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Microglia in Aging and Neurodegenerative Diseases
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Microglia in Aging and Neurodegenerative Diseases

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cellular Aging".

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Editor

Dr. Alessandro Tozzi

E-Mail Website
Collection Editor
Department of Experimental Medicine, Section of Physiology and Biochemistry, University of Perugia, Perugia, Italy
Interests: neuroscience

Topical Collection Information

Dear Colleagues,

It is now well accepted that the immune system and the central nervous system (CNS) dynamically interact in both physiological and pathological conditions and that neuroinflammation and immune molecules have the potential to influence the induction of CNS plasticity, learning, cognition and recovery processes.

During brain aging or in certain pathological conditions, this crosstalk can go beyond physiological control. The inflammatory process in the brain, accompanied by the presence of activated microglia, has recently gained much attention in several degenerative neurological diseases, including, but not limited to, Alzheimer’s and Parkinson’s diseases. While activated microglia may promote neuronal degeneration or neuroprotection, its precise role has not been clarified yet.

In this Topical Collection of Cells, I invite you to contribute, either in the form of original research articles, reviews, or shorter perspective articles on all aspects of the theme “Microglia in Aging and Neurodegenerative Diseases”. Expert articles describing mechanistic, functional, cellular, biochemical, or general aspects of microglial contribution in normal brain aging or neurodegeneration are highly welcome. Relevant topics include, but are not limited to

  • Cytokine signaling
  • Chemokine function
  • In vitro and in vivo models
  • Morphological characterizations
  • Electrophysiological changes
  • Inflammation
  • Bioimaging
  • Behavioral analysis
  • Translational medicine

Dr. Alessandro Tozzi
Collection Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the collection website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Cytokine
  • Chemokine
  • Morphology
  • Electrophysiology
  • Inflammation
  • Behavior
  • Neuroprotection
  • Neurodegeneration
  • Parkinson’s disease
  • Multiple sclerosis
  • Stroke
  • Synaptic plasticity
  • Learning

Published Papers (12 papers)

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2022

Jump to: 2021

23 pages, 790 KiB  
Review
Recent Advances in Microglia Modelling to Address Translational Outcomes in Neurodegenerative Diseases
by Carla Cuní-López, Romal Stewart, Hazel Quek and Anthony R. White
Cells 2022, 11(10), 1662; https://doi.org/10.3390/cells11101662 - 17 May 2022
Cited by 5 | Viewed by 3722
Abstract
Neurodegenerative diseases are deteriorating conditions of the nervous system that are rapidly increasing in the ageing population. Increasing evidence suggests that neuroinflammation, largely mediated by microglia, the resident immune cells of the brain, contributes to the onset and progression of neurodegenerative diseases. Hence, [...] Read more.
Neurodegenerative diseases are deteriorating conditions of the nervous system that are rapidly increasing in the ageing population. Increasing evidence suggests that neuroinflammation, largely mediated by microglia, the resident immune cells of the brain, contributes to the onset and progression of neurodegenerative diseases. Hence, microglia are considered a major therapeutic target that could potentially yield effective disease-modifying treatments for neurodegenerative diseases. Despite the interest in studying microglia as drug targets, the availability of cost-effective, flexible, and patient-specific microglia cellular models is limited. Importantly, the current model systems do not accurately recapitulate important pathological features or disease processes, leading to the failure of many therapeutic drugs. Here, we review the key roles of microglia in neurodegenerative diseases and provide an update on the current microglial plaforms utilised in neurodegenerative diseases, with a focus on human microglia-like cells derived from peripheral blood mononuclear cells as well as human-induced pluripotent stem cells. The described microglial platforms can serve as tools for investigating disease biomarkers and improving the clinical translatability of the drug development process in neurodegenerative diseases. Full article
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2021

