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PubMed1999

A predominant apoptotic death pathway of neuronal PC12 cells induced by activated microglia is displaced by a non-apoptotic death pathway following blockage of caspase-3-dependent cascade.

Activated microglia have been implicated in the regulation of neuronal cell death. However, the biochemical mechanism for neuronal death triggered by activated microglia is still unclear. When treated with activated microglia, neuronal PC12 cells undergo apoptosis accompanied by caspase-3-like protease activation and DNA fragmentation. Apoptotic bodies formed were subsequently phagocytosed by neighboring activated microglia. Pretreatment of the cells with the caspase-3-like protease inhibitor N-acetyl-Asp-Glu-Val-Asp-aldehyde did not reverse this cell death. Although Bcl-2 overexpression in the cells caused the inhibition of caspase-3-like protease activity and DNA fragmentation and the effective interference of apoptosis induced by deprivation of trophic factors, it could not suppress the activated microglia-induced neuronal death. At the electron microscopic level, degenerating cells with high levels of Bcl-2 were characterized by slightly condensed chromatins forming irregular-shaped masses, severely disintegrated perikarya, and marked vacuolation. Various protease inhibitors tested did not inhibit this cell death, whereas the radical oxygen species scavenger N-acetyl-L-cysteine significantly suppressed this death. Altogether, our study provides an alternative death pathway for the activated microglia-induced neuronal death by blockage of the caspase-3 protease cascade.

Acetylcysteine↗

PubMed2004

Tenascin-R plays a role in neuroprotection via its distinct domains that coordinate to modulate the microglia function.

Microglia are one of the main cell types activated by brain injury. In the present study, we have investigated how domains of the extracellular matrix molecule tenascin-R (TN-R) modulate microglia function. We found that epidermal growth factor-like repeats inhibited adhesion and migration of microglia via a protein kinase A-dependent mechanism. In contrast, fibronectin 6-8 repeats promoted adhesion and migration of the primary microglia via a protein kinase C-dependent mechanism. Both domains of TN-R induced an up-regulation in the secretion of cytokines, such as chemokine-induced cytokine 3 and tumor neurosis factor alpha. Interestingly, epidermal growth factor-like repeats and fibronectin 6-8 induced a dramatic up-regulation in the secretion of brain-derived neurotrophic factor/transforming growth factor-beta and nerve growth factor/transforming growth factor-beta, respectively, and conditioned medium from activated microglia was able to promote neurite outgrowth of N1E-115 cells and primary cortical neurons. These results suggest that TN-R plays a role in neuroprotection through distinct domains coordinating to modulate microglia function.

Animals↗

PubMed2005

Myelin basic protein-primed T cells of female but not male mice induce nitric-oxide synthase and proinflammatory cytokines in microglia: implications for gender bias in multiple sclerosis.

Females are more susceptible than males to multiple sclerosis (MS). However, the underlying mechanism behind this gender difference is poorly understood. Because the presence of neuroantigen-primed T cells within the CNS is necessary for the development of MS, the present study was undertaken to investigate the activation of microglia by myelin basic protein (MBP)-primed T cells of male, female, and castrated male mice. Interestingly, MBP-primed T cells isolated from female and castrated male but not from male mice induced the expression of inducible nitric-oxide synthase (iNOS) and proinflammatory cytokines (interleukin-1beta (IL-1beta), IL-1alpha, IL-6, and tumor necrosis factor-alpha) in microglia by cell-cell contact. Again there was no apparent defect in male microglia, because MBP-primed T cells isolated from female and castrated male but not male mice were capable of inducing the production of NO in male primary microglia. Inhibition of female T cell contact-mediated microglial expression of proinflammatory molecules by dominant-negative mutants of p65 and C/EBPbeta suggest that female MBP-primed T cells induce microglial expression of proinflammatory molecules through the activation of NF-kappaB and C/EBPbeta. Interestingly, MBP-primed T cells of male, female, and castrated male mice were able to induce microglial activation of NF-kappaB. However, MBP-primed T cells of female and castrated male but not male mice induced microglial activation of C/EBPbeta. These studies suggest that microglial activation of C/EBPbeta but not NF-kappaB by T cell:microglial contact is a gender-specific event and that male MBP-primed T cells are not capable of inducing microglial expression of proinflammatory molecules due to their inability to induce the activation of C/EBPbeta in microglia. This novel gender-sensitive activation of microglia by neuroantigen-primed T cell contact could be one of the mechanisms behind the female-loving nature of MS.

