrane glycoprotein expressed by cells in the monocyte lineage and a marker of phagocytic activity and activated microglia. The size of CD68 + cells was statistically different between AD and control microglial, with CD68 + cells being larger in AD. In contrast, there was no difference in either size or shape for CD68- microglia between the two groups, suggesting an important difference in the active states of CD68 + microglia in AD retina. There was also significantly increased CD68 immunoreactivity in individual microglia within the AD group. Overall, this study reveals unique differences in the size and activity of the retinal microglia, which may relate to their potential chronic activation due to increased levels of Aβs in the AD retina.

Keywords:  3-Dimensional morphology; Alzheimer’s disease; Machine learning; Microglia count; Microglia morphology; Microglia size; Neuroretinal microglia; Phagocytic cups

DOI:  https://doi.org/10.1186/s40478-024-01898-6
Prog Neurobiol. 2024 Dec 20. pii: S0301-0082(24)00142-4. [Epub ahead of print] 102706

The unanticipated contribution of Zap70 in retinal degeneration: implications for microglial inflammatory activation.

Kausik Bishayee, Seung-Hee Lee, Yeon-Jin Heo, Mi-La Cho, Yong Soo Park.

  Inflammation is a major mechanism of photoreceptor cell death in the retina during macular degeneration leading to the blindness. In this study, we investigated the role of the kinase molecule Zap70, which is an inflammatory regulator of the systemic immune system, to elucidate the control mechanism of inflammation in the retina. We observed activated microglial cells migrated and populated the retinal layer following blue LED-induced photoreceptor degeneration and activated microglial cells in the LED-injured retina expressed Zap70, unlike the inactive microglial cells in the normal retina. Visual function was considerably decreased in blue-LED light-exposed mice, and animals with Zap70 mutations were adversely affected. Furthermore, extensive photoreceptor cell death was observed in the SKG mice, bearing a Zap70 mutation that induces autoimmune disease. In the blue-LED light-exposed groups, SKG retinas had significantly higher levels of inflammatory cytokines than those in wild-type mice. Furthermore, regulating Zap70 activity has a significant influence on microglial inflammatory state. We discovered that active microglial cells expressing Zap70 could modify vascular endothelial growth factor A (Vegfa) signaling in primary retinal pigment epithelial (RPE) cells. Our novel study revealed that the production of Zap70 by retinal microglial cells is responsible for inflammatory signals that promote apoptosis in photoreceptor cells. Furthermore, Zap70-positive microglial cells were capable of regulating Vegfa signaling in RPE cells, which matches the hallmark of macular degeneration. Overall, we discovered Zap70's inflammatory activity in the retina, which is necessary for upregulating multiple inflammatory cytokines and cell death. Zap70 represents a novel therapeutic target for treating retinal degeneration.

Keywords:  SKG mice; Zap70; inflammation; microglia; photoreceptor cell death; retina

DOI:  https://doi.org/10.1016/j.pneurobio.2024.102706
Brain Pathol. 2024 Dec 24. e13327

Potentiating microglial efferocytosis by MFG-E8 improves survival and neurological outcome after successful cardiopulmonary resuscitation in mice.

Kunxue Zhang, Yuzhen Zhang, Zhentong Li, Jiancong Chen, Yuan Chang, Yongchuan Li, Shuxin Zeng, Sifan Pan, Suyue Pan, Kaibin Huang.

  Brain injury represents the leading cause of mortality and disability after cardiopulmonary resuscitation (CPR) from cardiac arrest (CA), in which the accumulation of dying cells aggravate tissue injury by releasing proinflammatory intracellular components. Microglia play an essential role in maintaining brain homeostasis via milk fat globule epidermal growth factor 8 (MFG-E8)-opsonized efferocytosis, the engulfment of dying cells and debris. This study investigates whether potentiating microglia efferocytosis by MFG-E8 provides neuroprotection after CA/CPR. After 8-minute asphyxial CA/CPR, male adult C57BL/6J mice were randomly assigned to receive recombinant mouse MFG-E8 (rmMFG-E8) or vehicle. We evaluated the survival and neurological deficits of mice, along with histological damages, phagocytosis index of dying cells, and microglia polarization. A transcriptome analysis was conducted to explore the downstream molecules modulated by MFG-E8. In mice resuscitated from CA, rmMFG-E8 administration significantly enhanced the efferocytosis of apoptotic cells by microglia, improved the survival and neurological function of mice, and attenuated neuropathological injuries. Additionally, rmMFG-E8 induced a prominent alteration in microglial gene expression and promoted a shift from a proinflammatory phenotype to an anti-inflammatory phenotype. Moreover, rmMFG-E8 treatment induced up-regulation of interferon regulatory factor 7 (IRF7), and IRF7 gene silencing largely reversed the neuroprotective effects of rmMFG-E8. This study demonstrates that rmMFG-E8 improves survival and neurological outcomes after CA/CPR by enhancing microglial efferocytosis and reshaping the inflammatory microenvironment in brain tissue. Potentiating MFG-E8 is a promising strategy to combat post-CA brain injury.

