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Diverse human astrocyte and microglial transcriptional responses to Alzheimer's pathology.
Acta Neuropathol. 2022 01; 143(1):75-91.AN

Abstract

To better define roles that astrocytes and microglia play in Alzheimer's disease (AD), we used single-nuclei RNA-sequencing to comprehensively characterise transcriptomes in astrocyte and microglia nuclei selectively enriched during isolation post-mortem from neuropathologically defined AD and control brains with a range of amyloid-beta and phospho-tau (pTau) pathology. Significant differences in glial gene expression (including AD risk genes expressed in both the astrocytes [CLU, MEF2C, IQCK] and microglia [APOE, MS4A6A, PILRA]) were correlated with tissue amyloid or pTau expression. The differentially expressed genes were distinct between with the two cell types and pathologies, although common (but cell-type specific) gene sets were enriched with both pathologies in each cell type. Astrocytes showed enrichment for proteostatic, inflammatory and metal ion homeostasis pathways. Pathways for phagocytosis, inflammation and proteostasis were enriched in microglia and perivascular macrophages with greater tissue amyloid, but IL1-related pathway enrichment was found specifically in association with pTau. We also found distinguishable sub-clusters in the astrocytes and microglia characterised by transcriptional signatures related to either homeostatic functions or disease pathology. Gene co-expression analyses revealed potential functional associations of soluble biomarkers of AD in astrocytes (CLU) and microglia (GPNMB). Our work highlights responses of both astrocytes and microglia for pathological protein clearance and inflammation, as well as glial transcriptional diversity in AD.

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Authors+Show Affiliations

Smith AM
UK Dementia Research Institute, Imperial College London, London, UK. E515, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, DuCane Road, London, WC12 0NN, UK.
Davey K
UK Dementia Research Institute, Imperial College London, London, UK. E515, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, DuCane Road, London, WC12 0NN, UK.
Tsartsalis S
E515, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, DuCane Road, London, WC12 0NN, UK. Department of Psychiatry, University of Geneva, Geneva, Switzerland.
Khozoie C
E515, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, DuCane Road, London, WC12 0NN, UK.
Fancy N
UK Dementia Research Institute, Imperial College London, London, UK. E515, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, DuCane Road, London, WC12 0NN, UK.
Tang SS
E515, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, DuCane Road, London, WC12 0NN, UK.
Liaptsi E
E515, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, DuCane Road, London, WC12 0NN, UK.
Weinert M
E515, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, DuCane Road, London, WC12 0NN, UK.
McGarry A
UK Dementia Research Institute, Imperial College London, London, UK. E515, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, DuCane Road, London, WC12 0NN, UK.
Muirhead RCJ
UK Dementia Research Institute, Imperial College London, London, UK. E515, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, DuCane Road, London, WC12 0NN, UK.
Gentleman S
E515, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, DuCane Road, London, WC12 0NN, UK.
Owen DR
E515, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, DuCane Road, London, WC12 0NN, UK.
Matthews PM
UK Dementia Research Institute, Imperial College London, London, UK. p.matthews@imperial.ac.uk. E515, Department of Brain Sciences, Imperial College London, Hammersmith Hospital, DuCane Road, London, WC12 0NN, UK. p.matthews@imperial.ac.uk.

MeSH

AgedAged, 80 and overAlzheimer DiseaseAstrocytesBrainFemaleHumansMaleMicrogliaTranscriptome

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34767070

Citation

Smith, Amy M., et al. "Diverse Human Astrocyte and Microglial Transcriptional Responses to Alzheimer's Pathology." Acta Neuropathologica, vol. 143, no. 1, 2022, pp. 75-91.
Smith AM, Davey K, Tsartsalis S, et al. Diverse human astrocyte and microglial transcriptional responses to Alzheimer's pathology. Acta Neuropathol. 2022;143(1):75-91.
Smith, A. M., Davey, K., Tsartsalis, S., Khozoie, C., Fancy, N., Tang, S. S., Liaptsi, E., Weinert, M., McGarry, A., Muirhead, R. C. J., Gentleman, S., Owen, D. R., & Matthews, P. M. (2022). Diverse human astrocyte and microglial transcriptional responses to Alzheimer's pathology. Acta Neuropathologica, 143(1), 75-91. https://doi.org/10.1007/s00401-021-02372-6
Smith AM, et al. Diverse Human Astrocyte and Microglial Transcriptional Responses to Alzheimer's Pathology. Acta Neuropathol. 2022;143(1):75-91. PubMed PMID: 34767070.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Diverse human astrocyte and microglial transcriptional responses to Alzheimer's pathology. AU - Smith,Amy M, AU - Davey,Karen, AU - Tsartsalis,Stergios, AU - Khozoie,Combiz, AU - Fancy,Nurun, AU - Tang,See Swee, AU - Liaptsi,Eirini, AU - Weinert,Maria, AU - McGarry,Aisling, AU - Muirhead,Robert C J, AU - Gentleman,Steve, AU - Owen,David R, AU - Matthews,Paul M, Y1 - 2021/11/12/ PY - 2021/06/22/received PY - 2021/09/13/accepted PY - 2021/08/26/revised PY - 2021/11/13/pubmed PY - 2022/3/8/medline PY - 2021/11/12/entrez KW - Alzheimer’s disease KW - Amyloid-beta KW - Astrocytes KW - Microglia KW - Tau KW - snRNA sequencing SP - 75 EP - 91 JF - Acta neuropathologica JO - Acta Neuropathol VL - 143 IS - 1 N2 - To better define roles that astrocytes and microglia play in Alzheimer's disease (AD), we used single-nuclei RNA-sequencing to comprehensively characterise transcriptomes in astrocyte and microglia nuclei selectively enriched during isolation post-mortem from neuropathologically defined AD and control brains with a range of amyloid-beta and phospho-tau (pTau) pathology. Significant differences in glial gene expression (including AD risk genes expressed in both the astrocytes [CLU, MEF2C, IQCK] and microglia [APOE, MS4A6A, PILRA]) were correlated with tissue amyloid or pTau expression. The differentially expressed genes were distinct between with the two cell types and pathologies, although common (but cell-type specific) gene sets were enriched with both pathologies in each cell type. Astrocytes showed enrichment for proteostatic, inflammatory and metal ion homeostasis pathways. Pathways for phagocytosis, inflammation and proteostasis were enriched in microglia and perivascular macrophages with greater tissue amyloid, but IL1-related pathway enrichment was found specifically in association with pTau. We also found distinguishable sub-clusters in the astrocytes and microglia characterised by transcriptional signatures related to either homeostatic functions or disease pathology. Gene co-expression analyses revealed potential functional associations of soluble biomarkers of AD in astrocytes (CLU) and microglia (GPNMB). Our work highlights responses of both astrocytes and microglia for pathological protein clearance and inflammation, as well as glial transcriptional diversity in AD. SN - 1432-0533 UR - https://www.unboundmedicine.com/medline/citation/34767070/Diverse_human_astrocyte_and_microglial_transcriptional_responses_to_Alzheimer's_pathology_ DB - PRIME DP - Unbound Medicine ER -