Jump to: 2022

20 pages, 38920 KiB  
Article
Differential Stimulation of Pluripotent Stem Cell-Derived Human Microglia Leads to Exosomal Proteomic Changes Affecting Neurons
by Anna Mallach, Johan Gobom, Charles Arber, Thomas M. Piers, John Hardy, Selina Wray, Henrik Zetterberg and Jennifer Pocock
Cells 2021, 10(11), 2866; https://doi.org/10.3390/cells10112866 - 24 Oct 2021
Cited by 4 | Viewed by 2975
Abstract
Microglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of triggering receptor expressed on myeloid cells-2 (TREM2) are associated with an increased risk of developing dementia. We investigated the influence of the TREM2 [...] Read more.
Microglial exosomes are an emerging communication pathway, implicated in fulfilling homeostatic microglial functions and transmitting neurodegenerative signals. Gene variants of triggering receptor expressed on myeloid cells-2 (TREM2) are associated with an increased risk of developing dementia. We investigated the influence of the TREM2 Alzheimer’s disease risk variant, R47Hhet, on the microglial exosomal proteome consisting of 3019 proteins secreted from human iPS-derived microglia (iPS-Mg). Exosomal protein content changed according to how the iPS-Mg were stimulated. Thus lipopolysaccharide (LPS) induced microglial exosomes to contain more inflammatory signals, whilst stimulation with the TREM2 ligand phosphatidylserine (PS+) increased metabolic signals within the microglial exosomes. We tested the effect of these exosomes on neurons and found that the exosomal protein changes were functionally relevant and influenced downstream functions in both neurons and microglia. Exosomes from R47Hhet iPS-Mg contained disease-associated microglial (DAM) signature proteins and were less able to promote the outgrowth of neuronal processes and increase mitochondrial metabolism in neurons compared with exosomes from the common TREM2 variant iPS-Mg. Taken together, these data highlight the importance of microglial exosomes in fulfilling microglial functions. Additionally, variations in the exosomal proteome influenced by the R47Hhet TREM2 variant may underlie the increased risk of Alzheimer’s disease associated with this variant. Full article
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13 pages, 32957 KiB  
Review
Beyond Activation: Characterizing Microglial Functional Phenotypes
by Julia Lier, Wolfgang J. Streit and Ingo Bechmann
Cells 2021, 10(9), 2236; https://doi.org/10.3390/cells10092236 - 28 Aug 2021
Cited by 71 | Viewed by 9997
Abstract
Classically, the following three morphological states of microglia have been defined: ramified, amoeboid and phagocytic. While ramified cells were long regarded as “resting”, amoeboid and phagocytic microglia were viewed as “activated”. In aged human brains, a fourth, morphologically novel state has been described, [...] Read more.
Classically, the following three morphological states of microglia have been defined: ramified, amoeboid and phagocytic. While ramified cells were long regarded as “resting”, amoeboid and phagocytic microglia were viewed as “activated”. In aged human brains, a fourth, morphologically novel state has been described, i.e., dystrophic microglia, which are thought to be senescent cells. Since microglia are not replenished by blood-borne mononuclear cells under physiological circumstances, they seem to have an “expiration date” limiting their capacity to phagocytose and support neurons. Identifying factors that drive microglial aging may thus be helpful to delay the onset of neurodegenerative diseases, such as Alzheimer’s disease (AD). Recent progress in single-cell deep sequencing methods allowed for more refined differentiation and revealed regional-, age- and sex-dependent differences of the microglial population, and a growing number of studies demonstrate various expression profiles defining microglial subpopulations. Given the heterogeneity of pathologic states in the central nervous system, the need for accurately describing microglial morphology and expression patterns becomes increasingly important. Here, we review commonly used microglial markers and their fluctuations in expression in health and disease, with a focus on IBA1 low/negative microglia, which can be found in individuals with liver disease. Full article
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12 pages, 1394 KiB  
Article