Keywords:  IRF7; MFG‐E8; cardiac arrest; efferocytosis; microglia/macrophage

DOI:  https://doi.org/10.1111/bpa.13327
Angew Chem Int Ed Engl. 2024 Dec 23. e202420547

A Self-Reinforced "Microglia Energy Modulator" for Synergistic Amyloid-β Clearance in Alzheimer's Disease Model.

Mengmeng Ma, Jing Wang, Kaiming Guo, Wenbin Zhong, Yu Cheng, Li Lin, Yanli Zhao.

  Microglial phagocytosis is a highly energy-consuming process that plays critical roles in clearing neurotoxic amyloid-β (Aβ) in Alzheimer's disease (AD). However, microglial metabolism is defective overall in AD, thereby undermining microglial phagocytic functions. Herein, we repurpose the existing antineoplastic drug lonidamine (LND) conjugated with hollow mesoporous Prussian blue (HMPB) as a "microglial energy modulator" (termed LND@HMPB-T7) for safe and synergistic Aβ clearance. The modified blood-brain barrier penetrating heptapeptide (T7) enables efficient transport of LND@HMPB-T7 to the AD brain. LND in LND@HMPB-T7 could fuel Aβ phagocytosis by stimulating microglial adenosine triphosphate (ATP) production, whereas HMPB with catalase and superoxide dismutase-mimicking activities substantially alleviates the mitochondrial side effects commonly associated with LND and thus further enhances ATP production. The synergism of LND and nanozyme affords a high microglial Aβ clearance efficacy without triggering mitochondrial dysfunction. In vivo experiments ascertain that LND@HMPB-T7 could synergistically promote phagocytic clearance of Aβ, relieve neuroinflammation and ameliorate cognitive function in AD mice. These findings indicate that LND@HMPB-T7 holds tremendous clinical potential as a repurposed drug for AD treatment.

Keywords:  Alzheimer's disease * amyloid-β * drug repurposing * microglial phagocytosis * nanozyme

DOI:  https://doi.org/10.1002/anie.202420547
Redox Biol. 2024 Dec 18. pii: S2213-2317(24)00451-8. [Epub ahead of print]79 103473

Microglial Nrf2-mediated lipid and iron metabolism reprogramming promotes remyelination during white matter ischemia.

Hang Zhang, Sheng Yang, Yi-Lin Lu, Luo-Qi Zhou, Ming-Hao Dong, Yun-Hui Chu, Xiao-Wei Pang, Lian Chen, Lu-Lu Xu, Lu-Yang Zhang, Li-Fang Zhu, Ting Xu, Wei Wang, Ke Shang, Dai-Shi Tian, Chuan Qin.

   BACKGROUND: Oxidative stress and microglial activation are critical pathomechanisms in ischemic white matter injury. Microglia, as resident immune cells in the brain, are the main cells undergoing oxidative stress response. However, the role and molecular mechanism of oxidative stress in microglia have not been clearly elucidated during white matter ischemia.
METHODS: Extensive histological analysis of the corpus callosum was performed in BCAS mice at different time points to assess white matter injury, oxidative stress and microglial activation. Flow cytometric sorting and transcriptomic sequencing were combined to explore the underlying mechanisms regulating microglial oxidative stress and functional phenotypes. The expression of critical molecule in microglia was regulated using Cx3cr1CreER mice and clinical-stage drugs to assess its effect on white matter injury and cognitive function.
RESULTS: Our study identified nuclear factor erythroid-2 related factor 2 (Nrf2) as a key transcription factor regulating oxidative stress and functional phenotype in microglia. Interestingly, we found that the sustained decrease in transiently upregulated expression of Nrf2 following chronic cerebral hypoperfusion resulted in abnormal microglial activation and white matter injury. In addition, high loads of myelin debris promoted lipid peroxidation and ferroptosis in microglia with diminished antioxidant function. Microglia with pharmacologically or genetically stimulated Nrf2 expression exhibited enhanced resistance to ferroptosis and pro-regenerative properties to myelination due to lipid and iron metabolism reprogramming.
CONCLUSION: Weakened Nrf2-mediated antioxidant responses in microglia induced metabolic disturbances and ferroptosis during chronic cerebral hypoperfusion. Targeted enhancement of Nrf2 expression in microglia may be a potential therapeutic strategy for ischemic white matter injury.

