Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease

Olah, Marta; Menon, Vilas; Habib, Naomi; Taga, Mariko; Ma, Yiyi; Yung, Christina J.; Cimpean, Maria; Khairallah, Anthony; Coronas‐Samano, Guillermo; Sankowski, Roman; Grün, Dominic; Kroshilina, Alexandra; Dionne, Danielle; Sarkis, Rani A.; Cosgrove, G. Rees; Helgager, Jeffrey; Golden, Jeffrey A.; Pennell, Page B.; Prinz, Marco; Vonsattel, Jean Paul; Teich, Andrew F.; Schneider, Julie A.; Bennett, David A.; Regev, Aviv; Elyaman, Wassim; Bradshaw, Elizabeth M.; Jager, Philip L. De

doi:10.1038/s41467-020-19737-2

Cited by 485 publications

(481 citation statements)

References 41 publications

(95 reference statements)

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“…This subpopulation also co‐expressed APOE, a marker for neurodegenerative microglia 27 and low amounts of genes associated with antigen‐presentation and phagocytosis, consistent with the minor demyelinating activity in chronic active lesions. A microglia study in Alzheimer’s disease demonstrated a similar FTH1‐ expressing microglia phenotype 28 …”

Section: Discussionmentioning

confidence: 97%

QSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions

Gillen

Mubarak

Park

et al. 2021

Ann Clin Transl Neurol

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Background Inflammation in chronic active lesions occurs behind a closed blood–brain barrier and cannot be detected with MRI. Activated microglia are highly enriched for iron and can be visualized with quantitative susceptibility mapping (QSM), an MRI technique used to delineate iron. Objective To characterize the histopathological correlates of different QSM hyperintensity patterns in MS lesions. Methods MS brain slabs were imaged with MRI and QSM, and processed for histology. Immunolabeled cells were quantified in the lesion rim, center, and adjacent normal‐appearing white matter (NAWM). Iron+ myeloid cell densities at the rims were correlated with susceptibilities. Human‐induced pluripotent stem cell (iPSC)‐derived microglia were used to determine the effect of iron on the production of reactive oxygen species (ROS) and pro‐inflammatory cytokines. Results QSM hyperintensity at the lesion perimeter correlated with activated iron+ myeloid cells in the rim and NAWM. Lesions with high punctate or homogenous QSM signal contained no or minimally activated iron− myeloid cells. In vitro, iron accumulation was highest in M1‐polarized human iPSC‐derived microglia, but it did not enhance ROS or cytokine production. Conclusion A high QSM signal outlining the lesion rim but not punctate signal in the center is a biomarker for chronic inflammation in white matter lesions.

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Section: Discussionmentioning

confidence: 97%

QSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions

Gillen

Mubarak

Park

et al. 2021

Ann Clin Transl Neurol

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“…A single-nucleus RNA-seq included approximately 2000 microglial cells that increased the expression of the DAM genes: CD81 , APOE , SPP1 , CD74 , and HLA-DRB when compared to other microglial cells [ 78 ]. The opposing results were acquired in a recent scRNA-seq study of 11 post-mortem samples from patients with a mild cognitive impartment (MCI) and AD, and three control samples derived from the epileptic brains [ 79 ]. In line with the previous animal studies [ 72 , 77 ], the authors found that the expression of early DAM response genes increased in a proliferative cell cluster that appears predominant in the MCI/AD samples.…”

Section: Microglia In Neurological Diseases—insights From Single-cmentioning

confidence: 99%

“…In line with the previous animal studies [ 72 , 77 ], the authors found that the expression of early DAM response genes increased in a proliferative cell cluster that appears predominant in the MCI/AD samples. However, other DAM genes ( APOE , LPL , SPP1, CD74 ) were distributed across all clusters, with the highest expression in clusters enriched in cells from epilepsy-derived controls [ 79 ]. Such low consistency of the findings is surprising, but it may stem from using epilepsy-derived tissues as controls, as other studies have shown an induction of the DAM profile in epileptic subjects and a mouse model of epilepsy (see Section 3.3 ).…”