Neuroinflammation and Alzheimer’s Disease: A Machine Learning Approach to CSF Proteomics
by Lorenzo Gaetani, Giovanni Bellomo, Lucilla Parnetti, Kaj Blennow, Henrik Zetterberg and Massimiliano Di Filippo
Cells 2021, 10(8), 1930; https://doi.org/10.3390/cells10081930 - 29 Jul 2021
Cited by 31 | Viewed by 5140
Abstract
In Alzheimer’s disease (AD), the contribution of pathophysiological mechanisms other than amyloidosis and tauopathy is now widely recognized, although not clearly quantifiable by means of fluid biomarkers. We aimed to identify quantifiable protein biomarkers reflecting neuroinflammation in AD using multiplex proximity extension assay [...] Read more.
In Alzheimer’s disease (AD), the contribution of pathophysiological mechanisms other than amyloidosis and tauopathy is now widely recognized, although not clearly quantifiable by means of fluid biomarkers. We aimed to identify quantifiable protein biomarkers reflecting neuroinflammation in AD using multiplex proximity extension assay (PEA) testing. Cerebrospinal fluid (CSF) samples from patients with mild cognitive impairment due to AD (AD-MCI) and from controls, i.e., patients with other neurological diseases (OND), were analyzed with the Olink Inflammation PEA biomarker panel. A machine-learning approach was then used to identify biomarkers discriminating AD-MCI (n: 34) from OND (n: 25). On univariate analysis, SIRT2, HGF, MMP-10, and CXCL5 showed high discriminatory performance (AUC 0.809, p = 5.2 × 10−4, AUC 0.802, p = 6.4 × 10−4, AUC 0.793, p = 3.2 × 10−3, AUC 0.761, p = 2.3 × 10−3, respectively), with higher CSF levels in AD-MCI patients as compared to controls. These same proteins were the best contributors to the penalized logistic regression model discriminating AD-MCI from controls (AUC of the model 0.906, p = 2.97 × 10−7). The biological processes regulated by these proteins include astrocyte and microglia activation, amyloid, and tau misfolding modulation, and blood-brain barrier dysfunction. Using a high-throughput multiplex CSF analysis coupled with a machine-learning statistical approach, we identified novel biomarkers reflecting neuroinflammation in AD. Studies confirming these results by means of different assays are needed to validate PEA as a multiplex technique for CSF analysis and biomarker discovery in the field of neurological diseases. Full article
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17 pages, 429 KiB  
Review
The Influence of Virus Infection on Microglia and Accelerated Brain Aging
by Luis Filgueira, Alexey Larionov and Nils Lannes
Cells 2021, 10(7), 1836; https://doi.org/10.3390/cells10071836 - 20 Jul 2021
Cited by 22 | Viewed by 4760
Abstract
Microglia are the resident immune cells of the central nervous system contributing substantially to health and disease. There is increasing evidence that inflammatory microglia may induce or accelerate brain aging, by interfering with physiological repair and remodeling processes. Many viral infections affect the [...] Read more.
Microglia are the resident immune cells of the central nervous system contributing substantially to health and disease. There is increasing evidence that inflammatory microglia may induce or accelerate brain aging, by interfering with physiological repair and remodeling processes. Many viral infections affect the brain and interfere with microglia functions, including human immune deficiency virus, flaviviruses, SARS-CoV-2, influenza, and human herpes viruses. Especially chronic viral infections causing low-grade neuroinflammation may contribute to brain aging. This review elucidates the potential role of various neurotropic viruses in microglia-driven neurocognitive deficiencies and possibly accelerated brain aging. Full article
34 pages, 1306 KiB  
Review
The Impact of Obesity on Microglial Function: Immune, Metabolic and Endocrine Perspectives
by Vasileia Ismini Alexaki
Cells 2021, 10(7), 1584; https://doi.org/10.3390/cells10071584 - 23 Jun 2021
Cited by 29 | Viewed by 4422
Abstract
Increased life expectancy in combination with modern life style and high prevalence of obesity are important risk factors for development of neurodegenerative diseases. Neuroinflammation is a feature of neurodegenerative diseases, and microglia, the innate immune cells of the brain, are central players in [...] Read more.