Keywords:  Chronic cerebral hypoperfusion; Ferroptosis; Lipid metabolism; Microglia; Nrf2; Oxidative stress

DOI:  https://doi.org/10.1016/j.redox.2024.103473
Commun Biol. 2024 Dec 26. 7(1): 1701

Therapeutic potential of microglial SMEK1 in regulating H3K9 lactylation in cerebral ischemia-reperfusion.

Wei-Yue Si, Chun-Lin Yang, Shu-Li Wei, Tong Du, Liang-Kang Li, Jing Dong, Yang Zhou, Heng Li, Peng Zhang, Qi-Ji Liu, Rui-Sheng Duan, Ruo-Nan Duan.

Acute ischemic stroke (AIS) triggers immune responses and neuroinflammation, contributing to brain injury. Histone lactylation, a metabolic stress-related histone modification, plays a critical role in various diseases, but its involvement in cerebral ischemia remains unclear. This study utilized a transient middle cerebral artery occlusion/reperfusion (MCAO/R) model and an oxygen-glucose deprivation/reoxygenation (OGD/R) model to investigate the role of microglial histone lactylation in ischemia-reperfusion injury. Lactate overload post-AIS increased histone lactylation, while reduced SMEK1 expression in microglia correlated with elevated lactate and neuroinflammation. Microglia-specific SMEK1 deficiency enhanced lactate production by inhibiting the pyruvate dehydrogenase kinase 3-pyruvate dehydrogenase (PDK3-PDH) pathway, increasing H3 lysine 9 lactylation (H3K9la), activating Ldha and Hif-1α transcription, and promoting glycolysis. SMEK1 overexpression improved neurological recovery in ischemic mice. This study highlights SMEK1 as a novel regulator of histone lactylation and a potential therapeutic target for mitigating neuroinflammation and enhancing recovery after AIS.

DOI: https://doi.org/10.1038/s42003-024-07425-6
Alzheimers Dement. 2024 Dec 23.

Microglia internalize tau monomers and fibrils using distinct receptors but similar mechanisms.

Kristian F Falkon, Liliana Danford, Eduardo Gutierrez Kuri, Paulina Esquinca-Moreno, Yaren L Peña Señeriz, Sabrina Smith, Jessica L Wickline, Ariel Louwrier, Jacob A McPhail, Naomi L Sayre, Sarah C Hopp.

   INTRODUCTION: Alzheimer's disease (AD) and other tauopathies are characterized by intracellular aggregates of microtubule-associated protein tau that are actively released and promote proteopathic spread. Microglia engulf pathological proteins, but how they endocytose tau is unknown.
METHODS: We measured endocytosis of different tau species by microglia after pharmacological modulation of macropinocytosis or clathrin-mediated endocytosis (CME) or antagonism/genetic depletion of known tau receptors heparan-sulfate proteoglycans (HSPGs) and low-density lipoprotein receptor-related protein 1 (LRP1).
RESULTS: Dynamin inhibition decreased microglial endocytosis of all tested tau species. Meanwhile, HSPG antagonism blocked only fibril uptake, and LRP1 antagonism or genetic depletion inconsistently inhibited the endocytosis of fibrils and monomers. Cre recombinase robustly enhanced tau uptake with partial selectivity for fibrils.
DISCUSSION: These data show that microglia take up both tau monomers and aggregates via a dynamin-dependent form of endocytosis (eg, CME) but may differ in using HSPGs for entry depending on species.
HIGHLIGHTS: Microglial endocytosis of tau monomers and fibrils is dynamin-dependent. HSPG antagonism blocks microglial uptake of tau fibrils but not monomers. LRP1 antagonism or knockdown inconsistently inhibits tau uptake. TAT-Cre stimulates semi-selective uptake of fibrils over monomers.

Keywords:  Alzheimer's disease; endocytosis; microglia; neuroinflammation; tau; tauopathy

DOI:  https://doi.org/10.1002/alz.14418
J Neurosci Methods. 2024 Dec 24. pii: S0165-0270(24)00299-1. [Epub ahead of print] 110354

Human pluripotent stem cell-derived microglia shape neuronal morphology and enhance network activity in vitro.

