bims-microg 2024-09-15 papers

bims-microg

Biomed News

on Microglia in health and disease

Issue of 2024–09–15
35 papers selected by
Marcus Karlstetter, Universität zu Köln

An anti-aging vaccine: BCG turns back the clock on remyelination failure.
Microglia bridge brain activity and blood pressure.
CYP7B1 deficiency impairs myeloid cell activation in autoimmune disease of the central nervous system.
Fibrotic response to anti-CSF-1R therapy potentiates glioblastoma recurrence.
Therapeutic efficacy of intracerebral hematopoietic stem cell gene therapy in an Alzheimer's disease mouse model.
Neuroinflammation revisited through the microglial lens.
miR-34a-5p Predicts the Risk of Diabetic Neuropathic Pain and Mediates Neuroinflammation in Microglia via Targeting ENPP3.
Neuronal AMPK regulates lipid transport to microglia.
Dynamic Brain Lipid Profiles Modulate Microglial Lipid Droplet Accumulation and Inflammation Under Ischemic Conditions in Mice.
Permethrin exposure primes neuroinflammatory stress response to drive depression-like behavior through microglial activation in a mouse model of Gulf War Illness.
A p75 neurotrophin receptor-sparing nerve growth factor protects retinal ganglion cells from neurodegeneration by targeting microglia.
Bi-allelic NRXN1α deletion in microglia derived from iPSC of an autistic patient increases interleukin-6 production and impairs supporting function on neuronal networking.
Small Hyperreflective Retinal Foci as in vivo imaging feature of resident microglia activation in geographic atrophy.
HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV.
A miR-383-5p signalling hub coordinates the axon regeneration response to inflammation.
TSPO Radioligands for Neuroinflammation: An Overview.
The microglial P2Y6 receptor as a therapeutic target for neurodegenerative diseases.
Combination AAV therapy with galectin-1 and SOD1 downregulation demonstrates superior therapeutic effect in a severe ALS mouse model.
Matrine protects against experimental autoimmune encephalomyelitis through modulating microglial ferroptosis.
Clearance and transport of amyloid β by peripheral monocytes correlate with Alzheimer's disease progression.
Pregnancy ameliorates neuropathic pain through suppression of microglia and upregulation of the δ-opioid receptor in the anterior cingulate cortex in late-pregnant mice.
Principal components analysis on genes related to inflammasome complex and microglial activation in the hypothalamus of obese mice treated with semaglutide (GLP-1 analog).
Dead foundation species create coral rubble habitat that benefits a resilient pest species.
Tunneling Nanotubes in the Brain.
Exploring the role of eosinophil cationic protein (ECP) in schizophrenia: Insights and implications.
DVL/GSK3/ISL1 pathway signaling: unraveling the mechanism of SIRT3 in neurogenesis and AD therapy.
Mesenchymal stem cells improve depressive disorder via inhibiting the inflammatory polarization of microglia.
TNFR2 signaling in oligodendrocyte precursor cells suppresses their immune-inflammatory function and detrimental microglia activation in CNS demyelinating disease.
Astrocyte-derived MFG-E8 facilitates microglial synapse elimination in Alzheimer's disease mouse models.
Fat mass and obesity-mediated m6A modification modulates neuroinflammatory responses after traumatic brain injury.
Inhibition of CRMP2 Phosphorylation Suppresses Microglia Activation in the Retina and Optic Nerve and Promotes Optic Nerve Regeneration After Optic Nerve Injury.
Sustained Microglial Activation Promotes Synaptic Loss and Neuronal Dysfunction after Recovery from ZIKV Infection.
Microglia contact cerebral vasculature through gaps between astrocyte endfeet.
Microglial process convergence onto injured axonal swellings, a human postmortem brain tissue study.
Microglial morphological/inflammatory phenotypes and endocannabinoid signaling in a preclinical model of periodontitis and depression.

Immunity. 2024 Sep 10. pii: S1074-7613(24)00374-1. [Epub ahead of print]57(9): 2005-2007

An anti-aging vaccine: BCG turns back the clock on remyelination failure.

Janssen M Kotah, Bart J L Eggen.

Aging leads to alterations that precipitate or aggravate several diseases that occur across our lifespan. In the CNS, aging affects the capacity to maintain and repair the myelin sheaths that protect axons and facilitate neuronal signaling. Tiwari et al. report aging-associated transcriptional responses in microglia after demyelination, which could be reversed by epigenetic remodeling after BCG vaccination.

DOI: https://doi.org/10.1016/j.immuni.2024.08.001
Immunity. 2024 Sep 10. pii: S1074-7613(24)00405-9. [Epub ahead of print]57(9): 2000-2002

Microglia bridge brain activity and blood pressure.

Yanxia Rao, Bo Peng.

Our brain is not an immune-privileged island isolated from peripheries, but how non-neuronal brain cells interact with the peripheral system is not well understood. Wei et al. report that microglia in the hypothalamic paraventricular nucleus (PVN) with unique vasculature can detect ATP derived from hemodynamic disturbance. These microglia in the PVN regulate the response to hypertension via ATP-P2Y12-C/EBPβ signaling.

DOI: https://doi.org/10.1016/j.immuni.2024.08.006
PNAS Nexus. 2024 Sep;3(9): pgae334

CYP7B1 deficiency impairs myeloid cell activation in autoimmune disease of the central nervous system.

Huanhuan Song, Aowei Lv, Zhibao Zhu, Runyun Li, Qiuping Zhao, Xintong Yu, Junyi Jiang, Xiang Lin, Cunjin Zhang, Rui Li, Yaping Yan, Wanjin Chen, Ning Wang, Ying Fu.

  Dysregulation of cholesterol metabolism underlies neurodegenerative disease and is increasingly implicated in neuroinflammatory diseases, such as multiple sclerosis (MS). Cytochrome P450 family 7 subfamily B member 1 (CYP7B1) is a key enzyme in alternative cholesterol metabolism. A recessive mutation in the gene CYP7B1 is known to cause a neurodegenerative disease, hereditary spastic paraplegia type 5 and oxysterol accumulation. However, the role of CYP7B1 in neuroinflammation has been little revealed. In this study, we induced experimental autoimmune encephalomyelitis (EAE), as a murine model of MS, using CYP7B1 homozygous knockout (KO) mice. We found that CYP7B1 deficiency can significantly attenuate EAE severity. CYP7B1 deficiency is sufficient to reduce leukocyte infiltration into the central nervous system, suppress proliferation of pathogenic CD4+ T cells, and decrease myeloid cell activation during EAE. Additionally, live-animal imaging targeting translocator protein expression, an outer mitochondrial membrane protein biomarker of neuroinflammation, showed that CYP7B1 deficiency results in suppressed neuroinflammation. Using human monocyte-derived microglia-like cellular disease model and primary microglia of CYP7B1 KO mice, we also found that activation of microglia of CYP7B1 deficiency was impaired. These cumulative results suggest that CYP7B1 can regulate neuroinflammation, thus providing potential new targets for therapeutic intervention.

Keywords:  cholesterol metabolism; cytochrome P450 family 7 subfamily B member 1; experimental autoimmune encephalomyelitis; myeloid cell; neuroinflammation

DOI:  https://doi.org/10.1093/pnasnexus/pgae334
Cancer Cell. 2024 Sep 09. pii: S1535-6108(24)00311-8. [Epub ahead of print]42(9): 1507-1527.e11

Fibrotic response to anti-CSF-1R therapy potentiates glioblastoma recurrence.

Spencer S Watson, Anoek Zomer, Nadine Fournier, Joao Lourenco, Manfredo Quadroni, Agnieszka Chryplewicz, Sina Nassiri, Pauline Aubel, Simona Avanthay, Davide Croci, Erik Abels, Marike L D Broekman, Douglas Hanahan, Jason T Huse, Roy T Daniel, Monika E Hegi, Krisztian Homicsko, Giulia Cossu, Andreas F Hottinger, Johanna A Joyce.

Glioblastoma recurrence is currently inevitable despite extensive standard-of-care treatment. In preclinical studies, an alternative strategy of targeting tumor-associated macrophages and microglia through CSF-1R inhibition was previously found to regress established tumors and significantly increase overall survival. However, recurrences developed in ∼50% of mice in long-term studies, which were consistently associated with fibrotic scars. This fibrotic response is observed following multiple anti-glioma therapies in different preclinical models herein and in patient recurrence samples. Multi-omics analyses of the post-treatment tumor microenvironment identified fibrotic areas as pro-tumor survival niches that encapsulated surviving glioma cells, promoted dormancy, and inhibited immune surveillance. The fibrotic treatment response was mediated by perivascular-derived fibroblast-like cells via activation by transforming growth factor β (TGF-β) signaling and neuroinflammation. Concordantly, combinatorial inhibition of these pathways inhibited treatment-associated fibrosis, and significantly improved survival in preclinical trials of anti-colony-stimulating factor-1 receptor (CSF-1R) therapy.

