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PubMed1979

The failure of microglia in normal brain to exhibit mononuclear phagocyte markers.

The origin of brain macrophages or "reactive microglia" has been the subject of considerable controversy. The fundamental question is whether or not there is a morphologically and functionally distinct population of cells, called microglia, which are resident in normal brain and differentiate into macrophages in response to inflammatory stimuli. The present study was performed to determine if any cells in the normal brain have the common markers of mononuclear phagocytes; phagocytosis, IgGFc receptors or macrophage specific antigens. In studies of the newborn and the adult murine brain and adult human brain no cells were detected which had any of those markers, although the highly sensitive marker methods were capable of detecting mononuclear phagocytes in all other tissues where they are known to occur. The results suggest that microglia, if they exist as a distinct cell type, are unrelated to mononuclear phagocytes. Furthermore, they suggest, but do not prove, that all inflammatory macrophages are derived from hematogenous precursors.

Animals↗
PubMed1979

[Microglia-type cells in normal and pathologic human embryonic brains].

The brains of 7--12 week embryos, developing in normal and mentally ill females (normal--14, schizophrenia--12, other mental disorders--10) were studied by means of electron microscopy. It was established that the cells of the microglia type may be encountered in the brain of embryos beginning from 7 weeks. In the brain of embryos from normal females these cells had mainly a round or oval form (globose microglia). Axons were encountered relatively rarely. Some of the cells had protrusions of the pseudopodia-like type. In the brain of embryos from mentally ill females the cells of the microglia type have diverse, sometimes sticklike forms; they form multiple thin axons, actively fagocyte. The ultrastructure in such conditions was not destructed. These changes are considered to be the result of an increased activity of microglial cells under the influence of factors of the pathological process.

Brain↗
PubMed2027

A Standardized Protocol for Generating iPSC-Derived Human Microglia for Functional Genomic Assays.

Human induced pluripotent stem cell (iPSC)-derived microglia (iMG) provide an in vitro experimental system for studying human microglial biology, neuroinflammation, and genetic risk mechanisms associated with neurological disease. This chapter describes a standardized, scalable, and reproducible protocol for the differentiation of human iPSCs into functional microglia-like cells, with particular emphasis on applications in transcriptional and epigenomic network analysis. The protocol supports high-viability floating iMG production, compatibility with pooled CRISPR perturbation approaches, and downstream multiomic profiling, including single-cell RNA sequencing, chromatin accessibility assays, and proteomics. Detailed procedures are provided for iPSC maintenance, hematopoietic progenitor cell generation, microglial maturation, functional genomics integration, and quality control.

Humans↗
PubMed1975

Origin of brain macrophages and the nature of the so-called microglia.

Two aspects of the so-called microglia were studied by silver impregnation and 3H-TdR ARG in light and electron microscopy. (1) So-called microglioblasts are glioblasts differentiated from matrix cells. They are progenitors of the so-called resting microglia as well as of astrocytes and oligodendroglia. (2) Brain macrophages in stab wounds, experimental Japanese encephalitis and retrograde degeneration of the facial nucleus are all found to be of hematogenous origin. Infiltrating hematogenous cells cannot stay permanently in the brain parenchyma unless pathological alterations persist indefinitely.

Animals↗
PubMedDate not supplied

A developmental study of epiplexus cells and supraependymal cells and their possible relationship to microglia.

Intraventricular macrophages are first seen attached to the presumptive choroid plexus in the 11 days postconception mouse. By 12 day postconception supraependymal macrophages are present as well as a few macrophages lying apparently free within the ventricles. The number of epiplexus, supraependymal and free macrophages increases rapidly and reaches a peak at 17 days postconception, then fall rapidly until 4 days post natum. A second increase in epiplexus and supraependymal cells occurs at 8 days post natum followed by another decrease up to 15 days post natum. Microglia were first observed in the brain at 13 days postconception and at 17 days postconception a microglial cell was observed apparently entering the ependyma from the ventricle. It is suggested that the large decrease in intraventricular macrophages after 17 days postconception is due to many of these cells migrating into the brain to give rise to microglia. The intraventricular macrophages themselves probably arise from within the choroid plexus, either from stromal cells or from blood-borne macrophages.

Animals↗
PubMed1979

[A modification of microglia impregnation (author's transl)].

