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24 pages, 4359 KiB

Open AccessArticle

Csf1 Deficiency Dysregulates Glial Responses to Demyelination and Disturbs CNS White Matter Remyelination

by Bartosz Wylot, Jakub Mieczkowski, Sylwia Niedziolka, Bozena Kaminska and Malgorzata Zawadzka

Cells 2020, 9(1), 99; https://doi.org/10.3390/cells9010099 - 31 Dec 2019

Cited by 20 | Viewed by 4770

Abstract

Remyelination, a highly efficient central nervous system (CNS) regenerative process, is performed by oligodendrocyte progenitor cells (OPCs), which are recruited to the demyelination sites and differentiate into mature oligodendrocytes to form a new myelin sheath. Microglia, the specialized CNS-resident phagocytes, were shown to [...] Read more.

Remyelination, a highly efficient central nervous system (CNS) regenerative process, is performed by oligodendrocyte progenitor cells (OPCs), which are recruited to the demyelination sites and differentiate into mature oligodendrocytes to form a new myelin sheath. Microglia, the specialized CNS-resident phagocytes, were shown to support remyelination through secretion of factors stimulating OPC recruitment and differentiation, and their pharmacological depletion impaired remyelination. Macrophage colony-stimulating factor (Csf1) has been implicated in the control of recruitment and polarization of microglia/macrophages in injury-induced CNS inflammation. However, it remains unclear how Csf1 regulates a glial inflammatory response to demyelination as well as axonal survival and new myelin formation. Here, we have investigated the effects of the inherent Csf1 deficiency in a murine model of remyelination. We showed that remyelination was severely impaired in Csf1-/- mutant mice despite the fact that reduction in monocyte/microglia accumulation affects neither the number of OPCs recruited to the demyelinating lesion nor their differentiation. We identified a specific inflammatory gene expression signature and found aberrant astrocyte activation in Csf1-/- mice. We conclude that Csf1-dependent microglia activity is essential for supporting the equilibrium between microglia and astrocyte pro-inflammatory vs. regenerative activation, demyelinated axons integration and, ultimately, reconstruction of damaged white matter. Full article

(This article belongs to the Special Issue Microglia in Neurodegenerative Diseases)

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13 pages, 1959 KiB

Open AccessArticle

Beta-Aminoisobutyric Acid Inhibits Hypothalamic Inflammation by Reversing Microglia Activation

by Byong Seo Park, Thai Hien Tu, Hannah Lee, Da Yeon Jeong, Sunggu Yang, Byung Ju Lee and Jae Geun Kim

Cells 2019, 8(12), 1609; https://doi.org/10.3390/cells8121609 - 11 Dec 2019

Cited by 16 | Viewed by 3670

Abstract

Beta-aminoisobutyric acid (BAIBA), a natural thymine catabolite, is involved in the beneficial effects of exercise on metabolic disorders. In particular, it has been reported to reverse the inflammatory processes observed in the peripheral organs of animal models of obesity. Therefore, this study aimed [...] Read more.

Beta-aminoisobutyric acid (BAIBA), a natural thymine catabolite, is involved in the beneficial effects of exercise on metabolic disorders. In particular, it has been reported to reverse the inflammatory processes observed in the peripheral organs of animal models of obesity. Therefore, this study aimed to investigate whether BAIBA improves hypothalamic inflammation, which is also tightly coupled with the development of obesity. We observed that treatment with BAIBA effectively reversed palmitic acid-induced hypothalamic inflammation and microglial activation in vivo. Consistent with these findings, we confirmed that BAIBA reversed body weight gain and increased adiposity observed in mice fed with a high-fat diet. Collectively, the current findings evidence the beneficial impacts of BAIBA on the imbalance of energy metabolism linked to hypothalamic inflammation. Full article

(This article belongs to the Special Issue Microglia in Neurodegenerative Diseases)

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19 pages, 9191 KiB

Open AccessArticle

The S100A4 Transcriptional Inhibitor Niclosamide Reduces Pro-Inflammatory and Migratory Phenotypes of Microglia: Implications for Amyotrophic Lateral Sclerosis

by Alessia Serrano, Savina Apolloni, Simona Rossi, Serena Lattante, Mario Sabatelli, Mina Peric, Pavle Andjus, Fabrizio Michetti, Maria Teresa Carrì, Mauro Cozzolino and Nadia D’Ambrosi

Cells 2019, 8(10), 1261; https://doi.org/10.3390/cells8101261 - 16 Oct 2019

Cited by 32 | Viewed by 4968

Abstract

S100A4, belonging to a large multifunctional S100 protein family, is a Ca²⁺-binding protein with a significant role in stimulating the motility of cancer and immune cells, as well as in promoting pro-inflammatory properties in different cell types. In the CNS, there [...] Read more.