Animals↗

PubMed2002

Mesoglia & microglia--a historical review of the concept of mononuclear phagocytes within the central nervous system.

More than a century and a half has elapsed since the first accounts of mesodermal phagocytic elements were proposed within the central nervous system. Over the intervening decades, body and substance were added to this concept through the advancement of histological techniques at the disposal of the researcher and the acute and keen-minded skills of the pathologist. Notable among these pioneering efforts were the contributions of W. Ford Robertson, Santiago Ramon y Cajal, Pio del Rio-Hortega and Wilder Penfield amongst an entire cavalcade of other noteworthy figures. The term 'mesoglia' and 'third element of the nervous system' was bestowed upon these cells towards the beginning of the twentieth century to account for their separate origins from neurons and macroglia. It was later amended by del Rio-Hortega in 1919, to 'microglia' in order to further discriminate between true mesodermal elements and oligodendrocytes, previously regarded as a component of 'mesoglia'. This particular contention sparked much controversy among del Rio-Hortega's peers and resulted in an escalation of fruitful research throughout Europe that eventually declined up to the outbreak of the Second World War. The post-war years were a period of the 'dark ages' that cast doubt on the very existence and nature of microglia, until the 'renaissance' of research was once again rejuvenated in the 1960s, by a new cohort of intrigued minds: Cammermeyer, Blinzinger, Kreutzberg and others who saw in the 'third element' the potential that is now commonly ascribed to microglia: the intrinsic immune effector cells of the CNS. It is now universally accepted that microglia are involved as the first line of rapid defence in any pathology of the nervous system, and as such, present a diagnostic tool for the neuropathologist. Although our knowledge of microglia stems from an extensive body of work conducted over the last two decades, much of the earlier work (pre-1960s) has remained somewhat obscure. This is partly accountable due to the limited availability of translated works, and additionally to the lack of a compendium of these articles. This paper will present a comprehensive overview of the pioneering research on mononuclear phagocytes within the central nervous system, which has direct bearing on our present-day understanding of the concept of microglia.

Animals↗

PubMed2006

Reconstitution of human immunodeficiency virus-induced neurodegeneration using isolated populations of human neurons, astrocytes, and microglia and neuroprotection mediated by insulin-like growth factors.

Primary human neuron cultures are an important in vitro model system for studies on mechanisms involved in human immunodeficiency virus (HIV)-associated dementia (HAD) and other neurological disorders. Here, more than 80 cell surface antigens were screened to identify a marker that could readily distinguish between neurons and astrocytes and found that neurons lack CD44 surface expression, whereas astrocytes and other cell types in brain are CD44+. Neurons and astrocytes were isolated from human fetal brain based on differential expression of CD44. Using purified neurons cocultured with astrocytes and/or microglia, it was demonstrated that HIV infection of microglia induces cellular activation and production of soluble factors that activate uninfected microglia and astrocytes and induce neuronal cell death. Activated astrocytes promoted HIV replication in microglia, thereby amplifying HIV-induced neurotoxicity. A screen for 120 cytokine/proteins detected upregulation of insulin-like growth factor (IGF)-binding protein (IGFBP)-2, interleukin (IL)-6, and CCL8/MCP-2 (monocyte chemoattractant protein 2) in supernatants of HIV-infected brain cell cultures. IGF-1 and -2 increased neuronal survival in HIV-infected brain cell cultures, whereas IGFBP-2 inhibited prosurvival effects of these growth factors. These findings identify CD44 as a marker that can be used to sort neurons from other cell types in brain, suggest the importance of microglia-astrocyte interactions in neurodegenerative mechanisms associated with HIV infection, and indicate a role for insulin-like growth factors in neuroprotection from HIV-induced neurodegeneration. The ability to reconstitute brain cultures using isolated populations of neurons, astrocytes, and microglia will be valuable for studies on pathogenic mechanisms in HAD and other neurological disorders, and will also facilitate neuroactive drug discovery.

AIDS Dementia Complex↗

PubMed1995

The temporal and spatial activation of microglia in fiber tracts undergoing anterograde and retrograde degeneration following spinal cord lesion.

