Iron loading is a prominent feature of activated microglia in Alzheimer’s disease patients

Kenkhuis, Boyd; Somarakis, Antonios; Haan, Lorraine de; Dzyubachyk, Oleh; Ijsselsteijn, Marieke E.; Miranda, Noel F C C de; Lelieveldt, Boudewijn P. F.; Dijkstra, Jouke; Roon‐Mom, Willeke M. C. van; Höllt, Thomas; Weerd, Louise van der

doi:10.1186/s40478-021-01126-5

Cited by 115 publications

(94 citation statements)

References 62 publications

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“…In Alzheimer's disease brains, the mRNA levels of TMEM119 were elevated, although no difference was observed in immunohistochemical analyses [28,45]. In contrast, Kenkhuis et al [47] demonstrated a microglial subset with an increased expression of the iron storage protein ferritin light chain (FTL) and IBA1, while exhibiting a decrease in TMEM119 and P2RY12 expression. This microglial subset presented a morphologically dystrophic phenotype.…”

Section: Tmem119mentioning

confidence: 95%

Beyond Activation: Characterizing Microglial Functional Phenotypes

Lier

Streit

Bechmann

2021

Cells

140

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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.

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Section: Tmem119mentioning

confidence: 95%

Beyond Activation: Characterizing Microglial Functional Phenotypes

Lier

Streit

Bechmann

2021

Cells

140

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“…Magnetic resonance imaging has been less utilized than PET to assess gliosis due to its lack of cell specificity. Of note, it was recently suggested that iron associates with microglia in AD, especially in dystrophic microglia defined as senescent or dysfunctional ( Streit et al, 2009 ), and microglia primed to phagocytose Aβ ( Kenkhuis et al, 2021 ). MRI is very sensitive to iron ( Zeineh et al, 2015 ) and therefore might be used to find brain areas with microglial populations involved in AD.…”

Section: Imaging Studiesmentioning

confidence: 99%

Microglia and Astrocyte Function and Communication: What Do We Know in Humans?

2022

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Microglia and astrocytes play essential roles in the central nervous system contributing to many functions including homeostasis, immune response, blood–brain barrier maintenance and synaptic support. Evidence has emerged from experimental models of glial communication that microglia and astrocytes influence and coordinate each other and their effects on the brain environment. However, due to the difference in glial cells between humans and rodents, it is essential to confirm the relevance of these findings in human brains. Here, we aim to review the current knowledge on microglia-astrocyte crosstalk in humans, exploring novel methodological techniques used in health and disease conditions. This will include an in-depth look at cell culture and iPSCs, post-mortem studies, imaging and fluid biomarkers, genetics and transcriptomic data. In this review, we will discuss the advantages and limitations of these methods, highlighting the understanding these methods have brought the field on these cells communicative abilities, and the knowledge gaps that remain.

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“…Through the production of these ROS, iron can induce severe brain damage [ 28 , 58 ]. Iron and ferritin are described to be associated with amyloid deposition and microglia [ 59 , 60 ]. Their levels are elevated in neuronal tissue and in the amyloid plaques [ 61 ].…”

Section: Products Of Oxidative Damage In Admentioning

confidence: 99%

Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery

et al. 2021

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Alzheimer’s disease (AD) is a neurodegenerative disorder accounting for over 50% of all dementia patients and representing a leading cause of death worldwide for the global ageing population. The lack of effective treatments for overt AD urges the discovery of biomarkers for early diagnosis, i.e., in subjects with mild cognitive impairment (MCI) or prodromal AD. The brain is exposed to oxidative stress as levels of reactive oxygen species (ROS) are increased, whereas cellular antioxidant defenses are decreased. Increased ROS levels can damage cellular structures or molecules, leading to protein, lipid, DNA, or RNA oxidation. Oxidative damage is involved in the molecular mechanisms which link the accumulation of amyloid-β and neurofibrillary tangles, containing hyperphosphorylated tau, to microglia response. In this scenario, microglia are thought to play a crucial role not only in the early events of AD pathogenesis but also in the progression of the disease. This review will focus on oxidative damage products as possible peripheral biomarkers in AD and in the preclinical phases of the disease. Particular attention will be paid to biological fluids such as blood, CSF, urine, and saliva, and potential future use of molecules contained in such body fluids for early differential diagnosis and monitoring the disease course. We will also review the role of oxidative damage and microglia in the pathogenesis of AD and, more broadly, in neurodegeneration.

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Iron loading is a prominent feature of activated microglia in Alzheimer’s disease patients

Cited by 115 publications

References 62 publications

Beyond Activation: Characterizing Microglial Functional Phenotypes

Beyond Activation: Characterizing Microglial Functional Phenotypes

Microglia and Astrocyte Function and Communication: What Do We Know in Humans?

Role of Oxidative Damage in Alzheimer’s Disease and Neurodegeneration: From Pathogenic Mechanisms to Biomarker Discovery

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