scholarly journals A core transcriptional signature of human microglia: Derivation and utility in describing region‐dependent alterations associated with Alzheimer's disease

Glia ◽  
2019 ◽  
Vol 67 (7) ◽  
pp. 1240-1253 ◽  
Author(s):  
Anirudh Patir ◽  
Barbara Shih ◽  
Barry W. McColl ◽  
Tom C. Freeman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Human Microglia ◽  
Transcriptional Signature

scholarly journals A core transcriptional signature of human microglia: derivation and utility in describing region-dependent alterations associated with Alzheimer's disease

2018 ◽  
Author(s):  
Anirudh Patir ◽  
Barbarah Shih ◽  
Barry McColl ◽  
Tom Freeman
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Phenotypic Diversity ◽  
Meta Analysis ◽  
Gene Signature ◽  
Brain Regions ◽  
Core Gene ◽  
Human Microglia ◽  
Transcriptional Signature ◽  
Health And Disease

Growing recognition of the pivotal role microglia play in neurodegenerative and neuroinflammatory disorders has accentuated the need to better characterize their function in health and disease. Studies in mouse, have applied transcriptome-wide profiling of microglia to reveal key features of microglial ontogeny, functional profile and phenotypic diversity. Whilst similar in many ways, human microglia exhibit clear differences to their mouse counterparts, underlining the need to develop a better understanding of the human microglial profile. On examining published microglia gene signatures, little consistency was observed between studies. Hence, we set out to define a conserved microglia signature of the human central nervous system (CNS), through a comprehensive meta-analysis of existing transcriptomic resources. Nine datasets derived from cells and tissue, isolated from different regions of the CNS across numerous donors, were subjected independently to an unbiased correlation network analysis. From each dataset, a list of coexpressing genes corresponding to microglia was identified. Comparison of individual microglia clusters showed 249 genes highly conserved between them. This core gene signature included all known markers and improves upon published microglial signatures. The utility of this signature was demonstrated by its use in detecting qualitative and quantitative region-specific alterations in aging and Alzheimer's disease. These analyses highlighted the reactive response of microglia in vulnerable brain regions such as the entorhinal cortex and hippocampus, additionally implicating pathways associated with disease progression. We believe this resource and the analyses described here, will support further investigations in the contribution of human microglia towards the CNS in health and disease.

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

2020 ◽  
Vol 16 (S2) ◽  
Author(s):  
Marta Olah ◽  
Vilas Menon ◽  
Naomi Habib ◽  
Mariko Taga ◽  
Yiyi Ma ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Single Cell ◽  
Rna Sequencing ◽  
Human Microglia ◽  
Single Cell Rna Sequencing

scholarly journals Genetics of the human microglia regulome refines Alzheimer's disease risk loci

2021 ◽  
Author(s):  
Roman Kosoy ◽  
John Fullard ◽  
Biao Zeng ◽  
Jaroslav Bendl ◽  
Pengfei Dong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Regulatory Networks ◽  
Disease Risk ◽  
Single Gene ◽  
Critical Role ◽  
Chromatin Accessibility ◽  
Human Microglia ◽  
Mapping Analysis ◽  
Regulatory Landscape

Microglia are brain resident myeloid cells that play a critical role in neuroimmunity and the etiology of Alzheimer's Disease (AD). Yet our understanding of how the genetic regulatory landscape controls microglial function and contributes to disease is limited. Here, we performed transcriptome and chromatin accessibility profiling in primary human microglia from 150 donors to identify genetically-driven variation and cell-specific enhancer-promoter interactions. Integrative fine-mapping analysis identified putative regulatory mechanisms for 21 AD risk loci, of which 18 were refined to a single gene, including 3 novel genes (KCNN4, FIBP and LRRC25). Transcription factor regulatory networks captured AD risk variation and identified SPI1 as a key regulator of microglia expression and AD risk. This comprehensive resource capturing variation in the human microglia regulome provides novel insights into the etiology of neurodegenerative disease.