The role of microglia in the response to CNS injury is not fully understood. We characterized the temporal activation of microglia in the adult spinal cord following a lesion that severed the axons of the dorsal columns and corticospinal tract at T8. Two days after lesion, microglia in the severed T4-T5 fasciculus (f.) gracilis were ameboid and expressed intense OX42 and increased class I major histocompatibility complex (MHC) antigen (OX18) immunoreactivities. No activated microglia were seen in the intact f. cuneatus or the corticospinal tract. Five days postlesion, OX42 immunoreactivity was slightly decreased in the f. gracilis, and OX18 expression was slightly enhanced. By 12 days postlesion, OX42 and OX18 immunoreactivities were near control levels. At L1-L2, activated microglia with increased OX18 expression were restricted to the corticospinal tract and were maximal 5 days postlesion, returning to near control levels by 12 days postlesion. In the medulla, enhanced OX42 and OX18 immunoreactivities were seen in the nucleus (n.) gracilis, but not the n. cuneatus, at 2 days postlesion. At 5 days postlesion, OX42 immunoreactivity was markedly decreased, but class I MHC antigen expression was still enhanced. GFAP immunoreactivity increased only in the n. gracilis and remained elevated 2-12 days postlesion. Microglial activation is an early lesion-induced event in the CNS, and activated microglia may play a role in mediating the regenerative capacity of injured CNS axons.

Animals↗

PubMedDate not supplied

Intermittent ethanol exposure increases the number of cerebellar microglia.

AIMS: The number of cerebellar microglia after 5(1)/2 months of continuous or intermittent ethanol exposure was studied using the optical dissector method. METHODS: Male Wistar rats were divided into three groups: an intermittently ethanol-exposed group, a continuously ethanol-exposed group and a control group (n = 6 in each group). The intermittently treated rats had two ethanol-withdrawal periods per week throughout the experiment. The number of microglia was measured in the anterior (folium II) and the posterior (folium X) cerebellar vermis. Tomato (Lycopersicon esculentum) lectin was used to stain the cerebellar microglia. RESULTS: The volumes of folia II and X were similar in all the groups. The number of microglia increased in the molecular layer of folium II in the intermittently ethanol-exposed group compared with the continuously exposed and control groups. In the granular layer, there were no differences between the groups in the number of microglia. CONCLUSIONS: The results suggest that the number of cerebellar microglia increases in the anterior vermis before any ethanol-induced cerebellar atrophy is discernible. Repeated ethanol withdrawals seem to be more essential in inducing microgliosis than ethanol intoxication per se.

Alcohol Drinking↗

PubMed2004

Nanometer size diesel exhaust particles are selectively toxic to dopaminergic neurons: the role of microglia, phagocytosis, and NADPH oxidase.

The contributing role of environmental factors to the development of Parkinson's disease has become increasingly evident. We report that mesencephalic neuron-glia cultures treated with diesel exhaust particles (DEP; 0.22 microM) (5-50 microg/ml) resulted in a dose-dependent decrease in dopaminergic (DA) neurons, as determined by DA-uptake assay and tyrosine-hydroxylase immunocytochemistry (ICC). The selective toxicity of DEP for DA neurons was demonstrated by the lack of DEP effect on both GABA uptake and Neu-N immunoreactive cell number. The critical role of microglia was demonstrated by the failure of neuron-enriched cultures to exhibit DEP-induced DA neurotoxicity, where DEP-induced DA neuron death was reinstated with the addition of microglia to neuron-enriched cultures. OX-42 ICC staining of DEP treated neuron-glia cultures revealed changes in microglia morphology indicative of activation. Intracellular reactive oxygen species and superoxide were produced from enriched-microglia cultures in response to DEP. Neuron-glia cultures from NADPH oxidase deficient (PHOX-/-) mice were insensitive to DEP neurotoxicity when compared with control mice (PHOX+/+). Cytochalasin D inhibited DEP-induced superoxide production in enriched-microglia cultures, implying that DEP must be phagocytized by microglia to produce superoxide. Together, these in vitro data indicate that DEP selectively damages DA neurons through the phagocytic activation of microglial NADPH oxidase and consequent oxidative insult.

Animals↗

PubMed2001

Uptake of fibrillar beta-amyloid by microglia isolated from MSR-A (type I and type II) knockout mice.