S100A4, belonging to a large multifunctional S100 protein family, is a Ca²⁺-binding protein with a significant role in stimulating the motility of cancer and immune cells, as well as in promoting pro-inflammatory properties in different cell types. In the CNS, there is limited information concerning S100A4 presence and function. In this study, we analyzed the expression of S100A4 and the effect of the S100A4 transcriptional inhibitor niclosamide in murine activated primary microglia. We found that S100A4 was strongly up-regulated in reactive microglia and that niclosamide prevented NADPH oxidase 2, mTOR (mammalian target of rapamycin), and NF-κB (nuclear factor-kappa B) increase, cytoskeletal rearrangements, migration, and phagocytosis. Furthermore, we found that S100A4 was significantly up-regulated in astrocytes and microglia in the spinal cord of a transgenic rat SOD1-G93A model of amyotrophic lateral sclerosis. Finally, we demonstrated the increased expression of S100A4 also in fibroblasts derived from amyotrophic lateral sclerosis (ALS) patients carrying SOD1 pathogenic variants. These results ascribe S100A4 as a marker of microglial reactivity, suggesting the contribution of S100A4-regulated pathways to neuroinflammation, and identify niclosamide as a possible drug in the control and attenuation of reactive phenotypes of microglia, thus opening the way to further investigation for a new application in neurodegenerative conditions. Full article

(This article belongs to the Special Issue Microglia in Neurodegenerative Diseases)

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17 pages, 2466 KiB

Open AccessArticle

Rifampicin and Its Derivative Rifampicin Quinone Reduce Microglial Inflammatory Responses and Neurodegeneration Induced In Vitro by α-Synuclein Fibrillary Aggregates

by Leonardo Acuña, Sabah Hamadat, Natalia S. Corbalán, Florencia González-Lizárraga, Mauricio dos-Santos-Pereira, Jérémy Rocca, Julia Sepúlveda Díaz, Elaine Del-Bel, Dulce Papy-García, Rosana N. Chehín, Patrick P. Michel and Rita Raisman-Vozari

Cells 2019, 8(8), 776; https://doi.org/10.3390/cells8080776 - 25 Jul 2019

Cited by 42 | Viewed by 6608

Abstract

Aggregated forms of the synaptic protein α-synuclein (αS) have been proposed to operate as a molecular trigger for microglial inflammatory processes and neurodegeneration in Parkinson´s disease. Here, we used brain microglial cell cultures activated by fibrillary forms of recombinant human αS to assess [...] Read more.

Aggregated forms of the synaptic protein α-synuclein (αS) have been proposed to operate as a molecular trigger for microglial inflammatory processes and neurodegeneration in Parkinson´s disease. Here, we used brain microglial cell cultures activated by fibrillary forms of recombinant human αS to assess the anti-inflammatory and neuroprotective activities of the antibiotic rifampicin (Rif) and its autoxidation product rifampicin quinone (RifQ). Pretreatments with Rif and RifQ reduced the secretion of prototypical inflammatory cytokines (TNF-α, IL-6) and the burst of oxidative stress in microglial cells activated with αS fibrillary aggregates. Note, however, that RifQ was constantly more efficacious than its parent compound in reducing microglial activation. We also established that the suppressive effects of Rif and RifQ on cytokine release was probably due to inhibition of both PI3K- and non-PI3K-dependent signaling events. The control of oxidative stress appeared, however, essentially dependent on PI3K inhibition. Of interest, we also showed that RifQ was more efficient than Rif in protecting neuronal cells from toxic factors secreted by microglia activated by αS fibrils. Overall, data with RifQ are promising enough to justify further studies to confirm the potential of this compound as an anti-parkinsionian drug. Full article

(This article belongs to the Special Issue Microglia in Neurodegenerative Diseases)

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22 pages, 5465 KiB

Open AccessEditor’s ChoiceArticle

Microglial Phenotyping in Neurodegenerative Disease Brains: Identification of Reactive Microglia with an Antibody to Variant of CD105/Endoglin

by Douglas G. Walker, Lih-Fen Lue, Thomas G. Beach and Ikuo Tooyama

Cells 2019, 8(7), 766; https://doi.org/10.3390/cells8070766 - 23 Jul 2019

Cited by 10 | Viewed by 7572

Abstract

Inflammation is considered a key pathological process in neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), but there are still mechanisms not understood. In the brain, most microglia are performing essential homeostatic functions, but can also respond to pathogenic stimuli by [...] Read more.