Increased life expectancy in combination with modern life style and high prevalence of obesity are important risk factors for development of neurodegenerative diseases. Neuroinflammation is a feature of neurodegenerative diseases, and microglia, the innate immune cells of the brain, are central players in it. The present review discusses the effects of obesity, chronic peripheral inflammation and obesity-associated metabolic and endocrine perturbations, including insulin resistance, dyslipidemia and increased glucocorticoid levels, on microglial function. Full article
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20 pages, 11059 KiB  
Review
Neuroinflammation: Integrated Nervous Tissue Response through Intercellular Interactions at the “Whole System” Scale
by Daniele Nosi, Daniele Lana, Maria Grazia Giovannini, Giovanni Delfino and Sandra Zecchi-Orlandini
Cells 2021, 10(5), 1195; https://doi.org/10.3390/cells10051195 - 13 May 2021
Cited by 18 | Viewed by 2729
Abstract
Different cell populations in the nervous tissue establish numerous, heterotypic interactions and perform specific, frequently intersecting activities devoted to the maintenance of homeostasis. Microglia and astrocytes, respectively the immune and the “housekeeper” cells of nervous tissue, play a key role in neurodegenerative diseases. [...] Read more.
Different cell populations in the nervous tissue establish numerous, heterotypic interactions and perform specific, frequently intersecting activities devoted to the maintenance of homeostasis. Microglia and astrocytes, respectively the immune and the “housekeeper” cells of nervous tissue, play a key role in neurodegenerative diseases. Alterations of tissue homeostasis trigger neuroinflammation, a collective dynamic response of glial cells. Reactive astrocytes and microglia express various functional phenotypes, ranging from anti-inflammatory to pro-inflammatory. Chronic neuroinflammation is characterized by a gradual shift of astroglial and microglial phenotypes from anti-inflammatory to pro-inflammatory, switching their activities from cytoprotective to cytotoxic. In this scenario, the different cell populations reciprocally modulate their phenotypes through intense, reverberating signaling. Current evidence suggests that heterotypic interactions are links in an intricate network of mutual influences and interdependencies connecting all cell types in the nervous system. In this view, activation, modulation, as well as outcomes of neuroinflammation, should be ascribed to the nervous tissue as a whole. While the need remains of identifying further links in this network, a step back to rethink our view of neuroinflammation in the light of the “whole system” scale, could help us to understand some of its most controversial and puzzling features. Full article
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18 pages, 1248 KiB  
Review
Microglial Adenosine Receptors: From Preconditioning to Modulating the M1/M2 Balance in Activated Cells
by Rafael Franco, Alejandro Lillo, Rafael Rivas-Santisteban, Irene Reyes-Resina and Gemma Navarro
Cells 2021, 10(5), 1124; https://doi.org/10.3390/cells10051124 - 07 May 2021
Cited by 22 | Viewed by 3911
Abstract
Neuronal survival depends on the glia, that is, on the astroglial and microglial support. Neurons die and microglia are activated not only in neurodegenerative diseases but also in physiological aging. Activated microglia, once considered harmful, express two main phenotypes: the pro-inflammatory or M1, [...] Read more.
Neuronal survival depends on the glia, that is, on the astroglial and microglial support. Neurons die and microglia are activated not only in neurodegenerative diseases but also in physiological aging. Activated microglia, once considered harmful, express two main phenotypes: the pro-inflammatory or M1, and the neuroprotective or M2. When neuroinflammation, i.e., microglial activation occurs, it is important to achieve a good M1/M2 balance, i.e., at some point M1 microglia must be skewed into M2 cells to impede chronic inflammation and to afford neuronal survival. G protein-coupled receptors in general and adenosine receptors in particular are potential targets for increasing the number of M2 cells. This article describes the mechanisms underlying microglial activation and analyzes whether these cells exposed to a first damaging event may be ready to be preconditioned to better react to exposure to more damaging events. Adenosine receptors are relevant due to their participation in preconditioning. They can also be overexpressed in activated microglial cells. The potential of adenosine receptors and complexes formed by adenosine receptors and cannabinoids as therapeutic targets to provide microglia-mediated neuroprotection is here discussed. Full article