DOI: https://doi.org/10.1016/j.ccell.2024.08.012
Nat Commun. 2024 Sep 13. 15(1): 8024

Therapeutic efficacy of intracerebral hematopoietic stem cell gene therapy in an Alzheimer's disease mouse model.

Rita Milazzo, Annita Montepeloso, Rajesh Kumar, Francesca Ferro, Eleonora Cavalca, Pietro Rigoni, Paolo Cabras, Yuri Ciervo, Sabyasachi Das, Alessia Capotondo, Danilo Pellin, Marco Peviani, Alessandra Biffi.

The conditions supporting the generation of microglia-like cells in the central nervous system (CNS) after transplantation of hematopoietic stem/progenitor cells (HSPC) have been studied to advance the treatment of neurodegenerative disorders. Here, we explored the transplantation efficacy of different cell subsets and delivery routes with the goal of favoring the establishment of a stable and exclusive engraftment of HSPCs and their progeny in the CNS of female mice. In this setting, we show that the CNS environment drives the expansion, distribution and myeloid differentiation of the locally transplanted cells towards a microglia-like phenotype. Intra-CNS transplantation of HSPCs engineered to overexpress TREM2 decreased neuroinflammation, Aβ aggregation and improved memory in 5xFAD female mice. Our proof of concept study demonstrates the therapeutic potential of HSPC gene therapy for Alzheimer's disease.

DOI: https://doi.org/10.1038/s41467-024-52301-w
Neural Regen Res. 2025 Jul 01. 20(7): 1989-1990

Neuroinflammation revisited through the microglial lens.

Renato Socodato, João B Relvas.

DOI: https://doi.org/10.4103/NRR.NRR-D-24-00284
Immunol Invest. 2024 Sep 09. 1-11

miR-34a-5p Predicts the Risk of Diabetic Neuropathic Pain and Mediates Neuroinflammation in Microglia via Targeting ENPP3.

Peiguo Zhang, Chenghua Wang, Chengxia Li, Jing Wang.

   INTRODUCTION: The pathogenesis of diabetic neuropathic pain (DNP) is complex involving various processes, which need exploring reliable biomarkers for its early detection and severity prediction.
METHODS: Study enrolled 181 patients diagnosed with diabetes, among which 74 patients developed DNP. Serum miR-34a-5p levels were compared between DNP patients and non-DNP patients by polymerase chain reaction (PCR), and the potential of miR-34a-5p in predicting the risk and discriminating patients with DNP was evaluated. The regulatory effect of miR-34a-5p on the inflammation, proliferation, and polarization of microglia was evaluated in HMC3 cells treated with high glucose.
RESULTS: Upregulated miR-34a-5p was identified as a risk factor and discriminated DNP patients miR-34a-5p was positively correlated with the levels of triglyceride (r = 0.797), fasting blood glucose (r = 0.840), and glycated hemoglobin (r = 0.894) of DNP patients. In HMC3 cells, the high-glucose-induced inflammation, promoted cell growth and caused polarization. The knockdown of miR-34a-5p showed the significant protective effect of microglia activation by high glucose, which was reversed by silencing ENPP3.
DISCUSSION: miR-34a-5p served as a biomarker for the prediction and early detection of DNP and mediated microglia inflammation caused by DNP via modulating ENPP3.

Keywords:  Complications; diabetic neuropathy; miRNA; neuroinflammation

DOI:  https://doi.org/10.1080/08820139.2024.2400550
Trends Cell Biol. 2024 Sep;pii: S0962-8924(24)00158-2. [Epub ahead of print]34(9): 695-697

Neuronal AMPK regulates lipid transport to microglia.

Ju-Young Bae, Julie Jacquemyn, Maria S Ioannou.

  In neurodegeneration, neurons release lipids that accumulate in glial lipid droplets (LDs). But what controls lipid transport and how does this affect glia? A recent study by Li et al. discovered that the loss of neuronal AMP-activated protein kinase (AMPK) activity promotes lipid efflux, which drives a proinflammatory state in microglia.

Keywords:  AMPK, neuron; inflammation; lipid droplet; lipid peroxidation; microglia; tau

DOI:  https://doi.org/10.1016/j.tcb.2024.08.001
Adv Sci (Weinh). 2024 Sep 09. e2306863

Dynamic Brain Lipid Profiles Modulate Microglial Lipid Droplet Accumulation and Inflammation Under Ischemic Conditions in Mice.

Wei Wei, Seyed Siyawasch Justus Lattau, Wenqiang Xin, Yongli Pan, Lars Tatenhorst, Lin Zhang, Irina Graf, Yaoyun Kuang, Xuan Zheng, Zhongnan Hao, Aurel Popa-Wagner, Stefan T Gerner, Sabine Huber, Manuel Nietert, Christian Klose, Ertugrul Kilic, Dirk M Hermann, Mathias Bähr, Hagen B Huttner, Hua Liu, Dirk Fitzner, Thorsten R Doeppner.

  Microglia are critically involved in post-stroke inflammation affecting neurological outcomes. Lipid droplet (LD) accumulation in microglia results in a dysfunctional and pro-inflammatory state in the aged brain and worsens the outcome of neuroinflammatory and neurodegenerative diseases. However, the role of LD-rich microglia (LDRM) under stroke conditions is unknown. Using in vitro and in vivo stroke models, herein accumulation patterns of microglial LD and their corresponding microglial inflammatory signaling cascades are studied. Interactions between temporal and spatial dynamics of lipid profiles and microglial phenotypes in different post-stroke brain regions are found. Hence, microglia display enhanced levels of LD accumulation and elevated perilipin 2 (PLIN2) expression patterns when exposed to hypoxia or stroke. Such LDRM exhibit high levels of TNF-α, IL-6, and IL-1β as well as a pro-inflammatory phenotype and differentially expressed lipid metabolism-related genes. These post-ischemic alterations result in distinct lipid profiles with spatial and temporal dynamics, especially with regard to cholesteryl ester and triacylglycerol levels, further exacerbating post-ischemic inflammation. The present study sheds new light on the dynamic changes of brain lipid profiles and aggregation patterns of LD in microglia exposed to ischemia, demonstrating a mutual mechanism between microglial phenotype and function, which contributes to progression of brain injury.

Keywords:  cholesterol metabolism; ischemic stroke; lipid droplets; lipid metabolism; lipidomics; microglia; neuroinflammation

DOI:  https://doi.org/10.1002/advs.202306863
J Neuroinflammation. 2024 Sep 13. 21(1): 222

Permethrin exposure primes neuroinflammatory stress response to drive depression-like behavior through microglial activation in a mouse model of Gulf War Illness.

Sean X Naughton, Eun-Jeong Yang, Umar Iqbal, Kyle Trageser, Daniel Charytonowicz, Sibilla Masieri, Molly Estill, Henry Wu, Urdhva Raval, Weiting Lyu, Qing-Li Wu, Li Shen, James Simon, Robert Sebra, Giulio Maria Pasinetti.

