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Proposed schematic depicting the CSF-1R mediated signaling in regulation of microglial proliferation and survival. Stimulated by binding of ligands, CSF1 or IL-34, CSF1-R undergoes a rapid dimerization and a self-tyrosine phosphorylation. Depending on the site of Tyrosine phosphorylation it activates different downstream signaling cascades. T-721/T-559 activates PI3K/Akt, JNK, and ERK1/2 cascades mediated activation and translocation of transcription factors (NF-kB/JNK/STAT3) within the nucleus, which promotes microglial proliferation and survival
Source publication
Colony Stimulating Factor-1 (CSF-1)/Colony Stimulating Factor-1 Receptor (CSF-1R) signaling axis plays an essential role in the development, maintenance, and proliferation of macrophage lineage cells. Within the central nervous system, CSF-1R signaling primarily maintains microglial homeostasis. Microglia, being the resident macrophage and first re...
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Colony-stimulating factors (CSFs) are glycoproteins that stimulate the proliferation and differentiation of hematopoietic progenitor cells in the bone marrow. But numerous studies have shown that these factors can stimulate the proliferation of non-hematopoietic cells, including cancer cells. Hence, in this study, Macrophage-CSF (M-CSF), macrophage...
Citations
... After CSF-1R activation, the expression of pro-inflammatory cytokines, chemokines, CD11b, and markers for M2 polarization found to be upregulated leading to neuroinflammation. Thus, CSF1R inhibitor emerged as the potential therapeutic target for neuroinflammation mediated AD (Tarale and Alam, 2022). PLX5622, PLX3397, GW5622, and PLX647 are some CSF-1 inhibitors that are permeable to BBB and cause microglia depletion . ...
... Further complicating matters, haploinsufficiency and total deficiency of TREM2 can lead to opposite effects, 44 and differing outcomes have also been reported with microglial depletion. 45,46 Notably, the timing of gene and/or total microglial manipulation is also critical, 47 and as we noted, we deliberately used conditional knockdown early in "disease" stage to mimic what might be therapeutically viable. ...
Introduction:
The inositol polyphosphate-5-phosphatase D (INPP5D) gene encodes a dual-specificity phosphatase that can dephosphorylate both phospholipids and phosphoproteins. Single nucleotide polymorphisms in INPP5D impact risk for developing late onset sporadic Alzheimer's disease (LOAD).
Methods:
To assess the consequences of inducible Inpp5d knockdown in microglia of APPKM670/671NL /PSEN1Δexon9 (PSAPP) mice, we injected 3-month-old Inpp5dfl/fl /Cx3cr1CreER/+ and PSAPP/Inpp5dfl/fl /Cx3cr1CreER/+ mice with either tamoxifen (TAM) or corn oil (CO) to induce recombination.
Results:
At age 6 months, we found that the percent area of 6E10+ deposits and plaque-associated microglia in Inpp5d knockdown mice were increased compared to controls. Spatial transcriptomics identified a plaque-specific expression profile that was extensively altered by Inpp5d knockdown.
Discussion:
These results demonstrate that conditional Inpp5d downregulation in the PSAPP mouse increases plaque burden and recruitment of microglia to plaques. Spatial transcriptomics highlighted an extended gene expression signature associated with plaques and identified CST7 (cystatin F) as a novel marker of plaques.
Highlights:
Inpp5d knockdown increases plaque burden and plaque-associated microglia number. Spatial transcriptomics identifies an expanded plaque-specific gene expression profile. Plaque-induced gene expression is altered by Inpp5d knockdown in microglia. Our plaque-associated gene signature overlaps with human Alzheimer's disease gene networks.
... This process has attracted attention because primed microglia have been proposed to be responsible for neurodegeneration and behavioral disturbances, among other alterations (Perry and Holmes, 2014;Colonna and Butovsky, 2017;Bartels et al., 2020). For this reason, strategies to modulate or inhibit microglial activation are under investigation (Spangenberg et al., 2016;Muzio et al., 2021;Tarale and Alam, 2022). In fact, using a strategy of microglial depletion Wendeln and colleagues concluded that microglia are mostly responsible for immune priming in the brain (Wendeln et al., 2018). ...
