A Genome-wide Gene-Expression Analysis and Database in Transgenic Mice during Development of Amyloid or Tau Pathology
Open accessAbstract
We provide microarray data comparing genome-wide differential expression and pathology throughout life in four lines of "amyloid" transgenic mice (mutant human APP, PSEN1, or APP/PSEN1) and "TAU" transgenic mice (mutant human MAPT gene). Microarray data were validated by qPCR and by comparison to human studies, including genome-wide association study (GWAS) hits. Immune gene expression correlated tightly with plaques whereas synaptic genes correlated negatively with neurofibrillary tangles. Network analysis of immune gene modules revealed six hub genes in hippocampus of amyloid mice, four in common with cortex. The hippocampal network in TAU mice was similar except that Trem2 had hub status only in amyloid mice. The cortical network of TAU mice was entirely different with more hub genes and few in common with the other networks, suggesting reasons for specificity of cortical dysfunction in FTDP17. This Resource opens up many areas for investigation. All data are available and searchable at http://www.mouseac.org.
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PLCG2 mRNA upregulation has been reported in transgenic mice carrying early-AD mutations or overexpressing human tau.
“and in transgenic mice carrying mutations associated with early AD (APP KM670/671 NL, PNSEN1 M146V) or overexpressing the human tau-4R/2N isoform (P301L) [34, 35].”
From Alzheimer’s disease phospholipase C-gamma-2 (PLCG2) protective variant is a functional hypermorph (2019) · cites this paper as [35]
The Introduction (p. 2) identifies the APP, PSEN1, and tau P301L mouse lines, and the Genome-wide Expression Analysis (p. 3) reports gene-expression changes in these models. However, searches for PLCG2 upregulation and phospholipase C gamma 2 found no passage in our copy reporting that gene's expression, so the specific claim cannot be verified. (LLM, conf=0.72)
Experimental — accuracy not yet measuredTranscriptome data for mouse models of amyloid-beta deposition and Tau hyperphosphorylation were obtained from MOUSEAC.
“We obtained transcriptome data for mouse models of amyloid-beta deposition and Tau hyperphosphorylation from MOUSEAC (55).”
From Single-nucleus transcriptome analysis reveals dysregulation of angiogenic endothelial cells and neuroprotective glia in Alzheimer’s disease (2020) · cites this paper as [55]
The H3K9Ac histone mark is found near active transcription start sites and enhancers.
“The H3K9Ac histone mark is found near active transcription start sites and enhancers24”
From A molecular network of the aging human brain provides insights into the pathology and cognitive decline of Alzheimer’s disease (2018) · cites this paper as [24]
Several immune-related Alzheimer disease risk variants are differentially expressed in models of amyloid deposition compared with tauopathy, suggesting they may be amyloid response genes.
“Of note, many of these immune-related AD risk factor SNPs or coding variants (Apoe, Trem2, Cd33, Ms4a6d) have been identified as genes differentially expressed in models of Aβ deposition as compared to tauopathy, suggesting they may represent amyloid response genes (Matarin et al., 2015).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Matarin et al., 2015
Trem2 expression showed a strong correlation with expression of a network of innate immune genes, suggesting Trem2 is a hub gene and may regulate the entire network.
“Trem2 expression also showed a strong correlation with the expression of a network of genes in the innate immune system suggesting Trem2 is a ‘hub’ gene, and may regulate the expression of the entire network.”
From Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk (2019) · cites this paper as Matarin et al., 2015
The immune module of genes showed a remarkable positive correlation to amyloid deposition and contained orthologues of established Alzheimer's disease risk genes such as Abca7 and Ms4a6d.
“This immune module of genes showed a remarkable positive correlation to amyloid deposition (Matarin et al., 2015), and contained orthologues of other already established Alzheimer’s disease risk genes such as Abca7 and Ms4a6d (Lambert et al., 2013).”
From Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk (2019) · cites this paper as Matarin et al., 2015
In previous microarray analysis, Trem2 was one of the genes whose expression was up-regulated the most in relation to amyloid deposition.