Inflammation is considered a key pathological process in neurodegenerative diseases, including Alzheimer’s disease (AD) and Parkinson’s disease (PD), but there are still mechanisms not understood. In the brain, most microglia are performing essential homeostatic functions, but can also respond to pathogenic stimuli by producing harmful pro-inflammatory cytokines or free radicals. Distinguishing between damaging and homeostatic microglia in human diseased brain tissues is a challenge. This report describes findings using a monoclonal antibody to CD105/Endoglin (R&D Systems MAB1097) that identifies subtypes of activated microglia. CD105/Endoglin is a co-receptor for transforming growth factor beta (TGFβ) receptor that antagonizes TGFβ signaling. CD105/Endoglin is a marker for vascular endothelial cells, but was originally identified as a marker for activated macrophages. This antibody did not identify endothelial cells in brain sections, only microglia-like cells. In this study, we examined with this antibody tissue section from middle temporal gyrus derived from human brains from normal control subjects with low-plaque pathology, high-plaque pathology, and AD cases, and also substantia nigra samples from control and PD cases, in conjunction with antibodies to markers of pathology and microglia. In low-plaque pathology cases, CD105-positive microglia were mostly absent, but noticeably increased with increasing pathology. CD105-positive cells strongly colocalized with amyloid-beta plaques, but not phosphorylated tau positive tangles. In substantia nigra, strong microglial CD105 staining was observed in microglia associated with degenerating dopaminergic neurons and neuromelanin. In PD cases with few surviving dopaminergic neurons, this staining had decreased. By Western blot, this antibody identified polypeptide bands of 70 kDa in brain samples, and samples from microglia, macrophages, and brain endothelial cells. In comparison with other tested CD105 antibodies, this antibody did not recognize the glycosylated forms of CD105 on Western blots. Overall, the data indicate that this antibody and this marker could have utility for subtyping of microglia in pathologically-involved tissue. Full article

(This article belongs to the Special Issue Microglia in Neurodegenerative Diseases)

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11 pages, 1574 KiB

Open AccessArticle

Synthesis and Evaluation of Novel Pyrazole Ethandiamide Compounds as Inhibitors of Human THP-1 Monocytic Cell Neurotoxicity

by Jordan A. McKenzie, Reham F. Barghash, Azhaar T. Alsaggaf, Omkar Kulkarni, Kalun Boudreau, Frederic Menard, Edward G. Neeland and Andis Klegeris

Cells 2019, 8(7), 655; https://doi.org/10.3390/cells8070655 - 29 Jun 2019

Cited by 9 | Viewed by 5013

Abstract

Neuroinflammation and microglia-mediated neurotoxicity contribute to the pathogenesis of a broad range of neurodegenerative diseases; therefore, identifying novel compounds that can suppress adverse activation of glia is an important goal. We have previously identified a class of trisubstituted pyrazoles that possess neuroprotective and [...] Read more.

Neuroinflammation and microglia-mediated neurotoxicity contribute to the pathogenesis of a broad range of neurodegenerative diseases; therefore, identifying novel compounds that can suppress adverse activation of glia is an important goal. We have previously identified a class of trisubstituted pyrazoles that possess neuroprotective and anti-inflammatory properties. Here, we describe a second generation of pyrazole analogs that were designed to improve their neuroprotective activity toward neurons under inflammatory conditions. Pyrazolyl oxalamide derivatives were designed to explore the effects of steric and electronic factors. Three in vitro assays were performed to evaluate the compounds’ anti-neurotoxic, neuroprotective, and cytotoxic activity using human THP-1, PC-3, and SH-SY5Y cells. Five compounds significantly reduced the neurotoxic secretions from immune-stimulated microglia-like human THP-1 monocytic cells. One of these compounds was also found to protect SH-SY5Y neuronal cells when they were exposed to cytotoxic THP-1 cell supernatants. While one of the analogs was discarded due to its interference with the cell viability assay, most compounds were innocuous to the cultured cells at the concentrations used (1–100 μM). The new compounds reported herein provide a design template for the future development of lead candidates as novel inhibitors of neuroinflammation and neuroprotective drugs. Full article

(This article belongs to the Special Issue Microglia in Neurodegenerative Diseases)

