Disease-associated astrocytes in Alzheimer’s disease and aging

Habib, Naomi; McCabe, Cristin; Medina, Sedi; Varshavsky, Miriam; Kitsberg, Daniel; Dvir-Szternfeld, Raz; Green, Gilad; Dionne, Danielle; Nguyễn, Lan; Marshall, Jamie L.; Chen, Fei; Zhang, Feng; Kaplan, Tommy; Regev, Aviv; Schwartz, Michal

doi:10.1038/s41593-020-0624-8

Cited by 659 publications

(729 citation statements)

References 38 publications

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“…Single-cell transcriptomics has emerged as a scalable technology enabling an unprecedented view of cell types and cell states in the mammalian brain. To date, only a few published studies have applied this approach to any neurodegenerative disease [18][19][20][21][22] . Here, we analyzed the nuclear transcriptomes of 4,524 striatal cells from a genetically precise knock-in mouse model of a juvenile-onset HD mutation, Htt Q175/+ .…”

Section: Introductionmentioning

confidence: 99%

Single-nucleus RNA-seq reveals dysregulation of striatal cell identity due to Huntington’s disease mutations

Malaiya

Cortes-Gutierrez

Herb

et al. 2020

Preprint

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ABSTRACTHuntington’s disease (HD) is a dominantly inherited neurodegenerative disorder caused by a trinucleotide expansion in exon 1 of the huntingtin (Htt) gene. Cell death in HD occurs primarily in striatal medium spiny neurons (MSNs), but the involvement of specific MSN subtypes and of other striatal cell types remains poorly understood. To gain insight into cell type-specific disease processes, we studied the nuclear transcriptomes of 4,524 cells from the striatum of a genetically precise knock-in mouse model of the HD mutation, HttQ175/+, and from wildtype controls. We used 14-15-month-old mice, a time point roughly equivalent to an early stage of symptomatic human disease. Cell type distributions indicated selective loss of D2 MSNs and increased microglia in aged HttQ175/+ mice. Thousands of differentially expressed genes were distributed across most striatal cell types, including transcriptional changes in glial populations that are not apparent from RNA-seq of bulk tissue. Reconstruction of cell typespecific transcriptional networks revealed a striking pattern of bidirectional dysregulation for many cell type-specific genes. Typically, these genes were repressed in their primary cell type, yet de-repressed in other striatal cell types. Integration with existing epigenomic and transcriptomic data suggest that partial loss-of-function of the Polycomb Repressive Complex 2 (PRC2) may underlie many of these transcriptional changes, leading to deficits in the maintenance of cell identity across virtually all cell types in the adult striatum.

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Section: Introductionmentioning

confidence: 99%

Single-nucleus RNA-seq reveals dysregulation of striatal cell identity due to Huntington’s disease mutations

Malaiya

Cortes-Gutierrez

Herb

et al. 2020

Preprint

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“…Moreover, a specific population of pro-inflammatory "disease-associated astrocytes" has recently been detected in the context of both brain aging and AD [14], and we note that the most significantly upregulated genes in these disease-associated astrocytes (e.g., GFAP, ApoE, Cst3, etc.) are also significantly upregulated by the Aβ/cytokine cocktail used in our experiments.…”

Section: Discussionmentioning

confidence: 57%

Amyloid beta acts synergistically as a pro-inflammatory cytokine

LaRocca

Cavalier

Roberts

et al. 2020

Preprint

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SUMMARYThe amyloid beta (Aβ) peptide is believed to play a central role in Alzheimer’s disease (AD), the most common age-related neurodegenerative disorder. However, the natural, evolutionarily-selected functions of Aβ are incompletely understood. Here, we report that nanomolar concentrations of Aβ act synergistically with known cytokines to promote pro-inflammatory activation in primary human astrocytes (a cell type increasingly implicated in brain aging and AD). Using transcriptomics (RNA-seq), we show that Aβ can directly substitute for the complement component C1q in a cytokine cocktail previously shown to induce astrocyte immune activation. Furthermore, we show that astrocytes synergistically activated by Aβ have a transcriptional signature similar to neurotoxic “A1” astrocytes known to accumulate with age and in AD. Interestingly, we find that this biological action of Aβ at low concentrations is distinct from the transcriptome changes induced by the high/supraphysiological doses of Aβ often used in in vitro studies. Collectively, our results suggest an important, cytokine-like function for Aβ and a novel mechanism by which it may directly contribute to the neuroinflammation associated with brain aging and AD.

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“…91 Recent omics advances especially on single-cell or single-nucleus RNA-sequencing have also shed light on a major role of immune cells (microglia and astrocytes) in AD. [92][93][94] Recent studies indicate a significant role for the brain-gut-microbiota axis in neuroinflammation in AD. [96][97][98] Bacteria populating the gut microbiome excrete substantial lipopolysaccharides (LPSs) and amyloids.…”

Section: Neuroinflammationmentioning

confidence: 99%

Harnessing endophenotypes and network medicine for Alzheimer's drug repurposing

Fang

Pieper

Nussinov

et al. 2020

Medicinal Research Reviews

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Following two decades of more than 400 clinical trials centered on the "one drug, one target, one disease" paradigm, there is still no effective disease-modifying therapy for Alzheimer's disease (AD). The inherent complexity of AD may challenge this reductionist strategy. Recent observations and advances in network medicine further indicate that AD likely shares common underlying mechanisms and intermediate pathophenotypes, or endophenotypes, with other diseases. In this review, we consider AD pathobiology, disease comorbidity, pleiotropy, and therapeutic development, and construct relevant endophenotype networks to guide future therapeutic development. Specifically, we discuss six main endophenotype hypotheses in AD: amyloidosis, tauopathy, neuroinflammation, mitochondrial dysfunction, vascular dysfunction, and lysosomal dysfunction. We further consider how

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Disease-associated astrocytes in Alzheimer’s disease and aging

Cited by 659 publications

References 38 publications

Single-nucleus RNA-seq reveals dysregulation of striatal cell identity due to Huntington’s disease mutations

Single-nucleus RNA-seq reveals dysregulation of striatal cell identity due to Huntington’s disease mutations

Amyloid beta acts synergistically as a pro-inflammatory cytokine

Harnessing endophenotypes and network medicine for Alzheimer's drug repurposing

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