L M L Kok, K Helwegen, N F Coveña, V M Heine.

   BACKGROUND: Microglia, the resident immune cells of the central nervous system, play a critical role in maintaining neuronal health, but are often overlooked in traditional neuron-focused in vitro models.
NEW METHOD: In this study, we developed a novel co-culture system of human pluripotent stem cell (hPSC)-derived microglia and neurons to investigate how hPSC-derived microglia influence neuronal morphology and network activity. Using high-content morphological analysis and multi-electrode arrays (MEA), we demonstrate that these microglia successfully incorporate into neuronal networks and modulate key aspects of neuronal function.
RESULTS: hPSC-derived microglia significantly reduced cellular debris and altered neuronal morphology by decreasing axonal and dendritic segments and reducing synapse density. Interestingly, despite the decrease in synapse density, neuronal network activity increased.
CONCLUSION: Our findings underscore the importance of including hPSC-derived microglia in in vitro models to better simulate in vivo neuroglial interactions and provide a platform for investigating neuron-glia dynamics in health and disease.

Keywords:  Multi-electrode arrays; human in vitro modelling; iPSC; microglia-neuron co-culture

DOI:  https://doi.org/10.1016/j.jneumeth.2024.110354
Glia. 2024 Dec 24.

Microglial Depletion, a New Tool in Neuroinflammatory Disorders: Comparison of Pharmacological Inhibitors of the CSF-1R.

David Guenoun, Nathan Blaise, Alexandre Sellam, Julie Roupret-Serzec, Alice Jacquens, Juliette Van Steenwinckel, Pierre Gressens, Cindy Bokobza.

  A growing body of evidence highlights the importance of microglia, the resident immune cells of the CNS, and their pro-inflammatory activation in the onset of many neurological diseases. Microglial proliferation, differentiation, and survival are highly dependent on the CSF-1 signaling pathway, which can be pharmacologically modulated by inhibiting its receptor, CSF-1R. Pharmacological inhibition of CSF-1R leads to an almost complete microglial depletion whereas treatment arrest allows for subsequent repopulation. Microglial depletion has shown promising results in many animal models of neurodegenerative diseases (Alzheimer's disease (AD), Parkinson's disease, or multiple sclerosis) where transitory microglial depletion reduced neuroinflammation and improved behavioral test results. In this review, we will focus on the comparison of three different pharmacological CSF-1R inhibitors (PLX3397, PLX5622, and GW2580) regarding microglial depletion. We will also highlight the promising results obtained by microglial depletion strategies in adult models of neurological disorders and argue they could also prove promising in neurodevelopmental diseases associated with microglial activation and neuroinflammation. Finally, we will discuss the lack of knowledge about the effects of these strategies on neurons, astrocytes, and oligodendrocytes in adults and during neurodevelopment.

Keywords:  CSF‐1; CSF‐1R; GW2580; PLX3397; PLX5622; depletion; microglia; neurology

DOI:  https://doi.org/10.1002/glia.24664
Metab Brain Dis. 2024 Dec 24. 40(1): 77

Molecular intersections of traumatic brain injury and Alzheimer's disease: the role of ADMSC-derived exosomes and hub genes in microglial polarization.

Pengtao Li, Liguo Ye, Sishuai Sun, Yue Wang, Yihao Chen, Jianbo Chang, Rui Yin, Xiaoyu Liu, Wei Zuo, Houshi Xu, Xiao Zhang, Robert Chunhua Zhao, Qin Han, Junji Wei.

  Traumatic brain injury (TBI) is a significant contributor to global mortality and morbidity, with emerging evidence indicating a heightened risk of developing Alzheimer's disease (AD) following TBI. This study aimed to explore the molecular intersections between TBI and AD, focusing on the role of adipose mesenchymal stem cell (ADMSC)-derived exosomes and hub genes involved in microglial polarization. Transcriptome profiles from TBI (GSE58485) and AD (GSE74614) datasets were analyzed to identify differentially expressed genes (DEGs). The hub genes were validated in independent datasets (GSE180811 for TBI and GSE135999 for AD) and localized to specific cell types using single-cell RNA (scRNA) sequencing data (GSE160763 for TBI and GSE224398 for AD). Experimental validation was conducted to investigate the role of these genes in microglial polarization using cell culture and ADMSC-derived exosomes interventions. Our results identified three hub genes-Bst2, B2m, and Lgals3bp-that were upregulated in both TBI and AD, with strong associations to inflammation, neuronal apoptosis, and tissue repair processes. scRNA sequencing revealed that these genes are predominantly expressed in microglia, with increased expression during M1 polarization. Knockdown of these genes reduced M1 polarization and promoted M2 phenotype in microglia. Additionally, ADMSC-derived exosomes attenuated M1 polarization and downregulated the expression of hub genes. This study provides novel insights into the shared molecular pathways between TBI and AD, highlighting potential therapeutic targets for mitigating neuroinflammation and promoting recovery in both conditions.

