Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease

Serrano-Pozo, Alberto; Li, Zhaozhi; Woodbury, Maya E.; Muñoz-Castro, Clara; Wachter, Astrid; Jayakumar, Rojashree; Bryant, Annie; Noori, Ayush; Welikovitch, Lindsay A.; Hu, Miwei; Zhao, Karen; Liao, Fan; Lin, Gen; Pastika, Timothy; Tamm, Joseph A.; Abdourahman, Aicha; Kwon, Taekyung; Bennett, Rachel E.; Talanian, Robert V.; Biber, Knut; Karran, Eric; Hyman, Bradley T.; Das, Sudeshna

doi:10.1101/2022.12.03.518999

Cited by 6 publications

(6 citation statements)

References 49 publications

(69 reference statements)

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“…A similar conclusion was reached in a comprehensive study by Serrano-Pozo et al ( 2022 ), who analyzed five brain regions consecutively affected during AD progression. The authors identified two reactive astrocyte clusters characterized by a reactive signature.…”

Section: Alzheimer's Diseasesupporting

confidence: 81%

Reactive astrogliosis in the era of single-cell transcriptomics

Matusova

Hol

Pekny

et al. 2023

Front. Cell. Neurosci.

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Reactive astrogliosis is a reaction of astrocytes to disturbed homeostasis in the central nervous system (CNS), accompanied by changes in astrocyte numbers, morphology, and function. Reactive astrocytes are important in the onset and progression of many neuropathologies, such as neurotrauma, stroke, and neurodegenerative diseases. Single-cell transcriptomics has revealed remarkable heterogeneity of reactive astrocytes, indicating their multifaceted functions in a whole spectrum of neuropathologies, with important temporal and spatial resolution, both in the brain and in the spinal cord. Interestingly, transcriptomic signatures of reactive astrocytes partially overlap between neurological diseases, suggesting shared and unique gene expression patterns in response to individual neuropathologies. In the era of single-cell transcriptomics, the number of new datasets steeply increases, and they often benefit from comparisons and integration with previously published work. Here, we provide an overview of reactive astrocyte populations defined by single-cell or single-nucleus transcriptomics across multiple neuropathologies, attempting to facilitate the search for relevant reference points and to improve the interpretability of new datasets containing cells with signatures of reactive astrocytes.

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Section: Alzheimer's Diseasesupporting

confidence: 81%

Reactive astrogliosis in the era of single-cell transcriptomics

Matusova

Hol

Pekny

et al. 2023

Front. Cell. Neurosci.

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“…3 D ). Of note, nonendothelial cell types collected are concurrently being analyzed in separate studies ( Serrano-Pozo et al, 2022 ; Alzheimer DataLENS, 2023 ).…”

Section: Resultsmentioning

confidence: 99%

Endothelial Cells Are Heterogeneous in Different Brain Regions and Are Dramatically Altered in Alzheimer's Disease

Bryant

Jayakumar

et al. 2023

J. Neurosci.

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Vascular endothelial cells play an important role in maintaining brain health, but their contribution to Alzheimer’s disease (AD) is obscured by limited understanding of the cellular heterogeneity in normal aged brain and in disease. To address this, we performed single nucleus RNAseq on tissue from 32 human AD and non-AD donors (19 female, 13 male) each with five cortical regions: entorhinal cortex, inferior temporal gyrus, prefrontal cortex, visual association cortex and primary visual cortex. Analysis of 51,586 endothelial cells revealed unique gene expression patterns across the five regions in non-AD donors. Alzheimer’s brain endothelial cells were characterized by upregulated protein folding genes and distinct transcriptomic differences in response to amyloid beta plaques and cerebral amyloid angiopathy (CAA). This dataset demonstrates previously unrecognized regional heterogeneity in the endothelial cell transcriptome in both aged non-AD and AD brain.SIGNIFICANCE STATEMENT:In this work, we show that vascular endothelial cells collected from five different brain regions display surprising variability in gene expression. In the presence of Alzheimer's disease pathology, endothelial cell gene expression is dramatically altered with clear differences in regional and temporal changes. These findings help explain why certain brain regions appear to differ in susceptibility to disease-related vascular remodeling events that may impact blood flow.

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“…While here, we focused on brain myeloid cells, our parent study included snRNA-seq of all brain cell types. We found that microglia are relatively uniform across the neocortex, whereas astrocytes and endothelial cells have brain region-specific signatures [ 6 , 46 ]. Astrocytes develop an apparent decreased activation (“burnt out”) phenotype in end-stage disease [ 46 ], whereas we see no evidence of an analogous state for microglia.…”

Section: Discussionmentioning

confidence: 99%

Landscape of brain myeloid cell transcriptome along the spatiotemporal progression of Alzheimer’s disease reveals distinct sequential responses to Aβ and tau

Wachter,

Woodbury,

Lombardo

et al. 2024

Acta Neuropathol

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Human microglia are critically involved in Alzheimer’s disease (AD) progression, as shown by genetic and molecular studies. However, their role in tau pathology progression in human brain has not been well described. Here, we characterized 32 human donors along progression of AD pathology, both in time—from early to late pathology—and in space—from entorhinal cortex (EC), inferior temporal gyrus (ITG), prefrontal cortex (PFC) to visual cortex (V2 and V1)—with biochemistry, immunohistochemistry, and single nuclei-RNA-sequencing, profiling a total of 337,512 brain myeloid cells, including microglia. While the majority of microglia are similar across brain regions, we identified a specific subset unique to EC which may contribute to the early tau pathology present in this region. We calculated conversion of microglia subtypes to diseased states and compared conversion patterns to those from AD animal models. Targeting genes implicated in this conversion, or their upstream/downstream pathways, could halt gene programs initiated by early tau progression. We used expression patterns of early tau progression to identify genes whose expression is reversed along spreading of spatial tau pathology (EC > ITG > PFC > V2 > V1) and identified their potential involvement in microglia subtype conversion to a diseased state. This study provides a data resource that builds on our knowledge of myeloid cell contribution to AD by defining the heterogeneity of microglia and brain macrophages during both temporal and regional pathology aspects of AD progression at an unprecedented resolution.

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Astrocyte transcriptomic changes along the spatiotemporal progression of Alzheimer’s disease

Cited by 6 publications

References 49 publications

Reactive astrogliosis in the era of single-cell transcriptomics

Reactive astrogliosis in the era of single-cell transcriptomics

Endothelial Cells Are Heterogeneous in Different Brain Regions and Are Dramatically Altered in Alzheimer's Disease

Landscape of brain myeloid cell transcriptome along the spatiotemporal progression of Alzheimer’s disease reveals distinct sequential responses to Aβ and tau

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