Title: Congruent gene expression in Alexander disease model mice and human Alzheimer’s disease
Legend: (A) A Rank-Rank Hypergeometric Overlap (RRHO) heatmap comparing a composite gene expression portrait of human Alzheimer’s disease (AD, X axis) with transcriptomic changes in hippocampus from Alexander disease model mice (GFAP mutation, Y axis) indicates high matching of up- and downregulated genes. (B) Congruent genes with the highest levels of protein-protein interaction determined via STRING analysis. Interactions are highlighted by connecting lines. Genes upregulated in both AD and GFAP mutant mice are shown in red and those downregulated are shown in blue. Increased font size for gene symbols reflects a higher number of connections among genes.
Citation: Gammie, S. C., Messing, A., Hill, M. A., Kelm-Nelson, C. A., & Hagemann, T. L. (2024). Large-scale gene expression changes in APP/PSEN1 and GFAP mutation models exhibit high congruence with Alzheimer’s disease. PloS one, 19(1), e0291995. https://doi.org/10.1371/journal.pone.0291995
Abstract: Alzheimer’s disease (AD) is a complex neurodegenerative disorder with both genetic and non-genetic causes. Animal research models are available for a multitude of diseases and conditions affecting the central nervous system (CNS), and large-scale CNS gene expression data exist for many of these. Although there are several models specifically for AD, each recapitulates different aspects of the human disease. In this study we evaluate over 500 animal models to identify those with CNS gene expression patterns matching human AD datasets. Approaches included a hypergeometric based scoring system that rewards congruent gene expression patterns but penalizes discordant gene expression patterns. The top two models identified were APP/PS1 transgenic mice expressing mutant APP and PSEN1, and mice carrying a GFAP mutation that is causative of Alexander disease, a primary disorder of astrocytes in the CNS. The APP/PS1 and GFAP models both matched over 500 genes moving in the same direction as in human AD, and both had elevated GFAP expression and were highly congruent with one another. Also scoring highly were the 5XFAD model (with five mutations in APP and PSEN1) and mice carrying CK-p25, APP, and MAPT mutations. Animals with the APOE3 and 4 mutations combined with traumatic brain injury ranked highly. Bulbectomized rats scored high, suggesting anosmia could be causative of AD-like gene expression. Other matching models included the SOD1G93A strain and knockouts for SNORD116 (Prader-Willi mutation), GRID2, INSM1, XBP1, and CSTB. Many top models demonstrated increased expression of GFAP, and results were similar across multiple human AD datasets. Heatmap and Uniform Manifold Approximation Plot results were consistent with hypergeometric ranking. Finally, some gene manipulation models, including for TYROBP and ATG7, were identified with reversed AD patterns, suggesting possible neuroprotective effects. This study provides insight for the pathobiology of AD and the potential utility of available animal models.
Investigator: Tracy L. Hagemann, PhD
About the Lab: The Alexander Disease Research Lab focuses on the role of astrocytes in neurodegenerative disease and the cellular consequences of their dysfunction. Astrocytes have traditionally been thought of as support cells that maintain ion and neurotransmitter homeostasis in the central nervous system (CNS). However, research over the past few decades has revealed more complex functions including the regulation of neurogenesis, synaptogenesis, neurotransmission and remyelination. In addition, astrocytes control blood flow, maintain the blood brain barrier, and contribute to the distribution and clearance of compounds through the CNS glymphatic system.