To characterize the receptors involved in binding fibrillar amyloid A-beta (fA beta), we compared the uptake of fA beta in microglia from wildtype (MSR-A+/+) and MSR-A knockout (MSR-A-/-) mice. On average, there was a 60% reduction in the uptake of Cy3-fA beta in microglia from the MSR-A-/- mice. Cy3-fA beta uptake in the MSR-A-/- mice was still competable by scavenger receptor ligands, including acetylated low-density lipoprotein (Ac-LDL) and fucoidan. This indicates that uptake by MSR-B and/or other MSRs is also involved in the uptake of fA beta by microglia. However, the significant reduction in the uptake of fA beta in the MSR-A-/- microglia suggests that fA beta gets internalized mostly by MSR-As in microglia. Uptake of modified fA beta (ClqA beta) was similar in the MSR-A-/- microglia as in the wildtype indicating that the uptake of the opsonized fA beta is independent of MSR-A.

Amyloid beta-Peptides↗

PubMed1996

Microglia are not exclusively associated with plaque-rich regions of the dentate gyrus in Alzheimer's disease.

The functional significance of microglia found in neuritic plaques in Alzheimer's disease (AD) remains a source of controversy. In the present study, we explored the anatomic relationships between microglia and neuritic plaques in order to determine the potential role of microglia in plaque formation. We chose to study the molecular layer of the hippocampal dentate gyrus, a brain region where plaques have a strong tendency to line up parallel to the adjacent granule cell layer. We found that ferritin-labeled microglia were indeed most numerous in the same distinct band as plaques, but that microglia were relatively more common in the outer molecular layer. The distribution of microglia was more variable than that of plaques. Overall, microglial cell distribution was a relatively poor predictor of plaque distribution, particularly when cases were considered individually. Thus, there must be multiple triggers for microglial cell activation and accumulation in the AD brain, triggers which do not all necessarily lead to neuritic plaque formation.

Aged↗

PubMed2006

Upregulated expression of purinergic P2X(7) receptor in Alzheimer disease and amyloid-beta peptide-treated microglia and in peptide-injected rat hippocampus.

The expression of the purinergic receptor subtype P2X(7)R, a nonselective cationic channel activated by high levels of adenosine triphosphate (ATP), has been studied in adult microglia obtained from Alzheimer disease (AD) and nondemented (ND) brains, in fetal human microglia exposed to Abeta(1-42) peptide and in vivo in Abeta(1-42)-injected rat hippocampus. Semiquantitative reverse transcriptase-polymerase chain reaction showed enhanced expression (increase of 70%) of P2X(7)R in AD microglia compared with ND cells (analysis of 6 AD and 8 ND cases). Immunohistochemical analysis showed prominent P2X(7)R expression in association with Abeta plaques and localized to HLA-DR-immunoreactive microglia. In cultured fetal human microglia, cells exposed to Abeta(1-42) (5 microM for 18 hours) had significantly elevated levels of P2X(7)R (by 106%) compared with untreated cells. Amplitudes of Ca(2+) responses in these cells, induced by the selective P2X(7)R agonist BzATP, were increased by 145% with Abeta(1-42) pretreatment relative to control (no peptide pretreatment) and were largely blocked if the P2X(7)R inhibitor-oxidized ATP (oxATP) was added with peptide in pretreatment solution. In vivo, double immunostaining analysis showed considerable P2X(7)R colocalized with microglia after injection of Abeta(1-42) (1 nmol) into rat hippocampus. The overall results suggest roles of P2X(7)R in mediating microglial purinergic inflammatory responses in AD brain.

Adenosine Triphosphate↗

PubMed2004

Microglia kill amyloid-beta1-42 damaged neurons by a CD14-dependent process.

Activated microglia are closely associated with neuronal damage in Alzheimer's disease. In the present study, neurons exposed to low concentrations of amyloid-beta1-42, a toxic fragment of the amyloid-beta protein, were killed by microglia in a process that required cell-cell contact. Pre-treating microglia with polyclonal antibodies to the CD14 protein, or treating neurons exposed to amyloid-beta1-42 with a CD14-IgG chimera, prevented the killing of amyloid-beta1-42 damaged neurons by microglia. Moreover, microglia from CD14 null mice failed to kill amyloid-beta1-42 damaged neurons. Increased neuronal survival was accompanied by a significant reduction in the production of interleukin-6 indicative of reduced microglial activation. These results indicate an important role for CD14 in the recognition and subsequent killing of amyloid-beta damaged neurons by microglia.