Gulf War Illness (GWI) is a chronic multisymptom disorder that affects approximately 25-32% of Gulf War veterans and is characterized by a number of symptoms such as cognitive impairment, psychiatric disturbances, chronic fatigue and gastrointestinal distress, among others. While the exact etiology of GWI is unknown, it is believed to have been caused by toxic exposures encountered during deployment in combination with other factors such as stress. In the present study we sought to evaluate the hypothesis that exposure to the toxin permethrin could prime neuroinflammatory stress response and elicit psychiatric symptoms associated with GWI. Specifically, we developed a mouse model of GWI, to evaluate the effects of chronic permethrin exposure followed by unpredictable stress. We found that subjecting mice to 14 days of chronic permethrin exposure followed by 7 days of unpredictable stress resulted in the development of depression-like behavior. This behavioral change coincided with distinct alterations in the microglia phenotype, indicating microglial activation in the hippocampus. We revealed that blocking microglial activation through Gi inhibitory DREADD receptors in microglia effectively prevented the behavioral change associated with permethrin and stress exposure. To elucidate the transcriptional networks impacted within distinct microglia populations linked to depression-like behavior in mice exposed to both permethrin and stress, we conducted a single-cell RNA sequencing analysis using 21,566 single nuclei collected from the hippocampus of mice. For bioinformatics, UniCell Deconvolve was a pre-trained, interpretable, deep learning model used to deconvolve cell type fractions and predict cell identity across spatial datasets. Our bioinformatics analysis identified significant alterations in permethrin exposure followed by stress-associated microglia population, notably pathways related to neuronal development, neuronal communication, and neuronal morphogenesis, all of which are associated with neural synaptic plasticity. Additionally, we observed permethrin exposure followed by stress-mediated changes in signal transduction, including modulation of chemical synaptic transmission, regulation of neurotransmitter receptors, and regulation of postsynaptic neurotransmitter receptor activity, a known contributor to the pathophysiology of depression in a subset of the hippocampal pyramidal neurons in CA3 subregions. Our findings tentatively suggest that permethrin may prime microglia towards a state of inflammatory activation that can be triggered by psychological stressors, resulting in depression-like behavior and alterations of neural plasticity. These findings underscore the significance of synergistic interactions between multi-causal factors associated with GWI.

DOI: https://doi.org/10.1186/s12974-024-03215-3
Br J Pharmacol. 2024 Sep 09.

A p75 neurotrophin receptor-sparing nerve growth factor protects retinal ganglion cells from neurodegeneration by targeting microglia.

Laura Latini, Daniel Souza Monteiro De Araujo, Rosario Amato, Alessio Canovai, Lucia Buccarello, Francesco De Logu, Elena Novelli, Anastasiia Vlasiuk, Francesca Malerba, Ivan Arisi, Rita Florio, Hiroki Asari, Simona Capsoni, Enrica Strettoi, Gino Villetti, Bruno Pietro Imbimbo, Massimo Dal Monte, Romina Nassini, Pierangelo Geppetti, Silvia Marinelli, Antonino Cattaneo.

   BACKGROUND AND PURPOSE: Retinal ganglion cells (RGCs) are the output stage of retinal information processing, via their axons forming the optic nerve (ON). ON damage leads to axonal degeneration and death of RGCs, and results in vision impairment. Nerve growth factor (NGF) signalling is crucial for RGC operations and visual functions. Here, we investigate a new neuroprotective mechanism of a novel therapeutic candidate, a p75-less, TrkA-biased NGF agonist (hNGFp) in rat RGC degeneration, in comparison with wild type human NGF (hNGFwt).
EXPERIMENTAL APPROACH: Both neonate and adult rats, whether subjected or not to ON lesion, were treated with intravitreal injections or eye drops containing either hNGFp or hNGFwt. Different doses of the drugs were administered at days 1, 4 or 7 after injury for a maximum of 10 days, when immunofluorescence, electrophysiology, cellular morphology, cytokine array and behaviour studies were carried out. Pharmacokinetic evaluation was performed on rabbits treated with hNGFp ocular drops.
RESULTS: hNGFp exerted a potent RGC neuroprotection by acting on microglia cells, and outperformed hNGFwt in rescuing RGC degeneration and reducing inflammatory molecules. Delayed use of hNGFp after ON lesion resulted in better outcomes compared with treatment with hNGFwt. Moreover, hNGFp-based ocular drops were less algogenic than hNGFwt. Pharmacokinetic measurements revealed that biologically relevant quantities of hNGFp were found in the rabbit retina.
CONCLUSIONS AND IMPLICATIONS: Our data point to microglia as a new cell target through which NGF-induced TrkA signalling exerts neuroprotection of the RGC, emphasizing hNGFp as a powerful treatment to tackle retinal degeneration.

Keywords:  NGF; hNGFp; microglia; retinal degeneration; retinal ganglion cells

DOI:  https://doi.org/10.1111/bph.17316
Brain Behav Immun. 2024 Sep 05. pii: S0889-1591(24)00595-6. [Epub ahead of print]123 28-42

Bi-allelic NRXN1α deletion in microglia derived from iPSC of an autistic patient increases interleukin-6 production and impairs supporting function on neuronal networking.

Raj Bose, Mercedes Posada-Pérez, Eleni Karvela, Martin Skandik, Lily Keane, Anna Falk, Stefan Spulber, Bertrand Joseph, Sandra Ceccatelli.

  Autism spectrum disorder (ASD) is a set of heterogeneous neurodevelopmental conditions, with a highly diverse genetic hereditary component, including altered neuronal circuits, that has an impact on communication skills and behaviours of the affected individuals. Beside the recognised role of neuronal alterations, perturbations of microglia and the associated neuroinflammatory processes have emerged as credible contributors to aetiology and physiopathology of ASD. Mutations in NRXN1, a member of the neurexin family of cell-surface receptors that bind neuroligin, have been associated to ASD. NRXN1 is known to be expressed by neurons where it facilitates synaptic contacts, but it has also been identified in glial cells including microglia. Asserting the impact of ASD-related genes on neuronal versus microglia functions has been challenging. Here, we present an ASD subject-derived induced pluripotent stem cells (iPSC)-based in vitro system to characterise the effects of the ASD-associated NRXN1 gene deletion on neurons and microglia, as well as on the ability of microglia to support neuronal circuit formation and function. Using this approach, we demonstrated that NRXN1 deletion, impacting on the expression of the alpha isoform (NRXN1α), in microglia leads to microglial alterations and release of IL6, a pro-inflammatory interleukin associated with ASD. Moreover, microglia bearing the NRXN1α-deletion, lost the ability to support the formation of functional neuronal networks. The use of recombinant IL6 protein on control microglia-neuron co-cultures or neutralizing antibody to IL6 on their NRXN1α-deficient counterparts, supported a direct contribution of IL6 to the observed neuronal phenotype. Altogether, our data suggest that, in addition to neurons, microglia are also negatively affected by NRXN1α-deletion, and this significantly contributes to the observed neuronal circuit aberrations.

Keywords:  Autism Spectrum Disorder; Cytokines; Induced pluripotent stem cells; Neuroepithelial stem cells; Neuronal network

DOI:  https://doi.org/10.1016/j.bbi.2024.09.001
Exp Eye Res. 2024 Sep 04. pii: S0014-4835(24)00285-9. [Epub ahead of print]248 110064

Small Hyperreflective Retinal Foci as in vivo imaging feature of resident microglia activation in geographic atrophy.

Elisabetta Pilotto, Federico Parolini, Giulia Midena, Eleonora Cosmo, Edoardo Midena.

  Geographic atrophy (GA), the atrophic late stage of age-related macular degeneration (AMD), is one of the leading causes of vision loss in developed countries. Based on genetic, histological and preclinical studies, the role of the innate immune system in the development and progression of GA is well established. Microglia, the principal resident immune cells, are recognized as key players in innate immunity and contributors to AMD development. Optical coherence tomography (OCT) allows to identify small hyperreflective retinal foci (HRF) with specific features known as aggregates of activated microglial cells as possible in vivo imaging feature of local neuroretinal inflammation. The purpose of this study was to evaluate the presence and amount of small HRF in the eyes of patients with different macular atrophic phenotypes. Patients with GA in both eyes (bilateral GA: B-GA group), patients with GA in one eye and macular new vessels (MNV) in the fellow-eye (unilateral GA: U-GA group) and patients with extensive macular atrophy with pseudodrusen (EMAP), a rare and aggressive variant of atrophic AMD, were retrospectively analyzed. HRF, defined as isolated punctiform elements of small dimensions (≤30 μm) with intermediate reflectivity (similar to that of the nerve fiber layer) and without a shadow cone, were manually identified and quantified. The amount of HRF was correlated to best corrected visual acuity (BCVA), GA lesion size, measured both at near infrared reflectance (NIR), and blue wavelength fundus autofluorescence (FAF) images, to some GA features (multifocal versus unifocal GA; presence versus absence of foveal sparing) and to central retinal thickness (CRT). Forty-six patients (26 in the B-GA group, 16 in the U-GA group and 4 in the EMAP group) were studied. Patients with EMAP were younger compared to patients with B-GA and to patients with U-GA (63.5 ± 6.8 years vs 80.4 ± 8.4 years B-GA, and vs 83.3 ± 6.1 years U-GA; p = 0.0004 and p= <0.0001, respectively). Mean BCVA, mean GA area at NIR and at FAF images, foveal sparing and multifocal versus unifocal GA distribution and mean CRT were not significantly different among groups. GA area was wider on NIR versus FAF in all groups, significantly in B-GA and U-GA groups (11.7 ± 7.6 mm2 vs 10.6 ± 7.1 mm2, p = 0.0087 in B-GA; 7.8 ± 9.2 mm2 vs 7.7 ± 9.4 mm2, p = 0.004 in U-GA). The number of HRF was significantly higher in U-GA compared to B-GA and to EMAP (47.4 ± 7.1 vs 31.6 ± 7.3 B-GA and 28.0 ± 4.9 EMAP, p < 0.0001 for both), while mean HRF number did not significantly differ between B-GA and EMAP (p = 0.1960). HRF count correlated only to CRT, positively in B-GA and negatively in U-GA group. The increase of small HRF, which mirrors retinal microglial activation, characterizes eyes with unilateral GA (and MNV in the fellow eye) but not eyes with bilateral GA or EMAP. The role of activated microglia in the retina of GA eyes needs to be better investigated, mainly considering the actual and new therapeutic strategies with which to reduce either the development or progression of the atrophic macular changes.