“We noted that Trem2 was one of the genes whose expression was up-regulated the most in relation to amyloid deposition.”
From Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk (2019) · cites this paper as Matarin et al., 2015
TREM2 expression is strongly increased by amyloid deposition in APP transgenic mice.
“and identified that its expression was strongly increased by amyloid deposition in APP transgenic mice (Guerreiro et al., 2013; Matarin et al., 2015; Cheng-Hathaway et al., 2018; Song et al., 2018).”
From Genetic variability in response to amyloid beta deposition influences Alzheimer’s disease risk (2019) · cites this paper as Matarin et al., 2015
IL-4 treatment significantly up-regulates expression of C1qa, Cd68 and Igf1.
“Expression of C1qa, Cd68 and Igf1 were all found to be significantly up-regulated with IL-4 treatment, which is similar to what we saw in transgenic mice in correlation with amyloid plaque load (43,44) (www.mouseac.org).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [43]
When genes that show substantial changes in transgenic mice associated with AD were tested, a number of aspects of gene expression were mimicked by anti-inflammatory IL-4 stimulation, particularly increased expression of genes associated with the neurodegenerative signature, including Igf1, Itgax, Clec7a and Arg1.
“Interestingly, when we tested expression of genes that show substantial changes in transgenic mice associated with AD (43,44) a number of aspects of gene expression were mimicked by anti-inflammatory IL-4 stimulation, particularly the increased expression of genes associated with the neurodegenerative signature, including Igf1, Itgax, Clec7a and Arg1 (58,59,61,84,86).”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [43]
The very strong microglial response to plaque deposition previously reported in transgenic mouse models of AD, particularly the up to 9-fold increase in Trem2 expression, preferentially involves engagement of anti-inflammatory pathways.
“This suggests that the very strong microglial response to plaque deposition that we have previously reported in transgenic mouse models of AD (43,44), particularly the up to 9-fold increase in Trem2 expression, preferentially involves engagement of anti-inflammatory pathways”
From <i>Trem2</i> promotes anti-inflammatory responses in microglia and is suppressed under pro-inflammatory conditions (2020) · cites this paper as [43]
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References 34 · Cited by 290
- Authors
- Matarin, M., Salih, D. A., Yasvoina, M., Cummings, D. M., Guelfi, S., Liu, W., Nahaboo Solim, M. A., Moens, T. G., Paublete, R. M., Ali, S. S., Perona, M., Desai, R., Smith, K. J., Latcham, J., Fulleylove, M., Richardson, J. C., Hardy, J., & Edwards, F. A.
- Affiliations
- University College London (GB)
- UCL Queen Square Institute of Neurology (GB)
- National Hospital for Neurology and Neurosurgery (GB)
- GlaxoSmithKline (United Kingdom) (GB)
- Corresponding author
- Hardy, John
- Edwards, Frances A.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2015-02
- Volume
- 10
- Issue
- 4
- Pages
- 633-644
- ISSN
- 2211-1247 (ISSN-L)
- OpenAlex
- W2061953902
- Cited by
- 290
- References
- 34
- Citations by year
- 2026: 8 · 2025: 21 · 2024: 21 · 2023: 28 · 2022: 28 · 2021: 41 · 2020: 28 · 2019: 34 · 2018: 34 · 2017: 22 · 2016: 19 · 2015: 5 · 2013: 1
- FWCI
- 19.64
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- UCL Discovery (University College London) (submittedVersion)
- CONICET Digital (CONICET) (submittedVersion, cc-by-nc-nd)
- Funders
- Parkinson's UK (G-0907)
- Medical Research Council (MR/J011851/1)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- tau transgenic mice, APP mutations, PSEN1 mutations, MAPT mutations, Alzheimer's disease, amyloid plaques, neurofibrillary tangles, gene expression profiling, immune gene expression, synaptic gene expression, hub genes, hippocampus, cortex, TREM2, FTDP-17, gene co-expression network
- MeSH terms
- Animals, Brain, Dementia, Gene Expression Regulation, Humans, Mice, Transgenic, tau Proteins, Mice, Genome-Wide Association Study, Plaque, Amyloid
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