Amyloid beta-Peptides↗

PubMed1994

Reactive cell proliferation and microglia following injury to the rat brain.

The non-astrocytic cells which proliferate in the rat brain after the induction of an area of necrosis have been characterized and counted by means of combined in vivo bromodeoxyuridine (BrdU) administration and immunohistochemical demonstration of glial fibrillary acid protein (GFAP), vimentin, Ricinus communis agglutinin 120 (RCA-1), Griffonia simplicifolia B4 isolectin (GSI-B4), keratan sulphate (KS), carbonic anhydrase C (CA.C), transferrin (TF) and ferritin. Two days after the injury, 7.5% of the proliferating cells were GFAP-positive reactive astrocytes, 5.7% were RCA-1-positive cells and 17.4% were GSI-B4-positive cells. Lectin-binding cells had the microscopic and ultrastructural aspects of microglia; they proliferated around the needle track and in the corpus callosum. Microglia represented a large fraction of the proliferating cells. Evidence is presented for the origin of at least a proportion of perilesional astrocytes and microglia from the periventricular matrix, and of microglia from blood precursors. Other non-proliferating microglia cells transiently appeared in the normal brain around the wound, in agreement with the existence of two different microglia cell populations reacting with different modalities to an area of necrosis.

Animals↗

PubMed1995

Reactive microglia in Creutzfeldt-Jakob disease.

Creutzfeldt-Jakob disease (CJD) is characterized by a loss of neurons accompanied by astrogliosis and spongiform changes in the neuropil. It has been recognized that reactive microglia occur in CJD but little is known about the regional distribution and extent of the microglial activation. We have, therefore, examined six brains from cases of sporadic CJD by immunohistochemical labelling of grey and white matter microglia from frontal, parietal, temporal, and occipital lobes, striatum, thalamus, cerebellum and brain stem with RCA-1, LCA, CD68, HLA-DR, and HAM56. Microglial activation occurred in the grey matter where astrogliosis and prion protein (PrP) deposits were prominent. Processes of activated microglia surrounded the outer rim of spongy vacuoles. A diffuse microglial response was seen in the white matter that was immunophenotypically different from grey matter. Double-labelling with microglial markers and anti-PrP showed that activated microglia did not contain PrP-immunoreactivity. Therefore a primary role of microglia in PrP processing seems unlikely. Activated microglia may contribute to neuronal damage in CJD due to their cytotoxic potential.

Aged↗

PubMed2005

Microglia-specific expression of microsomal prostaglandin E2 synthase-1 contributes to lipopolysaccharide-induced prostaglandin E2 production.

Microsomal prostaglandin E2 synthase (mPGES)-1 is an inducible protein recently shown to be an important enzyme in inflammatory prostaglandin E2 (PGE2) production in some peripheral inflammatory lesions. However, in inflammatory sites in the brain, the induction of mPGES-1 is poorly understood. In this study, we demonstrated the expression of mPGES-1 in the brain parenchyma in a lipopolysaccharide (LPS)-induced inflammation model. A local injection of LPS into the rat substantia nigra led to the induction of mPGES-1 in activated microglia. In neuron-glial mixed cultures, mPGES-1 was co-induced with cyclooxygenase-2 (COX-2) specifically in microglia, but not in astrocytes, oligodendrocytes or neurons. In microglia-enriched cultures, the induction of mPGES-1, the activity of PGES and the production of PGE2 were preceded by the induction of mPGES-1 mRNA and almost completely inhibited by the synthetic glucocorticoid dexamethasone. The induction of mPGES-1 and production of PGE2 were also either attenuated or absent in microglia treated with mPGES-1 antisense oligonucleotide or microglia from mPGES-1 knockout (KO) mice, respectively, suggesting the necessity of mPGES-1 for microglial PGE2 production. These results suggest that the activation of microglia contributes to PGE2 production through the concerted de novo synthesis of mPGES-1 and COX-2 at sites of inflammation of the brain parenchyma.

Animals↗

PubMed2005

Staphylococcus aureus-derived peptidoglycan induces Cx43 expression and functional gap junction intercellular communication in microglia.