A modification of the Weil and Davenport (1933) silver carbonate method for microglia impregnation is described. Formalin-dextran-CaCl2 solution was used as a fixation solution. The technique is simple, reproducible and improved. The staining method includes the demonstration of as well resting as progressive microglia.

Animals↗
PubMed1977

The microglia in brain granulomatoses. Histo-enzymological study.

The microglial participation in the different granulomatous processes was studied by silver impregnation techniques and histoenzymological methods. In florid granulomatous areas two types of metallophilic cells were detected, corresponding to the common macrophages and perhaps to the ameboid modification of the microglia. Hydrolytic enzyme preparations showed a pattern of distribution and intensity similar to that of the impregnated cells. Only in the adjacent nervous parenchyma the different methods evidenced the presence of hyperplastic ramified microglia associated with reactive astrocytes.

Brain Diseases↗
PubMed2026

Does high fructose consumption trigger microglia activation and neuroinflammation? A systematic review.

This systematic review evaluated the effects of fructose intake on neuroinflammatory markers in rodent models. The search terms Fructose AND neuroinflammation OR Neurodegeneration OR chemokines OR interleukins OR microglia OR behaviour OR memory OR cognition were used in Google Scholar, Scopus and Web of Science. Thirteen animal studies investigating fructose-induced neuroinflammation that matched the eligibility criteria were included in the study. Across the studies, 16 inflammatory markers were identified and significantly altered following exposure to fructose. The findings consistently demonstrated elevated expression of pro-inflammatory cytokines, TNF-α, IL-6, and IL-1β, following fructose administration. Fructose consumption also dysregulated MCP-1, fractalkine, and CX3CR1 levels, thereby promoting inflammatory signalling and microglial activation. Furthermore, fructose exposure significantly increased IBA-1 and CD11b, indicating sustained neuroimmune activation. Alterations in important inflammatory pathways involving TLR4, NLRP3, NF-κB, MyD88, iNOS, and cyclooxygenases (COX-1 and COX-2) were also observed. In contrast, expression of the anti-inflammatory regulator peroxisome proliferator-activated receptor gamma (PPARγ) was reduced after fructose treatment. Overall, the findings suggest that chronic fructose consumption induces neuroinflammation through multiple inflammatory and immune-related mechanisms in the brain. These effects appear to be dose- and duration-dependent and may contribute significantly to neurodegeneration and cognitive impairment.

Microglia↗
PubMed2025

Senescent-like microglia limit remyelination through the senescence associated secretory phenotype.

The capacity to regenerate myelin in the central nervous system diminishes with age. This decline is particularly evident in multiple sclerosis (MS), a chronic demyelinating disease. Whether cellular senescence, a hallmark of aging, contributes to remyelination impairment remains unknown. Here, we show that senescent cells accumulate within demyelinated lesions after injury, and treatments with senolytics enhances remyelination in young and middle-aged mice but not aged mice. In young mice, we observe the upregulation of senescence-associated transcripts, primarily in microglia and macrophages, after demyelination, followed by a reduction during remyelination. However, in aged mice, senescence-associated factors persist within lesions, correlating with inefficient remyelination. Proteomic analysis of the senescence-associated secretory phenotype (SASP) reveals elevated levels of CCL11/Eotaxin-1 in lesions of aged mice, which is found to inhibit oligodendrocyte maturation. These results suggest therapeutic targeting of SASP components, such as CCL11, may improve remyelination in aging and MS.

Animals↗
PubMed2026

Plasticity of human microglia and brain perivascular macrophages in aging and Alzheimer's disease.

Myeloid cells, including microglia and perivascular macrophages, are central to Alzheimer's disease (AD) neurobiology, yet their role remains incompletely understood. We profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 donors spanning the lifespan and showing varying degrees of AD neuropathology. We delineated six subclasses comprising 13 transcriptionally distinct subtypes and identified adaptive changes associated with aging and AD progression. Here we show that a disease-associated microglial subtype, characterized by elevated GPNMB expression and enriched for polygenic AD risk, expands with AD pathology and shows increased phagocytic activity. We identify MITF as an upstream regulator required to maintain this microglial state. Cell-cell interaction analyses prioritize APOE-SORL1 and APOE-TREM2 signaling pairs associated with disease progression. Using human and mouse models, we demonstrate that the neuroprotective effects of this microglial subtype depend on TREM2. These findings provide mechanistic insights into myeloid cell function in aging and AD, aiding therapeutic discovery.