scholarly journals Plaque-associated human microglia accumulate lipid droplets in a chimeric model of Alzheimer’s disease

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Christel Claes ◽  
Emma Pascal Danhash ◽  
Jonathan Hasselmann ◽  
Jean Paul Chadarevian ◽  
Sepideh Kiani Shabestari ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Lipid Droplet ◽  
Lipid Droplets ◽  
Foam Cells ◽  
Wild Type ◽  
Human Microglia ◽  
Model Of Alzheimer’S Disease ◽  
The Impact

Abstract Background Disease-associated microglia (DAMs), that surround beta-amyloid plaques, represent a transcriptionally-distinct microglial profile in Alzheimer’s disease (AD). Activation of DAMs is dependent on triggering receptor expressed on myeloid cells 2 (TREM2) in mouse models and the AD TREM2-R47H risk variant reduces microglial activation and plaque association in human carriers. Interestingly, TREM2 has also been identified as a microglial lipid-sensor, and recent data indicates lipid droplet accumulation in aged microglia, that is in turn associated with a dysfunctional proinflammatory phenotype. However, whether lipid droplets (LDs) are present in human microglia in AD and how the R47H mutation affects this remains unknown. Methods To determine the impact of the TREM2 R47H mutation on human microglial function in vivo, we transplanted wild-type and isogenic TREM2-R47H iPSC-derived microglial progenitors into our recently developed chimeric Alzheimer mouse model. At 7 months of age scRNA-seq and histological analyses were performed. Results Here we report that the transcriptome of human wild-type TREM2 and isogenic TREM2-R47H DAM xenografted microglia (xMGs), isolated from chimeric AD mice, closely resembles that of human atherosclerotic foam cells. In addition, much like foam cells, plaque-bound xMGs are highly enriched in lipid droplets. Somewhat surprisingly and in contrast to a recent in vitro study, TREM2-R47H mutant xMGs exhibit an overall reduction in the accumulation of lipid droplets in vivo. Notably, TREM2-R47H xMGs also show overall reduced reactivity to plaques, including diminished plaque-proximity, reduced CD9 expression, and lower secretion of plaque-associated APOE. Conclusions Altogether, these results indicate lipid droplet accumulation occurs in human DAM xMGs in AD, but is reduced in TREM2-R47H DAM xMGs, as it occurs secondary to TREM2-mediated changes in plaque proximity and reactivity.

scholarly journals Replicative senescence dictates the emergence of disease-associated microglia and contributes to Aβ pathology

2021 ◽  
Author(s):  
Yanling Hu ◽  
Gemma L. Fryatt ◽  
Mohammadmersad Ghorbani ◽  
Juliane Obst ◽  
David A. Menassa ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Replicative Senescence ◽  
Post Mortem ◽  
Telomere Shortening ◽  
Transcriptional Signature ◽  
Microglial Proliferation ◽  
Long Term Impact ◽  
Repeated Cycling

ABSTRACTThe sustained proliferation of microglia is a key hallmark of Alzheimer’s disease (AD), accelerating its progression. Here, we sought to understand the long-term impact of the early and prolonged microglial proliferation observed in AD, hypothesising that extensive and repeated cycling would engender a distinct transcriptional and phenotypic trajectory. We found that the early and sustained microglial proliferation seen in an AD-like model promotes replicative senescence, characterised by increased βgal activity, a senescence-associated transcriptional signature and telomere shortening, correlating with the appearance of disease-associated microglia (DAM) and senescent microglial profiles in human post-mortem AD cases. Prevention of early microglial proliferation hindered the development of senescence and DAM, impairing the accumulation of Aβ and associated neuritic damage. Overall, our results support that excessive microglial proliferation leads to the generation of senescent DAM, which contribute to early Aβ pathology in AD.