Gap junctions serve as intercellular conduits that allow the exchange of small molecular weight molecules (up to 1 kDa) including ions, metabolic precursors and second messengers. Microglia are capable of recognizing peptidoglycan (PGN) derived from the outer cell wall of Staphylococcus aureus, a prevalent CNS pathogen, and respond with the robust elaboration of numerous pro-inflammatory mediators. Based on recent reports demonstrating the ability of tumor necrosis factor-alpha and interferon-gamma to induce gap junction coupling in macrophages and microglia, it is possible that pro-inflammatory mediators released from PGN-activated microglia are capable of inducing microglial gap junction communication. In this study, we examined the effects of S. aureus-derived PGN on Cx43, the major connexin in microglial gap junction channels, and functional gap junction communication using single-cell microinjections of Lucifer yellow (LY). Exposure of primary mouse microglia to PGN led to a significant increase in Cx43 mRNA and protein expression. LY microinjection studies revealed that PGN-treated microglia were functionally coupled via gap junctions, the specificity of which was confirmed by the reversal of activation-induced dye coupling by the gap junction blocker 18-alpha-glycyrrhetinic acid. In contrast to PGN-activated microglia, unstimulated cells consistently failed to exhibit LY dye coupling. These results indicate that PGN stimulation can induce the formation of a functional microglial syncytium, suggesting that these cells may be capable of influencing neuro-inflammatory responses in the context of CNS bacterial infections through gap junction intercellular communication.

Animals↗

PubMed2006

Protective effects of an anti-inflammatory cytokine, interleukin-4, on motoneuron toxicity induced by activated microglia.

Microglia-mediated cytotoxicity has been implicated in models of neurodegenerative diseases, such as amyotrophic lateral sclerosis, Parkinson's disease and Alzheimer's disease, but few studies have documented how neuroprotective signals might mitigate such cytotoxicity. To explore the neuroprotective mechanism of anti-inflammatory cytokines, we applied interleukin-4 (IL-4) to primary microglial cultures activated by lipopolysaccharide as well as to activated microglia cocultured with primary motoneurons. lipopolysaccharide increased nitric oxide and superoxide (O(2) (.-)) and decreased insulin-like growth factor-1 (IGF-1) release from microglial cultures, and induced motoneuron injury in microglia-motoneuron cocultures. However, lipopolysaccharide had minimal effects on isolated motoneuron cultures. IL-4 interaction with microglial IL-4 receptors suppressed and nitric oxide release, and lessened lipopolysaccharide-induced microglia-mediated motoneuron injury. The extent of nitric oxide suppression correlated directly with the extent of motoneuron survival. Although IL-4 enhanced release of free IGF-1 from microglia in the absence of lipopolysaccharide, it did not enhance free IGF-1 release in the presence of lipopolysaccharide. These data suggest that IL-4 may provide a significant immunomodulatory signal which can protect against microglia-mediated neurotoxicity by suppressing the production and release of free radicals.

Animals↗

PubMed2025

Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder. Antiamyloid antibody treatments modestly slow disease progression in mild dementia due to AD. Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD. Xenon (Xe) gas is a noble gas used in human patients as an anesthetic and a neuroprotectant used for treating brain injuries. Xe penetrates the blood-brain barrier, which could make it an effective therapeutic. To assess the effect of Xe on microglia and AD pathology, we designed a custom Xe inhalation chamber and treated several mouse models of AD with Xe gas. Xe treatment induced mouse microglia to adopt an intermediate activation state that we have termed pre-neurodegenerative microglia (pre-MGnD). This microglial phenotypic transition was observed in mouse models of acute neurodegeneration and amyloidosis (APP/PS1 and 5xFAD mice) and tauopathy (P301S mice). This microglial state enhanced amyloid plaque compaction and reduced dystrophic neurites in the APP/PS1 and 5xFAD mouse models. Moreover, Xe inhalation reduced brain atrophy and neuroinflammation and improved nest-building behavior in P301S mice. Mechanistically, Xe inhalation induced homeostatic brain microglia toward a pre-MGnD state through IFN-γ signaling that maintained the microglial phagocytic response in APP/PS1 and 5xFAD mice while suppressing the microglial proinflammatory phenotype in P301S mice. These results support the translation of Xe inhalation as an approach for treating AD.

Animals↗