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Microglial immunophenotype in dementia with Alzheimer's pathology

Published on Dec 1, 2016in Journal of Neuroinflammation5.7
· DOI :10.1186/s12974-016-0601-z
Thais Minett19
Estimated H-index: 19
(University of Cambridge),
John Classey3
Estimated H-index: 3
(University of Southampton)
+ 7 AuthorsMrc Cfas10
Estimated H-index: 10
Abstract
Background Genetic risk factors for Alzheimer’s disease imply that inflammation plays a causal role in development of the disease. Experimental studies suggest that microglia, as the brain macrophages, have diverse functions, with their main role in health being to survey the brain parenchyma through highly motile processes.
  • References (37)
  • Citations (44)
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References37
Newest
#1Diego Gomez-Nicola (Southampton General Hospital)H-Index: 20
#2Delphine Boche (Southampton General Hospital)H-Index: 25
Since the genome-wide association studies in Alzheimer’s disease have highlighted inflammation as a driver of the disease rather than a consequence of the ongoing neurodegeneration, numerous studies have been performed to identify specific immune profiles associated with healthy, ageing, or diseased brain. However, these studies have been performed mainly in in vitro or animal models, which recapitulate only some aspects of the pathophysiology of human Alzheimer’s disease. In this review, we dis...
24 CitationsSource
#1Matthew J. Kan (Duke University)H-Index: 9
#2Jennifer E. Lee (Duke University)H-Index: 4
Last. Carol A. Colton (Duke University)H-Index: 47
view all 10 authors...
The pathogenesis of Alzheimer's disease (AD) is a critical unsolved question; and although recent studies have demonstrated a strong association between altered brain immune responses and disease progression, the mechanistic cause of neuronal dysfunction and death is unknown. We have previously described the unique CVN-AD mouse model of AD, in which immune-mediated nitric oxide is lowered to mimic human levels, resulting in a mouse model that demonstrates the cardinal features of AD, including a...
74 CitationsSource
#1Irene López-González (University of Barcelona)H-Index: 11
#2Agatha SchlüterH-Index: 15
Last. Isidre FerrerH-Index: 74
view all 13 authors...
To understand neuroinflammation-related gene regulation during normal aging and in sporadic Alzheimer disease (sAD), we performed functional genomics analysis and analyzed messenger RNA (mRNA) expression by quantitative reverse transcription–polymerase chain reaction of 22 genes involved in neuroinflammation-like responses in the cerebral cortex of wild-type and APP/PS1 transgenic mice. For direct comparisons, mRNA expression of 18 of the same genes was then analyzed in the entorhinal cortex, or...
64 CitationsSource
#1Michael T. Heneka (University Hospital Bonn)H-Index: 71
#2Monica J. Carson (UCR: University of California, Riverside)H-Index: 34
Last. Markus P. Kummer (University Hospital Bonn)H-Index: 32
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Summary Increasing evidence suggests that Alzheimer's disease pathogenesis is not restricted to the neuronal compartment, but includes strong interactions with immunological mechanisms in the brain. Misfolded and aggregated proteins bind to pattern recognition receptors on microglia and astroglia, and trigger an innate immune response characterised by release of inflammatory mediators, which contribute to disease progression and severity. Genome-wide analysis suggests that several genes that inc...
1,325 CitationsSource
#2Dominique BaetenH-Index: 55
Last. Jeroen den DunnenH-Index: 10
view all 4 authors...
Control of cytokine production by immune cells is pivotal for counteracting infections via orchestration of local and systemic inflammation. Although their contribution has long been underexposed, it has recently become clear that human Fc gamma receptors (FcγRs), which are receptors for the Fc region of IgG antibodies, play a critical role in this process by controlling tissue and pathogen-specific cytokine production. Whereas individual stimulation of FcγRs does not evoke cytokine production, ...