Keywords:  Biomarkers; EMAP; Fundus autofluorescence; Geographic atrophy; Hyperreflective retinal foci; Microglia; Near infrared reflectance; OCT

DOI:  https://doi.org/10.1016/j.exer.2024.110064
Brain Behav Immun. 2024 Sep 09. pii: S0889-1591(24)00602-0. [Epub ahead of print]

HIV-TAT dysregulates microglial lipid metabolism through SREBP2/miR-124 axis: Implication of lipid droplet accumulation microglia in NeuroHIV.

Yan Cheng, Jaekeun Jung, Liyang Guo, Dorela D Shuboni-Mulligan, Jian-Fu Chen, Wenhui Hu, Ming-Lei Guo.

  Chronic HIV infection can dysregulate lipid/cholesterol metabolism in the peripheral system, contributing to the higher incidences of diabetes and atherosclerosis in HIV (+) individuals. Recently, accumulating evidence indicate that HIV proteins can also dysregulate lipid/cholesterol metabolism in the brain and such dysregulation could be linked with the pathogenesis of HIV-associated neurological disorders (HAND)/NeuroHIV. To further characterize the association between lipid/cholesterol metabolism and HAND, we employed HIV-inducible transactivator of transcription (iTAT) and control mice to compare their brain lipid profiles. Our results reveal that HIV-iTAT mice possess dysregulated lipid profiles and have increased numbers of lipid droplets (LDs) accumulation microglia (LDAM) in the brains. HIV protein TAT can upregulate LDs formation through enhancing the lipid/cholesterol synthesis in vitro. Mechanistically, HIV-TAT increases the expression of sterol regulatory element-binding protein 2 (SREBP2) through microRNA-124 downregulation. Cholesterol synthesis inhibition can block HIV-TAT-mediated NLRP3 inflammasome activation and microglial activation in vitro as well as mitigate aging-related behavioral impairment and memory deficiency in HIV-iTAT mice. Taken together, our results indicate an inherent role of lipid metabolism and LDAM in the pathogenesis of NeuroHIV (immunometabolism). These findings suggest that LDAM reversal through modulating lipid/cholesterol metabolism could be a novel therapeutic target for ameliorating NeuroHIV symptoms in chronic HIV (+) individuals.

Keywords:  Cholesterol; HIV-TAT; Microglia; NeuroHIV; SREBP2; miR-124

DOI:  https://doi.org/10.1016/j.bbi.2024.09.011
J Neurosci. 2024 Sep 12. pii: e1822232024. [Epub ahead of print]

A miR-383-5p signalling hub coordinates the axon regeneration response to inflammation.

Matthew A Hintermayer, Camille A Juźwik, Barbara Morquette, Elizabeth Hua, Julia Zhang, Sienna Drake, Shan Shan Shi, Isabel Rambaldi, Vamshi Vangoor, Jeroen Pasterkamp, Craig Moore, Alyson E Fournier.

Neuroinflammation can positively influence axon regeneration following injury in the central nervous system (CNS). Inflammation promotes the release of neurotrophic molecules and stimulates intrinsic pro-regenerative molecular machinery in neurons, but the detailed mechanisms driving this effect are not fully understood. We evaluated how microRNAs are regulated in retinal neurons in response to intraocular inflammation to identify their potential role in axon regeneration. We found that miR-383-5p is downregulated in retinal ganglion cells in response to zymosan-induced intraocular inflammation. MiR-383-5p downregulation in neurons is sufficient to promote axon growth in vitro, and the intravitreal injection of a miR-383-5p inhibitor into the eye promotes axon regeneration following optic nerve crush. MiR-383-5p directly targets ciliary neurotrophic factor (CNTF) receptor components and miR-383-5p inhibition sensitizes adult retinal neurons to the outgrowth-promoting effects of CNTF. Interestingly, we also demonstrate that CNTF treatment is sufficient to reduce miR-383-5p levels in neurons, constituting a positive-feedback module whereby initial CNTF treatment reduces miR-383-5p levels, which then disinhibits CNTF receptor components to sensitize neurons to the ligand. Additionally, miR-383-5p inhibition de-represses the mitochondrial antioxidant protein peroxiredoxin-3 (PRDX3) which was required for the pro-regenerative effects associated with miR-383-5p loss of function in vitro. We have thus identified a positive feedback mechanism that facilitates neuronal CNTF sensitivity in neurons, and a new molecular signalling module that promotes inflammation-induced axon regeneration.Significance statement Inflammation can both positively and negatively influence the neuronal response to injury. Identifying molecular signalling pathways that mimic pro-regenerative effects of inflammation while bypassing cytotoxic effects is important for our understanding of the precise functions of inflammation in CNS injury and repair. We demonstrate that miR-383-5p is suppressed in neurons in response to inflammatory stimuli and regulates members of the ciliary neurotrophic factor (CNTF) receptor complex, as well as the expression of an antioxidant protein to improve axon regeneration in an optic nerve crush model. These findings identify a new molecular signalling module that promotes axon regeneration and that may bypass detrimental effects of inflammation.

DOI: https://doi.org/10.1523/JNEUROSCI.1822-23.2024
Molecules. 2024 Sep 05. pii: 4212. [Epub ahead of print]29(17):

TSPO Radioligands for Neuroinflammation: An Overview.

Silvia Salerno, Monica Viviano, Emma Baglini, Valeria Poggetti, Doralice Giorgini, Jacopo Castagnoli, Elisabetta Barresi, Sabrina Castellano, Federico Da Settimo, Sabrina Taliani.

  The translocator protein (TSPO) is predominately localized on the outer mitochondrial membrane in steroidogenic cells. In the brain, TSPO expression, low under normal conditions, results upregulated in response to glial cell activation, that occurs in neuroinflammation. As a consequence, TSPO has been extensively studied as a biomarker of such conditions by means of TSPO-targeted radiotracers. Although [11C]-PK11195, the prototypical TSPO radioligand, is still widely used for in vivo studies, it is endowed with severe limitations, mainly low sensitivity and poor amenability to quantification. Consequently, several efforts have been focused on the design of new radiotracers for the in vivo imaging of TSPO. The present review will provide an outlook on the latest advances in TSPO radioligands for neuroinflammation imaging. The final goal is to pave the way for (radio)chemists in the future design and development of novel effective and sensitive radiopharmaceuticals targeting TSPO.

Keywords:  diagnostic marker; neuroinflammation; radioligand; translocator protein

DOI:  https://doi.org/10.3390/molecules29174212
Transl Neurodegener. 2024 Sep 07. 13(1): 47

The microglial P2Y6 receptor as a therapeutic target for neurodegenerative diseases.

Jacob M Dundee, Guy C Brown.

  Neurodegenerative diseases are associated with chronic neuroinflammation in the brain, which can result in microglial phagocytosis of live synapses and neurons that may contribute to cognitive deficits and neuronal loss. The microglial P2Y6 receptor (P2Y6R) is a G-protein coupled receptor, which stimulates microglial phagocytosis when activated by extracellular uridine diphosphate, released by stressed neurons. Knockout or inhibition of P2Y6R can prevent neuronal loss in mouse models of Alzheimer's disease (AD), Parkinson's disease, epilepsy, neuroinflammation and aging, and prevent cognitive deficits in models of AD, epilepsy and aging. This review summarises the known roles of P2Y6R in the physiology and pathology of the brain, and its potential as a therapeutic target to prevent neurodegeneration and other brain pathologies.