Keywords:  ADMSC-derived exosomes; Alzheimer's disease; Microglial polarization; Traumatic brain injury

DOI:  https://doi.org/10.1007/s11011-024-01503-8
J Hazard Mater. 2024 Dec 17. pii: S0304-3894(24)03482-4. [Epub ahead of print]485 136901

Olfactory bulb microglia activation mediates neuronal pyroptosis in ozone-exposed mice with olfactory and cognitive dysfunction.

Ranhong Xu, Haiyu Chen, Yougang Wang, Haomin Qi, Yinuo Chen, Anqi Dai, Siqi Yang, Yue Wang, Yan Zeng, Jinquan Li.

  In recent years, there has been a notable increase in the concentration of air pollutants in the troposphere, especially ozone. However, limited research has gone beyond examining histopathological alterations in the olfactory bulb (OB) to explore the effects of ozone exposure on olfactory and cognitive functions. In our study, we exposed nine-month-old C57BL/6 mice to ozone at a concentration of 1.0 ppm for 13 weeks to examine the effects of ozone on the OB. The results indicated that ozone exposure induces olfactory and cognitive impairments in the mice. Subsequently, microglia in the OB are activated, leading to neuroinflammation. Ozone-induced downregulation of PSD95 and Synaptophysin, which was accompanied by a decrease in dendritic length and spine density. Simultaneously, increasing in the co-labeling of C1q, Iba1, and PSD95 after ozone exposure indicated that C1q-mediated synaptic phagocytosis by microglia might play a role in synaptic damage. Furthermore, the co-labeling of GSDMD-N and NEUN results suggests that ozone exposure triggers pyroptosis in neurons. Additionally, minocycline administration can alleviate ozone-induced olfactory and cognitive impairments by suppressing microglial activation. This study illustrates that prolonged ozone exposure leads to microglial activation in the OB, causing synaptic damage, neuronal pyroptosis, and subsequent deficits in olfactory and cognitive functions.

Keywords:  Cognitive impairment; Microglia; Olfactory dysfunction; Ozone; Pyroptosis

DOI:  https://doi.org/10.1016/j.jhazmat.2024.136901
Neurosci Lett. 2024 Dec 21. pii: S0304-3940(24)00468-3. [Epub ahead of print] 138089

Resveratrol ameliorates postoperative cognitive dysfunction in aged mice by regulating microglial polarization through CX3CL1/CX3CR1 signaling axis.

Jinming Liu, Yong Wang, Hong Sun, Daoyun Lei, Jufeng Liu, Yuanhui Fei, Chunhui Wang, Chao Han.

  Postoperative cognitive dysfunction (POCD) is a common cognitive challenge faced by older adults. One of the key contributors to the development of POCD is neuroinflammation induced by microglia. Resveratrol has emerged as a promising candidate for the prevention of cognitive decline. Previous studies have demonstrated its potential in alleviating cognitive deterioration, yielding encouraging results. Nonetheless, the mechanism of resveratrol improving cognitive function remains unclear. Therefore, we assessed the effect of resveratrol in both aged POCD model mice and BV2 cells on CX3CL1/CX3CR1 axis, a critical signaling pathway mediating microglial activity. Both in vitro and in vivo experiments have revealed that pre-administration of resveratrol not only mitigates cognitive deficits but also significantly reduces the levels of inflammatory cytokines. Additionally, it enhanced the expression of SIRT1 and CX3CR1 within the hippocampal region. We also evaluated the impact of resveratrol on CX3CR1 siRNA transfected BV2 cells. Delete of CX3CR1 reversed the preventive role of resveratrol. Our findings implied that resveratrol might inhibit microglial activation and improve cognition by mediating CX3CL1/CX3CR1 signaling.

Keywords:  CX3CL1/CX3CR1; Microglia; Postoperative cognitive dysfunction; Resveratrol

DOI:  https://doi.org/10.1016/j.neulet.2024.138089