45 CitationsSource
Microglia are known to remove dead and dying neurons in the brain by phagocytosis. In this Progress article, Brown and Neher discuss recent evidence indicating that, in certain situations, microglia can instigate the death of viable neurons through phagocytosis, a process they term phagoptosis.
283 CitationsSource
#1Suzanne E. HickmanH-Index: 16
#2Nathan D. KingeryH-Index: 3
Last. Joseph El KhouryH-Index: 49
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Microglia, the principal neuroimmune sentinels of the brain, continuously sense changes in their environment and respond to invading pathogens, toxins and cellular debris. Microglia exhibit plasticity and can assume neurotoxic or neuroprotective priming states that determine their responses to danger. We used direct RNA sequencing, without amplification or cDNA synthesis, to determine the quantitative transcriptomes of microglia of healthy adult and aged mice. We validated our findings by fluore...
569 CitationsSource
#1Elina Zotova (Southampton General Hospital)H-Index: 7
#2Viraj Bharambe (Southampton General Hospital)H-Index: 1
Last. Delphine Boche (Southampton General Hospital)H-Index: 25
view all 10 authors...
Inflammatory processes are important in the pathogenesis of Alzheimer's disease and in response to amyloid-b immunotherapy. We investigated the expression of multiple inflammatory markers in the brains of 28 non-immunized patients with Alzheimer's disease and 11 patients with Alzheimer's disease immunized against amyloid-b42 (AN1792): microglial ionized calcium-binding adaptor Iba-1, lysosome marker CD68, macrophage scavenger receptor A, Fcreceptors I (CD64) and II (CD32); and also immunoglobuli...
105 CitationsSource
#1Delphine Boche (University of Southampton)H-Index: 25
#2Victor Hugh Perry (University of Southampton)H-Index: 38
Last. James A. R. Nicoll (University of Southampton)H-Index: 57
view all 3 authors...
Microglia in the central nervous system are usually maintained in a quiescent state. When activated, they can perform many diverse functions which may be either beneficial or harmful depending on the situation. Although microglial activation may be accompanied by changes in morphology, morphological changes cannot accurately predict the function being undertaken by a microglial cell. Studies of peripheral macrophages and in vitro and animal studies of microglia have resulted in the definition of...
389 CitationsSource
#1David H. Cribbs (UCI: University of California, Irvine)H-Index: 49
#2Nicole C. Berchtold (UCI: University of California, Irvine)H-Index: 25
Last. Carl W. Cotman (UCI: University of California, Irvine)H-Index: 150
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Background This study undertakes a systematic and comprehensive analysis of brain gene expression profiles of immune/inflammation-related genes in aging and Alzheimer’s disease (AD).
203 CitationsSource
Cited By44
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#1Angélica María Sabogal-Guáqueta (UMCG: University Medical Center Groningen)H-Index: 1
#2Alejandro Marmolejo-Garza (UMCG: University Medical Center Groningen)
Last. Amalia M. Dolga (UG: University of Groningen)H-Index: 19
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Microglia are the main innate immune cells of the central nervous system (CNS). Unlike neurons and glial cells, which derive from ectoderm, microglia migrate early during embryo development from the yolk-sac, a mesodermal-derived structure. Microglia regulate synaptic pruning during development and induce or modulate inflammation during aging and chronic diseases. Microglia are sensitive to brain injuries and threats, altering their phenotype and function to adopt a so-called immune-activated st...
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#1Jacob Friedberg (BU: Boston University)
#2Nurgul Aytan (BU: Boston University)H-Index: 9
Last. Gyungah Jun (BU: Boston University)H-Index: 28
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Alzheimer disease (AD) is a chronic neurodegenerative disease with a multitude of contributing genetic factors, many of which are related to inflammation. The apolipoprotein E (APOE) e4 allele is the most common genetic risk factor for AD and is related to a pro-inflammatory state. To test the hypothesis that microglia and AD-implicated cytokines were differentially associated with AD pathology based on the presence of APOE e4, we examined the dorsolateral frontal cortex from deceased participan...