Keywords:  Alzheimer’s disease; Drug development; Microglia; Neurodegeneration; Neuroinflammation; P2Y6 receptor; Parkinson’s disease

DOI:  https://doi.org/10.1186/s40035-024-00438-5
Mol Ther Methods Clin Dev. 2024 Sep 12. 32(3): 101312

Combination AAV therapy with galectin-1 and SOD1 downregulation demonstrates superior therapeutic effect in a severe ALS mouse model.

Megan C Baird, Shibi B Likhite, Tatyana A Vetter, Joseph R Caporale, Holly B Girard, Florence S Roussel, Abigail E Howard, Maura K Schwartz, Addison R Reed, Abuzar Kaleem, Xiaojin Zhang, Kathrin C Meyer.

  Neuroinflammation is a miscreant in accelerating progression of many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). However, treatments targeting neuroinflammation alone have led to disappointing results in clinical trials. Both neuronal and non-neuronal cell types have been implicated in the pathogenesis of ALS, and multiple studies have shown correction of each cell type has beneficial effects on disease outcome. Previously, we shown that AAV9-mediated superoxide dismutase 1 (SOD1) suppression in motor neurons and astrocytes significantly improves motor function and extends survival in ALS mouse models. Despite neuron and astrocyte correction, ALS mice still succumb to death with microgliosis observed in endpoint tissue. Therefore, we hypothesized that the optimal therapeutic approach will target and simultaneously correct motor neurons, astrocytes, and microglia. Here, we developed a novel approach to indirectly target microglia with galectin-1 (Gal1) and combined this with our previously established AAV9.SOD1.short hairpin RNA treatment. We show Gal1 conditioning of SOD1 G93A microglia decreases inflammatory markers and rescues motor neuron death in vitro. When paired with SOD1 downregulation, we found a synergistic effect of combination treatment in vivo and show a significant extension of survival of SOD1 G93A mice over SOD1 suppression alone. These results highlight the importance of targeting inflammatory microglia as a critical component in future therapeutic development.

Keywords:  AAV; SOD1G93A mouse; amyotrophic lateral sclerosis; combination therapy; galectin; gene therapy; microglia; motor neuron disease; neuroinflammation; non-cell autonomous toxicity

DOI:  https://doi.org/10.1016/j.omtm.2024.101312
Biochem Biophys Res Commun. 2024 Sep 03. pii: S0006-291X(24)01187-2. [Epub ahead of print]735 150651

Matrine protects against experimental autoimmune encephalomyelitis through modulating microglial ferroptosis.

Furui Feng, Xinyu Li, Wenbin Wang, Mengmeng Dou, Silu Li, Xin Jin, Yaojuan Chu, Lin Zhu.

  Multiple sclerosis (MS) is an inflammatory demyelination neurodegenerative disease of the central nervous system (CNS). Ferroptosis has been implicated in a range of brain disorders, and iron-loaded microglia are frequently found in affected brain regions. However, the molecular mechanisms linking ferroptosis with MS have not been well-defined. The present study seeks to bridge this gap and investigate the impact of matrine (MAT), a herbal medicine with immunomodulatory capacities, on the regulation of oxidative stress and ferroptosis in the CNS of mice with experimental autoimmune encephalomyelitis (EAE), an animal model of MS. CNS of EAE mice contained elevated levels of ferroptosis-related molecules, e.g., MDA, LPCAT3 and PTGS2, but decreased expression of antioxidant molecules, including GSH and SOD, GPX4 and SLC7A11. This pathogenic process was reversed by MAT treatment, together with significant reduction of disease severity and CNS inflammatory demyelination. Furthermore, the expression of PTGS2 and LOX was largely increased in microglia of EAE mice, accompanied with increased production of IL-6 and TNF-α, indicating a proinflammatory phenotype of microglia that undergo oxidative stress/ferroptosis, and their expression was significantly reduced after MAT treatment. Together, our results indicate that ferroptosis/inflammation plays an important role in the pathogenesis of CNS autoimmunity, and inhibiting ferroptosis-induced microglial activation/inflammation could be a novel mechanism underlying the therapeutic effects of MAT on CNS inflammatory demyelination in EAE.

Keywords:  EAE; Ferroptosis; Inflammation; Matrine; Oxidative stress

DOI:  https://doi.org/10.1016/j.bbrc.2024.150651
Nat Commun. 2024 Sep 12. 15(1): 7998

Clearance and transport of amyloid β by peripheral monocytes correlate with Alzheimer's disease progression.

Xin Huang, Chris Fowler, Yihan Li, Qiao-Xin Li, Jiaqi Sun, Yijun Pan, Liang Jin, Keyla A Perez, Céline Dubois, Yen Y Lim, Candace Drysdale, Rebecca L Rumble, Holly R Chinnery, Christopher C Rowe, Ralph N Martins, Paul Maruff, James D Doecke, Yong Lin, Abdel A Belaidi, Kevin J Barnham, Colin L Masters, Ben J Gu.

Impaired clearance of amyloid β (Aβ) in late-onset Alzheimer's disease (AD) affects disease progression. The role of peripheral monocytes in Aβ clearance from the central nervous system (CNS) is unclear. We use a flow cytometry assay to identify Aβ-binding monocytes in blood, validated by confocal microscopy, Western blotting, and mass spectrometry. Flow cytometry immunophenotyping and correlation with AD biomarkers are studied in 150 participants from the AIBL study. We also examine monocytes in human cerebrospinal fluid (CSF) and their migration in an APP/PS1 mouse model. The assay reveals macrophage-like Aβ-binding monocytes with high phagocytic potential in both the periphery and CNS. We find lower surface Aβ levels in mild cognitive impairment (MCI) and AD-dementia patients compared to cognitively unimpaired individuals. Monocyte infiltration from blood to CSF and migration from CNS to peripheral lymph nodes and blood are observed. Here we show that Aβ-binding monocytes may play a role in CNS Aβ clearance, suggesting their potential as a biomarker for AD diagnosis and monitoring.

DOI: https://doi.org/10.1038/s41467-024-52396-1
J Anesth. 2024 Sep 08.

Pregnancy ameliorates neuropathic pain through suppression of microglia and upregulation of the δ-opioid receptor in the anterior cingulate cortex in late-pregnant mice.

Atsushi Sawada, Michiaki Yamakage.

   PURPOSE: Pregnancy-induced analgesia develops in late pregnancy, but its mechanisms are unclear. The anterior cingulate cortex (ACC) plays a key role in the pathogenesis of neuropathic pain. The authors hypothesized that pregnancy-induced analgesia ameliorates neuropathic pain by suppressing activation of microglia and the expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, and by upregulating opioid receptors in the ACC in late-pregnant mice.
METHODS: Neuropathic pain was induced in non-pregnant (NP) or pregnant (P) C57BL/6JJmsSlc female mice by partial sciatic nerve ligation (PSNL). The nociceptive response was evaluated by mechanical allodynia and activation of microglia in the ACC was evaluated by immunohistochemistry. The expressions of phosphorylated AMPA receptors and opioid receptors in the ACC were evaluated by immunoblotting.
RESULTS: In von Frey reflex tests, NP-PSNL-treated mice showed a lower 50% paw-withdrawal threshold than NP-Naïve mice on experimental day 9. No difference in 50% paw-withdrawal threshold was found among the NP-Naïve, NP-Sham, P-Sham, and P-PSNL-treated mice. The number of microglia in the ACC was significantly increased in NP-PSNL-treated mice compared to NP-Sham mice. Immunoblotting showed significantly increased expression of phosphorylated AMPA receptor subunit GluR1 at Ser831 in NP-PSNL-treated mice compared to NP-Sham mice. Immunoblotting also showed significantly increased δ-opioid receptor in the ACC in P-Sham and P-PSNL-treated mice compared to NP-Sham mice.
CONCLUSION: Pregnancy-induced analgesia ameliorated neuropathic pain by suppressing activation of microglia and the expression of phosphorylated AMPA receptor subunit GluR1 at Ser831, and by upregulation of the δ-opioid receptor in the ACC in late-pregnant mice.

Keywords:  Anterior cingulate cortex; Neuropathic pain; Opioid receptors; Pregnancy-induced analgesia

DOI:  https://doi.org/10.1007/s00540-024-03402-9
Brain Res. 2024 Sep 05. pii: S0006-8993(24)00479-7. [Epub ahead of print]1846 149225

Principal components analysis on genes related to inflammasome complex and microglial activation in the hypothalamus of obese mice treated with semaglutide (GLP-1 analog).