scholarly journals Largest GWAS (N=1,126,563) of Alzheimer’s Disease Implicates Microglia and Immune Cells

2020 ◽  
Author(s):  
Douglas P Wightman ◽  
Iris E Jansen ◽  
Jeanne E. Savage ◽  
Alexey A Shadrin ◽  
Shahram Bahrami ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Genetic Variants ◽  
Late Onset ◽  
Gene Expression Pattern ◽  
Human Microglia ◽  
Age Related ◽  
Causal Genes ◽  
Meta Analyses

SummaryLate-onset Alzheimer’s disease is a prevalent age-related polygenic disease that accounts for 50-70% of dementia cases1. Late-onset Alzheimer’s disease is caused by a combination of many genetic variants with small effect sizes and environmental influences. Currently, only a fraction of the genetic variants underlying Alzheimer’s disease have been identified2,3. Here we show that increased sample sizes allowed for identification of seven novel genetic loci contributing to Alzheimer’s disease. We highlighted eight potentially causal genes where gene expression changes are likely to explain the association. Human microglia were found as the only cell type where the gene expression pattern was significantly associated with the Alzheimer’s disease association signal. Gene set analysis identified four independent pathways for associated variants to influence disease pathology. Our results support the importance of microglia, amyloid and tau aggregation, and immune response in Alzheimer’s disease. We anticipate that through collaboration the results from this study can be included in larger meta-analyses of Alzheimer’s disease to identify further genetic variants which contribute to Alzheimer’s pathology. Furthermore, the increased understanding of the mechanisms that mediate the effect of genetic variants on disease progression will help identify potential pathways and gene-sets as targets for drug development.

scholarly journals Omega-3 Fatty Acids Enhance Phagocytosis of Alzheimer's Disease-Related Amyloid-β42 by Human Microglia and Decrease Inflammatory Markers

2013 ◽  
Vol 35 (4) ◽  
pp. 697-713 ◽  
Author(s):  
Erik Hjorth ◽  
Mingqin Zhu ◽  
Veronica Cortés Toro ◽  
Inger Vedin ◽  
Jan Palmblad ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fatty Acids ◽  
Inflammatory Markers ◽  
Omega 3 Fatty Acids ◽  
Omega 3 ◽  
Human Microglia

scholarly journals A transcriptional signature of Alzheimer’s disease is associated with a metastable subproteome at risk for aggregation

2016 ◽  
Vol 113 (17) ◽  
pp. 4753-4758 ◽  
Author(s):  
Prajwal Ciryam ◽  
Rishika Kundra ◽  
Rosie Freer ◽  
Richard I. Morimoto ◽  
Christopher M. Dobson ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorder ◽  
Meta Analysis ◽  
Protein Homeostasis ◽  
Human Central Nervous System ◽  
Transcriptional Signature ◽  
Biochemical Pathways ◽  
Transcriptional Changes ◽  
Cellular Dysfunction

It is well-established that widespread transcriptional changes accompany the onset and progression of Alzheimer’s disease. Because of the multifactorial nature of this neurodegenerative disorder and its complex relationship with aging, however, it remains unclear whether such changes are the result of nonspecific dysregulation and multisystem failure or instead are part of a coordinated response to cellular dysfunction. To address this problem in a systematic manner, we performed a meta-analysis of about 1,600 microarrays from human central nervous system tissues to identify transcriptional changes upon aging and as a result of Alzheimer’s disease. Our strategy to discover a transcriptional signature of Alzheimer’s disease revealed a set of down-regulated genes that encode proteins metastable to aggregation. Using this approach, we identified a small number of biochemical pathways, notably oxidative phosphorylation, enriched in proteins vulnerable to aggregation in control brains and encoded by genes down-regulated in Alzheimer’s disease. These results suggest that the down-regulation of a metastable subproteome may help mitigate aberrant protein aggregation when protein homeostasis becomes compromised in Alzheimer’s disease.

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