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22 pages, 2376 KiB

Open AccessArticle

Intranasal Administration of Mesenchymal Stem Cells Ameliorates the Abnormal Dopamine Transmission System and Inflammatory Reaction in the R6/2 Mouse Model of Huntington Disease

by Libo Yu-Taeger, Janice Stricker-Shaver, Katrin Arnold, Patrycja Bambynek-Dziuk, Arianna Novati, Elisabeth Singer, Ali Lourhmati, Claire Fabian, Janine Magg, Olaf Riess, Matthias Schwab, Alexandra Stolzing, Lusine Danielyan and Hoa Huu Phuc Nguyen

Cells 2019, 8(6), 595; https://doi.org/10.3390/cells8060595 - 15 Jun 2019

Cited by 54 | Viewed by 6957

Abstract

Intrastriatal administration of mesenchymal stem cells (MSCs) has shown beneficial effects in rodent models of Huntington disease (HD). However, the invasive nature of surgical procedure and its potential to trigger the host immune response may limit its clinical use. Hence, we sought to [...] Read more.

Intrastriatal administration of mesenchymal stem cells (MSCs) has shown beneficial effects in rodent models of Huntington disease (HD). However, the invasive nature of surgical procedure and its potential to trigger the host immune response may limit its clinical use. Hence, we sought to evaluate the non-invasive intranasal administration (INA) of MSC delivery as an effective alternative route in HD. GFP-expressing MSCs derived from bone marrow were intranasally administered to 4-week-old R6/2 HD transgenic mice. MSCs were detected in the olfactory bulb, midbrain and striatum five days post-delivery. Compared to phosphate-buffered saline (PBS)-treated littermates, MSC-treated R6/2 mice showed an increased survival rate and attenuated circadian activity disruption assessed by locomotor activity. MSCs increased the protein expression of DARPP-32 and tyrosine hydroxylase (TH) and downregulated gene expression of inflammatory modulators in the brain 7.5 weeks after INA. While vehicle treated R6/2 mice displayed decreased Iba1 expression and altered microglial morphology in comparison to the wild type littermates, MSCs restored both, Iba1 level and the thickness of microglial processes in the striatum of R6/2 mice. Our results demonstrate significantly ameliorated phenotypes of R6/2 mice after MSCs administration via INA, suggesting this method as an effective delivering route of cells to the brain for HD therapy. Full article

(This article belongs to the Special Issue Microglia in Neurodegenerative Diseases)

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15 pages, 3709 KiB

Open AccessArticle

Distinct Protein Expression Networks are Activated in Microglia Cells after Stimulation with IFN-γ and IL-4

by Daniele Vergara, Annamaria Nigro, Alessandro Romano, Stefania De Domenico, Marina Damato, Julien Franck, Chiara Coricciati, Maxence Wistorski, Tristan Cardon, Isabelle Fournier, Angelo Quattrini, Michel Salzet, Roberto Furlan and Michele Maffia

Cells 2019, 8(6), 580; https://doi.org/10.3390/cells8060580 - 12 Jun 2019

Cited by 17 | Viewed by 5823

Abstract

Microglia cells are the primary immune population of the central nervous system with a role in the regulation of several physiological and pathological conditions. Upon appropriate stimulation, microglia cells can be polarized in a pro-inflammatory M1-like or anti-inflammatory M2-like status. Biological processes and [...] Read more.

Microglia cells are the primary immune population of the central nervous system with a role in the regulation of several physiological and pathological conditions. Upon appropriate stimulation, microglia cells can be polarized in a pro-inflammatory M1-like or anti-inflammatory M2-like status. Biological processes and pathways engaged in microglia polarization are starting to be elucidated. To help clarify this, we used a liquid chromatography-mass spectrometry (LC-MS/MS) label free approach to characterize the proteomic profile of human microglia cell line (CHME-5) stimulated with gamma-interferon (IFN-γ) and interleukin-4 (IL-4) to induce a M1 or M2 phenotype, respectively. Outside the classical M1/M2 polarization markers, the M1 status appears to center around the activation of a classical inflammatory response and through the activation of multiple signaling pathways. M2 polarization resulted in a different pattern of protein modulation related to RNA and cellular metabolic processes. Together, our findings provide information regarding the protein changes specific to M1 and M2 activation states, and potentially link the polarization of microglia cells to the acquisition of a specific proteomic profile. Full article

(This article belongs to the Special Issue Microglia in Neurodegenerative Diseases)

