Article, 2024

Early amyloid‐induced changes in microglia gene expression in male APP/PS1 mice

Journal of Neuroscience Research, ISSN 0360-4012, 1097-4547, Volume 102, 3, Page e25295, 10.1002/jnr.25295

Contributors

Oshima, Takuya 0000-0002-1430-4211 [1] [2] Kater, Mandy S J 0000-0003-4832-2597 [3] Huffels, Christiaan F M 0000-0002-9070-3644 [4] Wesseling, Evelyn M [1] [2] Middeldorp, Jinte 0000-0002-9198-8020 [4] [5] Hol, Elly M 0000-0001-5604-2603 [4] Verheijen, Mark H G 0000-0002-3739-3755 [3] Smit, August Benjamin [3] Boddeke, Erik W G M 0000-0002-5058-9648 [1] [2] [6] Eggen, Bart J L 0000-0001-8941-0353 (Corresponding author) [1] [2]

Affiliations

  1. [1] University Medical Center Groningen
    2. [NORA names: Netherlands; Europe, EU; OECD];
  2. [2] University of Groningen
    3. [NORA names: Netherlands; Europe, EU; OECD];
  3. [3] Amsterdam Neuroscience
    4. [NORA names: Netherlands; Europe, EU; OECD];
  4. [4] Utrecht University
    5. [NORA names: Netherlands; Europe, EU; OECD];
  5. [5] Biomedical Primate Research Centre
    6. [NORA names: Netherlands; Europe, EU; OECD];

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia, characterized by deposition of extracellular amyloid-beta (Aβ) aggregates and intraneuronal hyperphosphorylated Tau. Many AD risk genes, identified in genome-wide association studies (GWAS), are expressed in microglia, the innate immune cells of the central nervous system. Specific subtypes of microglia emerged in relation to AD pathology, such as disease-associated microglia (DAMs), which increased in number with age in amyloid mouse models and in human AD cases. However, the initial transcriptional changes in these microglia in response to amyloid are still unknown. Here, to determine early changes in microglia gene expression, hippocampal microglia from male APPswe/PS1dE9 (APP/PS1) mice and wild-type littermates were isolated and analyzed by RNA sequencing (RNA-seq). By bulk RNA-seq, transcriptomic changes were detected in hippocampal microglia from 6-months-old APP/PS1 mice. By performing single-cell RNA-seq of CD11c-positive and negative microglia from 6-months-old APP/PS1 mice and analysis of the transcriptional trajectory from homeostatic to CD11c-positive microglia, we identified a set of genes that potentially reflect the initial response of microglia to Aβ.

Keywords

AD cases, AD pathology, AD risk genes, APP/PS1, APP/PS1 mice, APPswe/PS1dE9, Abs, Alzheimer, Alzheimer's disease, CD11c-positive, CD11c-positive microglia, RNA, RNA sequencing, RNA-seq, age, aggregation, amyloid, amyloid mouse model, amyloid-beta, analysis, association studies, cases, cause, cause of dementia, cells, central nervous system, changes, dementia, deposition, deposition of extracellular amyloid-beta, disease, disease-associated microglia, expression, extracellular amyloid-beta, gene expression, genes, genome-wide association studies, hippocampal microglia, human AD cases, immune cells, innate immune cells, littermates, male, male APP/PS1 mice, male APPswe/PS1dE9, mice, microglia, microglia gene expression, model, mouse model, nervous system, neurodegenerative diseases, pathology, progressive neurodegenerative disease, response, response of microglia, response to amyloid, risk genes, sequence, single-cell RNA-seq, study, subtypes, subtypes of microglia, system, tau, trajectory, transcriptional changes, transcriptional trajectories, transcriptomic changes, wild-type littermates

Funders

  • Netherlands Organisation for Health Research and Development

Data Provider: Digital Science

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