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28 pages, 2683 KiB  
Review
Microglial Function and Regulation during Development, Homeostasis and Alzheimer’s Disease
by Brad T. Casali and Erin G. Reed-Geaghan
Cells 2021, 10(4), 957; https://doi.org/10.3390/cells10040957 - 20 Apr 2021
Cited by 25 | Viewed by 5566
Abstract
Microglia are the resident immune cells of the brain, deriving from yolk sac progenitors that populate the brain parenchyma during development. During development and homeostasis, microglia play critical roles in synaptogenesis and synaptic plasticity, in addition to their primary role as immune sentinels. [...] Read more.
Microglia are the resident immune cells of the brain, deriving from yolk sac progenitors that populate the brain parenchyma during development. During development and homeostasis, microglia play critical roles in synaptogenesis and synaptic plasticity, in addition to their primary role as immune sentinels. In aging and neurodegenerative diseases generally, and Alzheimer’s disease (AD) specifically, microglial function is altered in ways that significantly diverge from their homeostatic state, inducing a more detrimental inflammatory environment. In this review, we discuss the receptors, signaling, regulation and gene expression patterns of microglia that mediate their phenotype and function contributing to the inflammatory milieu of the AD brain, as well as strategies that target microglia to ameliorate the onset, progression and symptoms of AD. Full article
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22 pages, 8027 KiB  
Article
Aging and Microglial Response following Systemic Stimulation with Escherichia coli in Mice
by Inge C.M. Hoogland, Dunja Westhoff, Joo-Yeon Engelen-Lee, Mercedes Valls Seron, Judith H.M.P. Houben-Weerts, David J. van Westerloo, Tom van der Poll, Willem A. van Gool and Diederik van de Beek
Cells 2021, 10(2), 279; https://doi.org/10.3390/cells10020279 - 30 Jan 2021
Cited by 5 | Viewed by 2972
Abstract
Systemic infection is an important risk factor for the development cognitive impairment and neurodegeneration in older people. Animal experiments show that systemic challenges with live bacteria cause a neuro-inflammatory response, but the effect of age on this response in these models is unknown. [...] Read more.
Systemic infection is an important risk factor for the development cognitive impairment and neurodegeneration in older people. Animal experiments show that systemic challenges with live bacteria cause a neuro-inflammatory response, but the effect of age on this response in these models is unknown. Young (2 months) and middle-aged mice (13–14 months) were intraperitoneally challenged with live Escherichia coli (E. coli) or saline. The mice were sacrificed at 2, 3 and 7 days after inoculation; for all time points, the mice were treated with ceftriaxone (an antimicrobial drug) at 12 and 24 h after inoculation. Microglial response was monitored by immunohistochemical staining with an ionized calcium-binding adaptor molecule 1 (Iba-1) antibody and flow cytometry, and inflammatory response by mRNA expression of pro- and anti-inflammatory mediators. We observed an increased microglial cell number and moderate morphologically activated microglial cells in middle-aged mice, as compared to young mice, after intraperitoneal challenge with live E. coli. Flow cytometry of microglial cells showed higher CD45 and CD11b expressions in middle-aged infected mice compared to young infected mice. The brain expression levels of pro-inflammatory genes were higher in middle-aged than in young infected mice, while middle-aged infected mice had similar expression levels of these genes in the systemic compartment. We conclude that systemic challenge with live bacteria causes an age-dependent neuro-inflammatory and microglial response. Our data show signs of an age-dependent disconnection of the inflammatory transcriptional signature between the brain and the systemic compartment. Full article
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17 pages, 2112 KiB  