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15 pages, 3116 KiB

Open AccessArticle

Oxytocin Suppresses Inflammatory Responses Induced by Lipopolysaccharide through Inhibition of the eIF-2α–ATF4 Pathway in Mouse Microglia

by Takayuki Inoue, Hajime Yamakage, Masashi Tanaka, Toru Kusakabe, Akira Shimatsu and Noriko Satoh-Asahara

Cells 2019, 8(6), 527; https://doi.org/10.3390/cells8060527 - 31 May 2019

Cited by 56 | Viewed by 5958

Abstract

Microglia maintain brain homeostasis and modulate neuroinflammation and are implicated in the pathogenesis of various neurological diseases such as Alzheimer’s disease. In this study, we found that in lipopolysaccharide (LPS)-stimulated microglia, the endoplasmic reticulum (ER) stress-related eIF-2α–ATF4 pathway plays significant roles in TNF-α [...] Read more.

Microglia maintain brain homeostasis and modulate neuroinflammation and are implicated in the pathogenesis of various neurological diseases such as Alzheimer’s disease. In this study, we found that in lipopolysaccharide (LPS)-stimulated microglia, the endoplasmic reticulum (ER) stress-related eIF-2α–ATF4 pathway plays significant roles in TNF-α and IL-6 production, as well as in the inflammasome-mediated production of IL-1β. Furthermore, our analysis revealed that oxytocin (OT), a nonapeptide synthesized in the hypothalamus, suppressed the production of these proinflammatory cytokines by inhibiting activation of the eIF-2α–ATF4 pathway. Our findings therefore suggest a novel anti-inflammatory axis of OT in activated microglia, which would be helpful for developing the novel effective strategies for regulating microglia-associated neuroinflammation. Full article

(This article belongs to the Special Issue Microglia in Neurodegenerative Diseases)

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Review

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19 pages, 1343 KiB

Open AccessReview

Alzheimer’s Disease Research Using Human Microglia

by Lih-Fen Lue, Thomas G. Beach and Douglas G. Walker

Cells 2019, 8(8), 838; https://doi.org/10.3390/cells8080838 - 5 Aug 2019

Cited by 19 | Viewed by 8350

Abstract

Experimental studies of neuroinflammation in Alzheimer’s disease (AD) have mostly investigated microglia, the brain-resident macrophages. This review focused on human microglia obtained at rapid autopsies. Studies employing methods to isolate and culture human brain microglia in high purity for experimental studies were discussed. [...] Read more.

Experimental studies of neuroinflammation in Alzheimer’s disease (AD) have mostly investigated microglia, the brain-resident macrophages. This review focused on human microglia obtained at rapid autopsies. Studies employing methods to isolate and culture human brain microglia in high purity for experimental studies were discussed. These methods were employed to isolate human microglia for investigation of a number of features of neuroinflammation, including activation phenotypes, neurotoxicity, responses to abnormal aggregated proteins such as amyloid beta, phagocytosis, and the effects of aging and disease on microglia cellular properties. In recent years, interest in human microglia and neuroinflammation has been renewed due to the identification of inflammation-related AD genetic risk factors, in particular the triggering receptor expressed on myeloid cells (TREM)-2. Because of the difficulties in developing effective treatments for AD, there has been a general need for greater understanding of the functions of microglia in normal and AD brains. While most experimental studies on neuroinflammation have employed rodent microglia, this review considered the role of human microglia in experimental studies. This review focused on the development of in vitro methodology for the culture of postmortem human microglia and the key findings obtained from experimental studies with these cells. Full article

(This article belongs to the Special Issue Microglia in Neurodegenerative Diseases)

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17 pages, 372 KiB

Open AccessFeature PaperReview

Physical Exercise Inhibits Inflammation and Microglial Activation

by Onanong Mee-inta, Zi-Wei Zhao and Yu-Min Kuo

Cells 2019, 8(7), 691; https://doi.org/10.3390/cells8070691 - 9 Jul 2019

Cited by 162 | Viewed by 13837

Abstract

Accumulating evidence indicates that exercise can enhance brain function and attenuate neurodegeneration. Besides improving neuroplasticity by altering the synaptic structure and function in various brain regions, exercise also modulates multiple systems that are known to regulate neuroinflammation and glial activation. Activated microglia and [...] Read more.