Thatiany S Marinho, Matheus M Fabiano, Marcia B Aguila, Carlos A Mandarim-de-Lacerda.

  We studied the effect of semaglutide (glucagon-like peptide type 1 agonist) on hypothalamic pro-inflammatory genes in diet-induced obese mice. Male C57BL/6J mice were fed a control (C) or high-fat (HF) diet for 16 weeks, then divided into six groups and maintained for an additional four-week study: C, C+semaglutide (CS), C pair-feeding (CP), HF, HF+semaglutide (HFS), and HF pair-feeding (HFP).Weight gain (WG), food efficiency (FE), and plasmatic biochemistry were determined. The hypothalamus was removed and prepared for molecular analysis. Semaglutide reduced WG and FE in the HF group. High cytokines levels (tumor necrosis factor alpha, TNF alpha, monocyte chemoattractant protein 1, MCP1, and Resistin) in HF mice were reduced in HFS mice. High pro-inflammatory gene expressions were seen in HF (toll-like receptor 4, Tlr4; Mcp1; interleukin 6, Il6; Tnfa), inflammasome complex (Pirina domain-containing receptor 3, Nlrp3; Caspase 1, Il1b, Il18), and microglial activation (ionized calcium-binding adapter molecule 1, Iba1; cluster differentiation 68, Cd68; argirase 1, Arg1) but mitigated in HFS. The principal components analysis (PCA) based on these markers in a PC1 x PC2 scatterplot put HF and HFP together but far away from a cluster formed by C and HFS, indicating little significance of weight loss (HFP) but decisive action of semaglutide (HFS) in the results. In conclusion, semaglutide benefits hypothalamic pro-inflammatory genes, inflammasome complex, and microglial activation independent of the weight loss effect. Since GLP-1 receptor agonists such as semaglutide are already indicated to treat obesity and diabetes, the potential translational effects on neuroinflammation should be considered.

Keywords:  GLP1 analog; Hypothalamus; Neuroinflammation; Nutrition; Obesity

DOI:  https://doi.org/10.1016/j.brainres.2024.149225
Mar Environ Res. 2024 Sep 05. pii: S0141-1136(24)00401-X. [Epub ahead of print]202 106740

Dead foundation species create coral rubble habitat that benefits a resilient pest species.

Kennedy Wolfe, Maria Byrne.

  Critical loss of habitat is the greatest threat to biodiversity, yet some species are inherently plastic to and may even benefit from changes in ecosystem states. The crown-of-thorns sea star (CoTS; Acanthaster spp.) may be one such organism. CoTS are large corallivores native to the tropical Indo-Pacific and in unexplained high densities, can adversely affect entire coral reefs. Proximal causes of CoTS outbreaks remain elusive, so this phenomenon remains a daunting and costly challenge for reef conservation and management. Amplifying anthropogenic impacts and new empirical data point to the degraded reef hypothesis to explain the episodic nature of CoTS population outbreaks. We posit that loss of live coral paradoxically benefits CoTS juveniles, which accumulate in their rubble nursery habitat before conditions trigger their pulsed emergence as coral-eaters. We review trait plasticity across the CoTS life cycle and present the degraded reef hypothesis in an integrative understanding of their propensity to outbreak.

Keywords:  Acanthaster; CoTS; Habitat degradation; Negative feedback; Population; Starfish

DOI:  https://doi.org/10.1016/j.marenvres.2024.106740
Results Probl Cell Differ. 2024 ;73 203-227

Tunneling Nanotubes in the Brain.

Dimitri Budinger, Vivian Baker, Michael T Heneka.

Tunneling nanotubes (TNTs) have emerged as intriguing structures facilitating intercellular communications across diverse cell types, which are integral to several biological processes, as well as participating in various disease progression. This review provides an in-depth analysis of TNTs, elucidating their structural characteristics and functional roles, with a particular focus on their significance within the brain environment and their implications in neurological and neurodegenerative disorders. We explore the interplay between TNTs and neurological diseases, offering potential mechanistic insights into disease progression, while also highlighting their potential as viable therapeutic targets. Additionally, we address the significant challenges associated with studying TNTs, from technical limitations to their investigation in complex biological systems. By addressing some of these challenges, this review aims to pave the way for further exploration into TNTs, establishing them as a central focus in advancing our understanding of neurodegenerative disorders.

DOI: https://doi.org/10.1007/978-3-031-62036-2_10
Medicine (Baltimore). 2024 May 31. 103(22): e38380

Exploring the role of eosinophil cationic protein (ECP) in schizophrenia: Insights and implications.

Emmanuel Ifeanyi Obeagu.

Schizophrenia, a multifaceted neuropsychiatric disorder characterized by disruptions in perception, cognition, and behavior, has been associated with neuroinflammatory processes. Emerging research has increasingly recognized the potential involvement of immune-related factors in the pathogenesis of schizophrenia, prompting investigations into biomarkers associated with inflammatory cascades. Among these biomarkers, Eosinophil Cationic Protein (ECP), traditionally known for its role in eosinophil-mediated immune responses, has garnered attention for its putative association with neuroinflammation in schizophrenia. This paper critically examines the current understanding of the role of ECP in schizophrenia. ECP, a cytotoxic protein released by eosinophils, has diverse immunomodulatory effects and has been identified in altered concentrations in individuals with schizophrenia. Studies have reported elevated levels of ECP in peripheral fluids of schizophrenia patients, suggesting a possible link between ECP dysregulation and the inflammatory milieu characteristic of the disorder. Moreover, the potential implications of ECP in neuroinflammatory processes relevant to schizophrenia pathophysiology are discussed. ECP's role in modulating immune responses and its potential impact on neuronal function, synaptic plasticity, and neurotoxicity within the central nervous system (CNS) are considered, highlighting the potential contribution of ECP to the neuroinflammatory mechanisms underlying schizophrenia. In conclusion, while the precise role of ECP in schizophrenia pathogenesis warrants further elucidation, exploring its association with neuroinflammation holds promise in unraveling new biomarkers and therapeutic avenues for managing this complex psychiatric disorder.

DOI: https://doi.org/10.1097/MD.0000000000038380
Stem Cell Res Ther. 2024 Sep 12. 15(1): 299

DVL/GSK3/ISL1 pathway signaling: unraveling the mechanism of SIRT3 in neurogenesis and AD therapy.

Nan Dai, Xiaorong Su, Aihua Li, Jinglan Li, Deqi Jiang, Yong Wang.

   BACKGROUND: The established association between Alzheimer's disease (AD) and compromised neural regeneration is well-documented. In addition to the mitigation of apoptosis in neural stem cells (NSCs), the induction of neurogenesis has been proposed as a promising therapeutic strategy for AD. Our previous research has demonstrated the effective inhibition of NSC injury induced by microglial activation through the repression of oxidative stress and mitochondrial dysfunction by Sirtuin 3 (SIRT3). Nonetheless, the precise role of SIRT3 in neurogenesis remains incompletely understood.
METHODS: In vivo, SIRT3 overexpression adenovirus was firstly injected by brain stereotaxic localization to affect the hippocampal SIRT3 expression in APP/PS1 mice, and then behavioral experiments were performed to investigate the cognitive improvement of SIRT3 in APP/PS1 mice, as well as neurogenic changes in hippocampal region by immunohistochemistry and immunofluorescence. In vitro, under the transwell co-culture condition of microglia and neural stem cells, the mechanism of SIRT3 improving neurogenesis of neural stem cells through DVL/GSK3/ISL1 axis was investigated by immunoblotting, immunofluorescence and other experimental methods.
RESULTS: Our findings indicate that the overexpression of SIRT3 in APP/PS1 mice led to enhanced cognitive function and increased neurogenesis. Additionally, SIRT3 was observed to promote the differentiation of NSCs into neurons during retinoic acid (RA)-induced NSC differentiation in vitro, suggesting a potential role in neurogenesis. Furthermore, we observed the activation of the Wnt/ß-catenin signaling pathway during this process, with Glycogen Synthase Kinase-3a (GSK3a) primarily governing NSC proliferation and GSK3ß predominantly regulating NSC differentiation. Moreover, the outcomes of our study demonstrate that SIRT3 exerts a protective effect against microglia-induced apoptosis in neural stem cells through its interaction with DVLs.
CONCLUSIONS: Our results show that SIRT3 overexpressing APP/PS1 mice have improved cognition and neurogenesis, as well as improved neurogenesis of NSC in microglia and NSC transwell co-culture conditions through the DVL/GSK3/ISL1 axis.