Humans↗
PubMed2024

Plasticity of Human Microglia and Brain Perivascular Macrophages in Aging and Alzheimer's Disease.

The complex roles of myeloid cells, including microglia and perivascular macrophages, are central to the neurobiology of Alzheimer's disease (AD), yet they remain incompletely understood. Here, we profiled 832,505 human myeloid cells from the prefrontal cortex of 1,607 unique donors covering the human lifespan and varying degrees of AD neuropathology. We delineated 13 transcriptionally distinct myeloid subtypes organized into 6 subclasses and identified AD-associated adaptive changes in myeloid cells over aging and disease progression. The GPNMB subtype, linked to phagocytosis, increased significantly with AD burden and correlated with polygenic AD risk scores. By organizing AD-risk genes into a regulatory hierarchy, we identified and validated MITF as an upstream transcriptional activator of GPNMB, critical for maintaining phagocytosis. Through cell-to-cell interaction networks, we prioritized APOE-SORL1 and APOE-TREM2 ligand-receptor pairs, associated with AD progression. In both human and mouse models, TREM2 deficiency disrupted GPNMB expansion and reduced phagocytic function, suggesting that GPNMB's role in neuroprotection was TREM2-dependent. Our findings clarify myeloid subtypes implicated in aging and AD, advancing the mechanistic understanding of their role in AD and aiding therapeutic discovery.

Journal Article↗
PubMed1977

Light and electron microscopic demonstration of some lysosomal enzymes in the amoeboid microglia in neonatal rat brain.

A cytochemical study of the amoeboid microglial cells in the brain of the neonatal rat has shown that these vacuolated cells exhibit strong acid phosphatase, aryl sulphatase and adenosine triphosphatase (ATPase) activities. Endogenous peroxidase, however, was not present. With the electron microscope the reaction product of acid phosphatase was found to be localized in some of the Golgi cisternae, in the majority of the electron-dense secretory granules, and in an occasional long tubular profile. The secretory granules were not uniformly stained for this enzyme, some showing only a focal reaction or none at all. The distribution of the activity of aryl sulphatase corresponded to that of acid phosphatase except that all the granules appeared to contain the former enzyme. With the light microscope the amoeboid microglial cells were intensely stained for ATPase. From these observations it was concluded that amoeboid microglia are active phagocytes and their enzyme-rich secretory granules are lysosomes.

Acid Phosphatase↗
PubMed1979

Evidence for a haematogenous origin of some of the macrophages appearing in the spinal cord of the rat after dorsal rhizotomy.

A single dose of colloidal carbon was given intravascularly to young adult rats in order to label circulating monocytes. Two days after injection dorsal rhizotomies were performed on the fifth to eighth cervical nerves on the right side. The rats were killed 1, 3, 4 and 8 days later. Electron microscopic examination of the spinal cord showed wide-spread tissue degeneration on the operated side in the dorsolateral fasciculus, the dorsal horn and the dorsal neuronal white column, the changes in the last named being the most severe. A variety of non-neuronal elements was found in the dorsolateral fasciculus and dorsal horn. These included astrocytes, oligodendrocytes, microglia-like cells, plasma cells, mast cells, polymorphonuclear leucocytes, monocytes and macrophages. Monocytes and macrophages were most common 3 and 4 days after operation. Some of these cells carried intracytoplasmic carbon particles. Carbon-labelled monocytes were observed in blood vessel lumina, perivascularly and in the neuropil. Monocytes crossing blood vessel walls were also encountered, indicating that the neuropil monocytes were derived from circulating cells. Macrophages were characterized by pleomorphic phagosomes which seemed to be composed largely of myelin remnants. The presence of carbon particles in their cytoplasm, and also their general similarity to monocytes, suggested that they originated from the latter. Local microglial cells were considered to be another source of macrophages. Indeed, there were present some microglia-like cells which were regarded as 'activated microglia' as they showed morphological resemblances to microglia on the one hand and to macrophages on the other. In particular their cytoplasm always included phagosomes. It is concluded that the macrophages which appear in the altered spinal cord following rhizotomy are derived both from circulating monocytes and from indigenous microglia.

Animals↗