Accumulating evidence indicates that exercise can enhance brain function and attenuate neurodegeneration. Besides improving neuroplasticity by altering the synaptic structure and function in various brain regions, exercise also modulates multiple systems that are known to regulate neuroinflammation and glial activation. Activated microglia and several pro-inflammatory cytokines play active roles in the pathogenesis of neurodegenerative diseases, such as Alzheimer’s disease and Parkinson’s disease. The purpose of this review is to highlight the impacts of exercise on microglial activation. Possible mechanisms involved in exercise-modulated microglial activation are also discussed. Undoubtedly, more studies are needed in order to disclose the detailed mechanisms, but this approach offers therapeutic potential for improving the brain health of millions of aging people where pharmacological intervention has failed. Full article

(This article belongs to the Special Issue Microglia in Neurodegenerative Diseases)

21 pages, 3884 KiB

Open AccessReview

Molecular Mechanisms of Microglial Motility: Changes in Ageing and Alzheimer’s Disease

by Diana K. Franco-Bocanegra, Ciaran McAuley, James A. R. Nicoll and Delphine Boche

Cells 2019, 8(6), 639; https://doi.org/10.3390/cells8060639 - 25 Jun 2019

Cited by 85 | Viewed by 11913

Abstract

Microglia are the tissue-resident immune cells of the central nervous system, where they constitute the first line of defense against any pathogens or injury. Microglia are highly motile cells and in order to carry out their function, they constantly undergo changes in their [...] Read more.

Microglia are the tissue-resident immune cells of the central nervous system, where they constitute the first line of defense against any pathogens or injury. Microglia are highly motile cells and in order to carry out their function, they constantly undergo changes in their morphology to adapt to their environment. The microglial motility and morphological versatility are the result of a complex molecular machinery, mainly composed of mechanisms of organization of the actin cytoskeleton, coupled with a “sensory” system of membrane receptors that allow the cells to perceive changes in their microenvironment and modulate their responses. Evidence points to microglia as accountable for some of the changes observed in the brain during ageing, and microglia have a role in the development of neurodegenerative diseases, such as Alzheimer’s disease. The present review describes in detail the main mechanisms driving microglial motility in physiological conditions, namely, the cytoskeletal actin dynamics, with emphasis in proteins highly expressed in microglia, and the role of chemotactic membrane proteins, such as the fractalkine and purinergic receptors. The review further delves into the changes occurring to the involved proteins and pathways specifically during ageing and in Alzheimer’s disease, analyzing how these changes might participate in the development of this disease. Full article

(This article belongs to the Special Issue Microglia in Neurodegenerative Diseases)

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25 pages, 1142 KiB

Open AccessReview

Microglial Progranulin: Involvement in Alzheimer’s Disease and Neurodegenerative Diseases

by Anarmaa Mendsaikhan, Ikuo Tooyama and Douglas G. Walker

Cells 2019, 8(3), 230; https://doi.org/10.3390/cells8030230 - 11 Mar 2019

Cited by 52 | Viewed by 11691

Abstract

Neurodegenerative diseases such as Alzheimer’s disease have proven resistant to new treatments. The complexity of neurodegenerative disease mechanisms can be highlighted by accumulating evidence for a role for a growth factor, progranulin (PGRN). PGRN is a glycoprotein encoded by the GRN/Grn gene with [...] Read more.

Neurodegenerative diseases such as Alzheimer’s disease have proven resistant to new treatments. The complexity of neurodegenerative disease mechanisms can be highlighted by accumulating evidence for a role for a growth factor, progranulin (PGRN). PGRN is a glycoprotein encoded by the GRN/Grn gene with multiple cellular functions, including neurotrophic, anti-inflammatory and lysosome regulatory properties. Mutations in the GRN gene can lead to frontotemporal lobar degeneration (FTLD), a cause of dementia, and neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease. Both diseases are associated with loss of PGRN function resulting, amongst other features, in enhanced microglial neuroinflammation and lysosomal dysfunction. PGRN has also been implicated in Alzheimer’s disease (AD). Unlike FTLD, increased expression of PGRN occurs in brains of human AD cases and AD model mice, particularly in activated microglia. How microglial PGRN might be involved in AD and other neurodegenerative diseases will be discussed. A unifying feature of PGRN in diseases might be its modulation of lysosomal function in neurons and microglia. Many experimental models have focused on consequences of PGRN gene deletion: however, possible outcomes of increasing PGRN on microglial inflammation and neurodegeneration will be discussed. We will also suggest directions for future studies on PGRN and microglia in relation to neurodegenerative diseases. Full article

(This article belongs to the Special Issue Microglia in Neurodegenerative Diseases)

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