Keywords:  Neural stem cells; Neurogenesis; Neuronal differentiation; SIRT3; Wnt/β-catenin pathway

DOI:  https://doi.org/10.1186/s13287-024-03925-8
J Psychiatr Res. 2024 Sep 08. pii: S0022-3956(24)00528-4. [Epub ahead of print]179 105-116

Mesenchymal stem cells improve depressive disorder via inhibiting the inflammatory polarization of microglia.

Qianqian Wang, Yifan Xu, Sijie Zhu, Longwei Jiang, Lu Yao, Xuerui Yu, Yuheng Zhang, Shaochang Jia, Min Hong, Jie Zheng.

  Depressive disorder (DD) ranks among the most prevalent, burdensome, and costly psychiatric conditions globally. It manifests through a range of emotional, cognitive, somatic, and behavioral symptoms. Mesenchymal Stem Cells (MSCs) have garnered significant attention due to their therapeutic potential via immunomodulation in neurological disorders. Our research indicates that MSCs treatment demonstrates a notable effect on a Chronic Unpredictable Mild Stress (CUMS)-induced DD model in mice, surpassing even Fluoxetine in its antidepressant efficacy. MSCs mitigate DD by inhibiting central nervous system inflammation and facilitating the conversion of microglial cells into an Arg1high anti-inflammatory state. The MSCs-derived TGF-β1 is crucial for this Arg1high microglial cell transformation in DD treatment.

Keywords:  Chronic unpredictable mild stress; Depressive disorder; Mesenchymal stem cells; Neuroinflammation; TGF-β1

DOI:  https://doi.org/10.1016/j.jpsychires.2024.09.005
Brain Behav Immun. 2024 Sep 05. pii: S0889-1591(24)00594-4. [Epub ahead of print]123 81-98

TNFR2 signaling in oligodendrocyte precursor cells suppresses their immune-inflammatory function and detrimental microglia activation in CNS demyelinating disease.

Haritha L Desu, Estrid Thougaard, Brianna N Carney, Placido Illiano, Melanie J Plastini, Yoleinny Florimon, Antonella Mini, Chelsea Guastucci, Brian Kang, Jae K Lee, Kate L Lambersten, Roberta Brambilla.

  Multiple Sclerosis (MS) is a chronic degenerative disease of the central nervous system (CNS) characterized by inflammation, demyelination, and progressive neurodegeneration. These processes, combined with the failure of reparative remyelination initiated by oligodendrocyte precursor cells (OPCs), lead to irreversible neurological impairment. The cytokine tumor necrosis factor (TNF) has been implicated in CNS repair via activation of its cognate receptor TNFR2 in glia. Here, we demonstrate the important role of TNFR2 in regulating OPC function in vivo during demyelinating disease, and that TNFR2 expressed in OPCs modulates OPC-microglia interactions. In PdgfrαCreERT:Tnfrsf1bfl/fl:Eyfp mice with selective TNFR2 ablation in OPCs, we observed an earlier onset and disease peak in experimental autoimmune encephalomyelitis (EAE). This was associated with accelerated immune cell infiltration and increased microglia activation in the spinal cord. Similarly, PdgfrαCreERT:Tnfrsf1bfl/fl:Eyfp mice showed rapid and increased microglia reactivity compared to control mice in the corpus callosum after cuprizone-induced demyelination, followed by chronic reduction in the number of mature myelinating oligodendrocytes (OLs). With EAE and cuprizone models combined, we uncovered that TNFR2 does not have a cell autonomous role in OPC differentiation, but may be important for survival of newly formed mature OLs. Finally, using an in vitro approach, we demonstrated that factors released by Tnfrsf1b ablated OPCs drove microglia to develop an exacerbated "foamy" phenotype when incubated with myelin-rich spinal cord homogenate, aberrantly increasing lysosomal lipid accumulation. Together, our data indicate that TNFR2 signaling in OPCs is protective by dampening their immune-inflammatory activation and by suppressing neurotoxic microglia reactivity. This suggests that boosting TNFR2 activation or its downstream cascades could be an effective strategy to restore OPC reparative capacity in neuroimmune and demyelinating disease.

Keywords:  Immunomodulation; Microglia; Multiple sclerosis; Neuroinflammation; OPCs; Remyelination; TNFR2

DOI:  https://doi.org/10.1016/j.bbi.2024.09.002
bioRxiv. 2024 Sep 01. pii: 2024.08.31.606944. [Epub ahead of print]

Astrocyte-derived MFG-E8 facilitates microglial synapse elimination in Alzheimer's disease mouse models.

Dimitra Sokolova, Shari Addington Ghansah, Francesca Puletti, Tatiana Georgiades, Sebastiaan De Schepper, Yongjing Zheng, Gerard Crowley, Ling Wu, Javier Rueda-Carrasco, Angeliki Koutsiouroumpa, Philip Muckett, Oliver J Freeman, Baljit S Khakh, Soyon Hong.

Region-specific synapse loss is an early pathological hallmark in Alzheimer's disease (AD). Emerging data in mice and humans highlight microglia, the brain-resident macrophages, as cellular mediators of synapse loss; however, the upstream modulators of microglia-synapse engulfment remain elusive. Here, we report a distinct subset of astrocytes, which are glial cells essential for maintaining synapse homeostasis, appearing in a region-specific manner with age and amyloidosis at onset of synapse loss. These astrocytes are distinguished by their peri-synaptic processes which are 'bulbous' in morphology, contain accumulated p62-immunoreactive bodies, and have reduced territorial domains, resulting in a decrease of astrocyte-synapse coverage. Using integrated in vitro and in vivo approaches, we show that astrocytes upregulate and secrete phagocytic modulator, milk fat globule-EGF factor 8 (MFG-E8), which is sufficient and necessary for promoting microglia-synapse engulfment in their local milieu. Finally, we show that knocking down Mfge8 specifically from astrocytes using a viral CRISPR-saCas9 system prevents microglia-synapse engulfment and ameliorates synapse loss in two independent amyloidosis mouse models of AD. Altogether, our findings highlight astrocyte-microglia crosstalk in determining synapse fate in amyloid models and nominate astrocytic MFGE8 as a potential target to ameliorate synapse loss during the earliest stages of AD.

DOI: https://doi.org/10.1101/2024.08.31.606944
Neural Regen Res. 2024 Sep 06.

Fat mass and obesity-mediated m6A modification modulates neuroinflammatory responses after traumatic brain injury.

Xiangrong Chen, Jinqing Lai, Zhe Wu, Jianlong Chen, Baoya Yang, Chunnuan Chen, Chenyu Ding.

The neuroinflammatory response mediated by microglial activation plays an important role in the secondary nerve injury of traumatic brain injury. The post-transcriptional modification of N6-methyladenosine (m6A) is ubiquitous in the immune response of the central nervous system. The fat mass and obesity (FTO)-related protein catalyzes the demethylation of m6A modifications on mRNA and is widely expressed in various tissues, participating in the regulation of multiple diseases' biological processes. However, the role of FTO in microglial activation and the subsequent neuroinflammatory response after traumatic brain injury is unclear. In this study, we found that the expression of FTO was significantly down-regulated in both lipopolysaccharide-treated BV2 cells and a traumatic brain injury mouse model. After FTO interference, BV2 cells exhibited a pro-inflammatory phenotype as shown by the increased proportion of CD11b+/CD86+ cells and the secretion of pro-inflammatory cytokines. FTO-mediated m6A demethylation accelerated the degradation of ADAM17 mRNA, while silencing of FTO enhanced the stability of ADAM17 mRNA. Therefore, down-regulation of FTO expression leads to the abnormally high expression of ADAM17 in microglia. These results indicate that the activation of microglia and neuroinflammatory response regulated by FTO-related m6A modification plays an important role in the pro-inflammatory process of secondary injury following traumatic brain injury.

DOI: https://doi.org/10.4103/NRR.NRR-D-23-01854
Neuromolecular Med. 2024 Sep 12. 26(1): 37

Inhibition of CRMP2 Phosphorylation Suppresses Microglia Activation in the Retina and Optic Nerve and Promotes Optic Nerve Regeneration After Optic Nerve Injury.

Yuebing Wang, Sayaka Harada, Yoshio Goshima, Toshio Ohshima.