Article
Lipoprotein Lipase Regulates Microglial Lipid Droplet Accumulation
by Bailey A. Loving, Maoping Tang, Mikaela C. Neal, Sachi Gorkhali, Robert Murphy, Robert H. Eckel and Kimberley D. Bruce
Cells 2021, 10(2), 198; https://doi.org/10.3390/cells10020198 - 20 Jan 2021
Cited by 31 | Viewed by 5786
Abstract
Microglia become increasingly dysfunctional with aging and contribute to the onset of neurodegenerative disease (NDs) through defective phagocytosis, attenuated cholesterol efflux, and excessive secretion of pro-inflammatory cytokines. Dysfunctional microglia also accumulate lipid droplets (LDs); however, the mechanism underlying increased LD load is unknown. [...] Read more.
Microglia become increasingly dysfunctional with aging and contribute to the onset of neurodegenerative disease (NDs) through defective phagocytosis, attenuated cholesterol efflux, and excessive secretion of pro-inflammatory cytokines. Dysfunctional microglia also accumulate lipid droplets (LDs); however, the mechanism underlying increased LD load is unknown. We have previously shown that microglia lacking lipoprotein lipase (LPL KD) are polarized to a pro-inflammatory state and have impaired lipid uptake and reduced fatty acid oxidation (FAO). Here, we also show that LPL KD microglia show excessive accumulation of LD-like structures. Moreover, LPL KD microglia display a pro-inflammatory lipidomic profile, increased cholesterol ester (CE) content, and reduced cholesterol efflux at baseline. We also show reduced expression of genes within the canonical cholesterol efflux pathway. Importantly, PPAR agonists (rosiglitazone and bezafibrate) rescued the LD-associated phenotype in LPL KD microglia. These data suggest that microglial-LPL is associated with lipid uptake, which may drive PPAR signaling and cholesterol efflux to prevent inflammatory lipid distribution and LD accumulation. Moreover, PPAR agonists can reverse LD accumulation, and therefore may be beneficial in aging and in the treatment of NDs. Full article
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17 pages, 1519 KiB  
Review
Microglial Turnover in Ageing-Related Neurodegeneration: Therapeutic Avenue to Intervene in Disease Progression
by Shofiul Azam, Md. Ezazul Haque, In-Su Kim and Dong-Kug Choi
Cells 2021, 10(1), 150; https://doi.org/10.3390/cells10010150 - 14 Jan 2021
Cited by 22 | Viewed by 4665
Abstract
Microglia are brain-dwelling macrophages and major parts of the neuroimmune system that broadly contribute to brain development, homeostasis, ageing and injury repair in the central nervous system (CNS). Apart from other brain macrophages, they have the ability to constantly sense changes in the [...] Read more.
Microglia are brain-dwelling macrophages and major parts of the neuroimmune system that broadly contribute to brain development, homeostasis, ageing and injury repair in the central nervous system (CNS). Apart from other brain macrophages, they have the ability to constantly sense changes in the brain’s microenvironment, functioning as housekeepers for neuronal well-being and providing neuroprotection in normal physiology. Microglia use a set of genes for these functions that involve proinflammatory cytokines. In response to specific stimuli, they release these proinflammatory cytokines, which can damage and kill neurons via neuroinflammation. However, alterations in microglial functioning are a common pathophysiology in age-related neurodegenerative diseases, such as Alzheimer’s, Parkinson’s, Huntington’s and prion diseases, as well as amyotrophic lateral sclerosis, frontotemporal dementia and chronic traumatic encephalopathy. When their sentinel or housekeeping functions are severely disrupted, they aggravate neuropathological conditions by overstimulating their defensive function and through neuroinflammation. Several pathways are involved in microglial functioning, including the Trem2, Cx3cr1 and progranulin pathways, which keep the microglial inflammatory response under control and promote clearance of injurious stimuli. Over time, an imbalance in this system leads to protective microglia becoming detrimental, initiating or exacerbating neurodegeneration. Correcting such imbalances might be a potential mode of therapeutic intervention in neurodegenerative diseases. Full article
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