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#1Songlin Li (Wenzhou University)H-Index: 2
#2Eric Y. Hayden (UCLA: University of California, Los Angeles)H-Index: 11
Last. Ueli Rutishauser (Cedars-Sinai Medical Center)
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Impaired synaptic integrity and function due to accumulation of amyloid β-protein (Aβ42) oligomers is thought to be a major contributor to cognitive decline in Alzheimer's disease (AD). However, the exact role of Aβ42 oligomers in synaptotoxicity and the ability of peripheral innate immune cells to rescue synapses remain poorly understood due to the metastable nature of oligomers. Here, we utilized photo-induced cross-linking to stabilize pure oligomers and study their effects versus fibrils on ...
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#1Carlos PomilioH-Index: 6
Last. Gustavo SevleverH-Index: 20
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Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by the presence of misfolded proteins, amyloid-β (Aβ) aggregates, and neuroinflammation in the brain. Microglial cells are key players in the context of AD, being capable of releasing cytokines in response to Aβ and degrading aggregated proteins by mechanisms involving the ubiquitin-proteasome system and autophagy. Here, we present in vivo and in vitro evidence showing that microglial autophagy is affected during ...
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Neuroinflammation is considered a key pathological process in neurodegenerative diseases of aging, including Alzheimer’s disease (AD). Many studies have defined phenotypes of reactive microglia, the brain-resident macrophages, with different antigenic markers to identify those potentially causing inflammatory damage. We took an alternative approach with the goal of characterizing the distribution of purinergic receptor P2RY12-positive microglia, a marker previously defined as identifying homeost...
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#1A. A. Lagunin (RSMU: Russian National Research Medical University)H-Index: 2
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Dementia is a major cause of disability and dependency among older people. If the lives of people with dementia are to be improved, research and its translation into druggable target are crucial. Ancient systems of healthcare (Ayurveda, Siddha, Unani and Sowa-Rigpa) have been used from centuries for the treatment vascular diseases and dementia. This traditional knowledge can be transformed into novel targets through robust interplay of network pharmacology (NetP) with reverse pharmacology (RevP)...
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Astrocytes play a major role in the pathogenesis of a range of neurodegenerative diseases, including Alzheimer’s disease (AD), undergoing dramatic morphological and molecular changes that can cause potentially both beneficial and detrimental effects. They comprise a heterogeneous population, requiring a panel of specific phenotype markers to identify astrocyte subtypes, changes in function and their relation to pathology. This study aimed to characterise expression of the astrocyte marker N-myc ...
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#1Claire Hull (Aberd.: University of Aberdeen)H-Index: 1
#2Ruta Dekeryte (Aberd.: University of Aberdeen)H-Index: 1
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Diabetes and obesity have been implicated as risk factors for dementia. However, metabolic mechanisms and associated signalling pathways have not been investigated in detail in frontotemporal dementia. We therefore here characterised physiological, behavioural and molecular phenotypes of 3- and 8-month-old male tau knock-in (PLB2TAU) vs wild-type (PLBWT) mice. Homecage analysis suggested intact habituation but a dramatic reduction in exploratory activity in PLB2TAU mice. Deficits in motor streng...
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#1Aleksandra P. Pitera (University of Southampton)
#2Iain J Hartnell (University of Southampton)
Last. Katrin Deinhardt (University of Southampton)H-Index: 21
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Tauopathies are the neurodegenerative diseases associated with the accumulation of misfolded tau protein. Despite many years of investigation, the mechanisms underpinning tau dependent proteinopathy remains to be elucidated. A protein quality control pathway within the endoplasmic reticulum (ER), called unfolded protein response (UPR), has been suggested as a possible response implicated in the misfolded tau-mediated neurodegeneration. However, the question arose: how does the cytosolic protein ...
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