  As the primary connection between the eye and brain, the optic nerve plays a pivotal role in visual information transmission. Injuries to the optic nerve can occur for various reasons, including trauma, glaucoma, and neurodegenerative diseases. Retinal ganglion cells (RGCs), a type of neurons that extend axons through the optic nerve, can rapidly respond to injury and initiate cell death. Additionally, following optic nerve injury microglia, which serve as markers of neuroinflammation, transition from a resting state to an activated state. The phosphorylation of collapsin response mediator protein2 (CRMP2) in the semaphorin 3A (Sema3A) signalling pathway affects several processes, including axon guidance and neuron regeneration. In this study, we used an optic nerve crush (ONC) mouse model to investigate the effects of suppressing CRMP2 phosphorylation on microglia activation. We found that CRMP2 phosphorylation inhibitor suppressed RGCs loss and promoted neuronal regeneration following ONC. In addition, CRMP2 S522A mutant (CRMP2 KI) mice exhibited decreased microglial activation in both the retina and optic nerve following ONC. These results suggest that inhibiting the phosphorylation of CRMP2 can alleviate the loss of RGCs and microglial activation after optic nerve injury, providing insight into the development of treatments for optical neuropathies and neurodegenerative diseases.

Keywords:  Collapsin mediator protein 2; Microglia; Optic nerve injury; Phosphorylation

DOI:  https://doi.org/10.1007/s12017-024-08805-1
Int J Mol Sci. 2024 Aug 30. pii: 9451. [Epub ahead of print]25(17):

Sustained Microglial Activation Promotes Synaptic Loss and Neuronal Dysfunction after Recovery from ZIKV Infection.

Nahyun Kim, Hanul Choi, Uijin Kim, Suyeon Kim, Young Bong Kim, Ha Youn Shin.

  Zika virus (ZIKV), transmitted by Aedes mosquitoes, has been a global health concern since 2007. It primarily causes fetal microcephaly and neuronal defects through maternal transmission and induces neurological complications in adults. Recent studies report elevated proinflammatory cytokines and persistent neurological alterations post recovery, but the in vivo mechanisms remain unclear. In our study, viral RNA loads in the brains of mice infected with ZIKV peaked at 7 days post infection and returned to baseline by day 21, indicating recovery. RNA sequencing of the cerebral cortex at 7 and 21 days revealed upregulated genes related to neuroinflammation and microglial activation. Histological analyses indicated neuronal cell death and altered neurite morphology owing to severe neuroinflammation. Additionally, sustained microglial activation was associated with increased phospho-Tau levels, constituting a marker of neurodegeneration. These findings highlight how persistent microglial activation leads to neuronal dysfunction post ZIKV recovery, providing insights into the molecular pathogenesis of ZIKV-induced brain abnormalities.

Keywords:  ZIKV; long-term effects; microglial activation; neuroinflammation; synaptic loss

DOI:  https://doi.org/10.3390/ijms25179451
J Cereb Blood Flow Metab. 2024 Sep 10. 271678X241280775

Microglia contact cerebral vasculature through gaps between astrocyte endfeet.

Gary P Morris, Catherine G Foster, Brad A Sutherland, Søren Grubb.

  The close spatial relationship between microglia and cerebral blood vessels implicates microglia in vascular development, homeostasis and disease. In this study we used the publicly available Cortical MM^3 electron microscopy dataset to systematically investigate microglial interactions with the vasculature. Our analysis revealed that approximately 20% of microglia formed direct contacts with blood vessels through gaps between adjacent astrocyte endfeet. We termed these contact points "plugs". Plug-forming microglia exhibited closer proximity to blood vessels than non-plug forming microglia and formed multiple plugs, predominantly near the soma, ranging in surface area from ∼0.01 μm2 to ∼15 μm2. Plugs were enriched at the venule end of the vascular tree and displayed a preference for contacting endothelial cells over pericytes at a ratio of 3:1. In summary, we provide novel insights into the ultrastructural relationship between microglia and the vasculature, laying a foundation for understanding how these contacts contribute to the functional cross-talk between microglia and cells of the vasculature in health and disease.

Keywords:  Astrocyte endfeet; capillaries; endothelial cells; microglia; pericytes

DOI:  https://doi.org/10.1177/0271678X241280775
Sci Rep. 2024 Sep 12. 14(1): 21369

Microglial process convergence onto injured axonal swellings, a human postmortem brain tissue study.

Amanda L Logan-Wesley, Karen M Gorse, Audrey D Lafrenaye.

  Traumatic brain injury (TBI) affects millions globally, with a majority of TBI cases being classified as mild, in which diffuse pathologies prevail. Two of the pathological hallmarks of TBI are diffuse axonal injury (DAI) and microglial activation. While progress has been made investigating the breadth of TBI-induced axonal injury and microglial changes in rodents, the neuroinflammatory progression and interaction between microglia and injured axons in humans is less well understood. Our group previously investigated microglial process convergence (MPC), in which processes of non-phagocytic microglia directly contact injured proximal axonal swellings, in rats and micropigs acutely following TBI. These studies demonstrated that MPC occurred on injured axons in the micropig, but not in the rat, following diffuse TBI. While it has been shown that microglia co-exist and interact with injured axons in humans post-TBI, the occurrence of MPC has not been quantitatively measured in the human brain. Therefore, in the current study we sought to validate our pig findings in human postmortem tissue. We investigated MPC onto injured axonal swellings and intact myelinated fibers in cases from individuals with confirmed DAI and control human brain tissue using multiplex immunofluorescent histochemistry. We found an increase in MPC onto injured axonal swellings, consistent with our previous findings in micropigs, indicating that MPC is a clinically relevant phenomenon that warrants further investigation.

Keywords:  Axonal injury; Microglial process convergence; Postmortem tissue; Traumatic brain injury

DOI:  https://doi.org/10.1038/s41598-024-71312-7
J Neuroinflammation. 2024 Sep 08. 21(1): 219

Microglial morphological/inflammatory phenotypes and endocannabinoid signaling in a preclinical model of periodontitis and depression.

Javier Robledo-Montaña, César Díaz-García, María Martínez, Nagore Ambrosio, Eduardo Montero, María José Marín, Leire Virto, Marina Muñoz-López, David Herrera, Mariano Sanz, Juan Carlos Leza, Borja García-Bueno, Elena Figuero, David Martín-Hernández.

   BACKGROUND: Depression is a chronic psychiatric disease of multifactorial etiology, and its pathophysiology is not fully understood. Stress and other chronic inflammatory pathologies are shared risk factors for psychiatric diseases, and comorbidities are features of major depression. Epidemiological evidence suggests that periodontitis, as a source of low-grade chronic systemic inflammation, may be associated with depression, but the underlying mechanisms are not well understood.
METHODS: Periodontitis (P) was induced in Wistar: Han rats through oral gavage with the pathogenic bacteria Porphyromonas gingivalis and Fusobacterium nucleatum for 12 weeks, followed by 3 weeks of chronic mild stress (CMS) to induce depressive-like behavior. The following four groups were established (n = 12 rats/group): periodontitis and CMS (P + CMS+), periodontitis without CMS, CMS without periodontitis, and control. The morphology and inflammatory phenotype of microglia in the frontal cortex (FC) were studied using immunofluorescence and bioinformatics tools. The endocannabinoid (EC) signaling and proteins related to synaptic plasticity were analyzed in FC samples using biochemical and immunohistochemical techniques.
RESULTS: Ultrastructural and fractal analyses of FC revealed a significant increase in the complexity and heterogeneity of Iba1 + parenchymal microglia in the combined experimental model (P + CMS+) and increased expression of the proinflammatory marker inducible nitric oxide synthase (iNOS), while there were no changes in the expression of cannabinoid receptor 2 (CB2). In the FC protein extracts of the P + CMS + animals, there was a decrease in the levels of the EC metabolic enzymes N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), and monoacylglycerol lipase (MAGL) compared to those in the controls, which extended to protein expression in neurons and in FC extracts of cannabinoid receptor 1 (CB1) and to the intracellular signaling molecules phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2). The protein levels of brain-derived neurotrophic factor (BDNF) and synaptophysin were also lower in P + CMS + animals than in controls.
CONCLUSIONS: The combined effects on microglial morphology and inflammatory phenotype, the EC signaling, and proteins related to synaptic plasticity in P + CMS + animals may represent relevant mechanisms explaining the association between periodontitis and depression. These findings highlight potential therapeutic targets that warrant further investigation.

Keywords:  Depression; Endocannabinoid signaling; Microglia; Periodontitis; Synaptic plasticity

DOI:  https://doi.org/10.1186/s12974-024-03213-5