Innate immune memory explains the plasticity of immune responses after repeated immune stimulation, leading to either enhanced or suppressed immune responses. This process has been extensively reported in peripheral immune cells and also, although modestly, in the brain. Here we explored two relevant aspects of brain immune priming: its persistence over time and its dependence on TLR receptors. For this purpose, we used an experimental paradigm consisting in applying two inflammatory stimuli three months apart. Wild type, toll-like receptor (TLR) 4 and TLR2 mutant strains were used. The priming stimulus was the intracerebroventricular injection of neuraminidase (an enzyme that is present in various pathogens able to provoke brain infections), which triggers an acute inflammatory process in the brain. The second stimulus was the intraperitoneal injection of lipopolysaccharide (a TLR4 ligand) or Pam3CSK4 (a TLR2 ligand). One day after the second inflammatory challenge the immune response in the brain was examined. In wild type mice, microglial and astroglial density, as well as the expression of 4 out of 5 pro-inflammatory genes studied (TNFα, IL1β, Gal-3, and NLRP3), were increased in mice that received the double stimulus compared to those exposed only to the second one, which were initially injected with saline instead of neuraminidase. Such enhanced response suggests immune training in the brain, which lasts at least 3 months. On the other hand, TLR2 mutants under the same experimental design displayed an enhanced immune response quite similar to that of wild type mice. However, in TLR4 mutant mice the response after the second immune challenge was largely dampened, indicating the pivotal role of this receptor in the establishment of immune priming. Our results demonstrate that neuraminidase-induced inflammation primes an enhanced immune response in the brain to a subsequent immune challenge, immune training that endures and that is largely dependent on TLR4 receptor.
... Since the discovery of CSF1R mutations in families with CSF1R-microglial encephalopathy, 115 mutation sites have been identified worldwide, including 93 missense mutations, four nonsense mutations, four insertions or deletions, seven frameshift mutations, and 14 splice-site mutations (Tian et al., 2019;Wu et al., 2022). The CSF1R is a protein tyrosine kinase receptor that consists of five immunoglobulin-like domains in the extracellular ligand-binding portion, a single transmembrane domain, a juxtamembrane domain, a kinase insertion domain, and two intracellular TKDs (Tarale and Alam, 2022). Approximately 95% of CSF1R gene mutations are located in the TKD of CSF1R encoded by exons 12-21, especially exons 18 and 19 (Leng et al., 2019;Zhuang et al., 2020;Chitu et al., 2021). ...
Objective: To describe two novel heterozygous splicing variants of the CSF1R gene responsible for CSF1R-microglial encephalopathy in two unrelated Han Chinese families and further explore the relationship between the pathological and neuroimaging findings in this disease.
Methods: The demographic data, detailed medical history, and clinical manifestations of two unrelated Han families with CSF1R-microglial encephalopathy were recorded. Some family members also underwent detailed neuropsychological evaluation, neuroimaging, and genetic testing. The probands underwent whole-exome sequencing (WES) or next-generation sequencing (NGS) to confirm the diagnosis. The findings were substantiated using Sanger sequencing, segregation analysis, and phenotypic reevaluation.
Results: Both families presented with a dominant hereditary pattern. Five of 27 individuals (four generations) from the first family, including the proband and his sister, father, uncle, and grandmother, presented with cognitive impairments clinically during their respective lifetimes. Brain magnetic resonance imaging (MRI) depicted symmetric, confluent, and diffuse deep white matter changes, atrophy of the frontoparietal lobes, and thinning of the corpus callosum. The proband’s brother remained asymptomatic; brain MRI revealed minimal white matter changes, but pseudo-continuous arterial spin labeling (pCASL) demonstrated a marked reduction in the cerebral blood flow (CBF) in the bilateral deep white matter and corpus callosum. Seven family members underwent WES, which identified a novel splice-site heterozygous mutation (c.2319+1C>A) in intron 20 of the CSF1R gene in four members. The proband from the second family presented with significant cognitive impairment and indifference; brain MRI depicted symmetric diffuse deep white matter changes and thinning of the corpus callosum. The proband’s mother reported herself to be asymptomatic, while neuropsychological evaluation suggested mild cognitive impairment, and brain MRI demonstrated abnormal signals in the bilateral deep white matter and corpus callosum. NGS of 55 genes related to hereditary leukodystrophy was performed for three members, which confirmed a novel splice-site heterozygous mutation (c.1858+5G>A) in intron 13 of the CSF1R gene in two members.
Conclusions: Our study identified two novel splicing mutation sites in the CSF1R gene within two independent Chinese families with CSF1R-microglial encephalopathy, broadening the genetic spectrum of CSF1R-microglial encephalopathy and emphasizing the value of pCASL for early detection of this disease.