Section: Microglia In Neurological Diseases—insights From Single-cmentioning

confidence: 99%

“…Microglia isolated from the human temporal cortex resected from the vicinity of the epileptogenic focus showed increased levels of P2Y12 , IRF8 , and CD68 [ 64 ], and enrichment within the cell clusters that upregulated genes encoding cytokines ( CCL2 , CCL3 , CCL4 ), anti-inflammatory interleukins ( IL-10 , IL-4 , IL-13 ), and genes involved in antigen presentation ( CD74 , HLA - DMB ,), although a majority of microglial cells from the epileptic brain belonged to the homeostatic microglia population [ 79 ]. Thus, it might be that microglia isolated from histologically non-pathological brain tissue of epileptic brain exhibits signs of polarization.…”

Section: Microglia In Neurological Diseases—insights From Single-cmentioning

confidence: 99%

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Microglia Diversity in Healthy and Diseased Brain: Insights from Single-Cell Omics

Ochocka

Kamińska

2021

IJMS

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Microglia are the resident immune cells of the central nervous system (CNS) that have distinct ontogeny from other tissue macrophages and play a pivotal role in health and disease. Microglia rapidly react to the changes in their microenvironment. This plasticity is attributed to the ability of microglia to adapt a context-specific phenotype. Numerous gene expression profiling studies of immunosorted CNS immune cells did not permit a clear dissection of their phenotypes, particularly in diseases when peripheral cells of the immune system come to play. Only recent advances in single-cell technologies allowed studying microglia at high resolution and revealed a spectrum of discrete states both under homeostatic and pathological conditions. Single-cell technologies such as single-cell RNA sequencing (scRNA-seq) and mass cytometry (Cytometry by Time-Of-Flight, CyTOF) enabled determining entire transcriptomes or the simultaneous quantification of >30 cellular parameters of thousands of individual cells. Single-cell omics studies demonstrated the unforeseen heterogeneity of microglia and immune infiltrates in brain pathologies: neurodegenerative disorders, stroke, depression, and brain tumors. We summarize the findings from those studies and the current state of knowledge of functional diversity of microglia under physiological and pathological conditions. A precise definition of microglia functions and phenotypes may be essential to design future immune-modulating therapies.

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“…In human AD, the microglia acquire a quite distinct signature characterized by the increased expression of “homeostatic” genes along with genes that are absent in the DAM signature (Zhou et al, 2020 ). Using single-cell RNA sequencing of live microglia purified from the human cerebral cortex, researchers have found at least one subset of cortical microglia that may be related to AD (Olah et al, 2020 ). Thus, the subset of cortical microglia related to AD should be prioritized in further validation efforts.…”

Section: Co-related Pro-inflammatory Molecules Between Systemic Inflamentioning

confidence: 99%

Inflammation Spreading: Negative Spiral Linking Systemic Inflammatory Disorders and Alzheimer’s Disease

2021

Front. Cell. Neurosci.

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As a physiological response to injury in the internal body organs, inflammation is responsible for removing dangerous stimuli and initiating healing. However, persistent and exaggerative chronic inflammation causes undesirable negative effects in the organs. Inflammation occurring in the brain and spinal cord is known as neuroinflammation, with microglia acting as the central cellular player. There is increasing evidence suggesting that chronic neuroinflammation is the most relevant pathological feature of Alzheimer’s disease (AD), regulating other pathological features, such as the accumulation of amyloid-β (Aβ) and hyperphosphorylation of Tau. Systemic inflammatory signals caused by systemic disorders are known to strongly influence neuroinflammation as a consequence of microglial activation, inflammatory mediator production, and the recruitment of peripheral immune cells to the brain, resulting in neuronal dysfunction. However, the neuroinflammation-accelerated neuronal dysfunction in AD also influences the functions of peripheral organs. In the present review, we highlight the link between systemic inflammatory disorders and AD, with inflammation serving as the common explosion. We discuss the molecular mechanisms that govern the crosstalk between systemic inflammation and neuroinflammation. In our view, inflammation spreading indicates a negative spiral between systemic diseases and AD. Therefore, “dampening inflammation” through the inhibition of cathepsin (Cat)B or CatS may be a novel therapeutic approach for delaying the onset of and enacting early intervention for AD.

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Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer’s disease

Cited by 485 publications

References 41 publications

QSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions

QSM is an imaging biomarker for chronic glial activation in multiple sclerosis lesions

Microglia Diversity in Healthy and Diseased Brain: Insights from Single-Cell Omics

Inflammation Spreading: Negative Spiral Linking Systemic Inflammatory Disorders and Alzheimer’s Disease

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