Transcriptional signatures of tau and amyloid neuropathology
Open accessAbstract
Alzheimer's disease (AD) is associated with the intracellular aggregation of hyperphosphorylated tau and the accumulation of β-amyloid in the neocortex. We use transgenic mice harboring human tau (rTg4510) and amyloid precursor protein (J20) mutations to investigate transcriptional changes associated with the progression of tau and amyloid pathology. rTg4510 mice are characterized by widespread transcriptional differences in the entorhinal cortex with changes paralleling neuropathological burden across multiple brain regions. Differentially expressed transcripts overlap with genes identified in genetic studies of familial and sporadic AD. Systems-level analyses identify discrete co-expression networks associated with the progressive accumulation of tau that are enriched for genes and pathways previously implicated in AD pathology and overlap with co-expression networks identified in human AD cortex. Our data provide further evidence for an immune-response component in the accumulation of tau and reveal molecular pathways associated with the progression of AD neuropathology.
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Several studies have shown that transcriptional signatures can be used to investigate Aβ accumulation, region-specific expression of tau, and activated immune response.
“Several studies have shown that this hypothesis-generating, unbiased readout can be used to investigate Aβ accumulation (Sierksma et al., 2020), region-specific expression of tau (Castanho et al., 2020), and activated immune response (Kang et al., 2018).”
From Network analysis identifies strain-dependent response to tau and tau seeding-associated genes (2023) · cites this paper as Castanho et al., 2020
The Introduction and Results describe transcriptional changes associated with tau pathology in the entorhinal cortex and compare findings with the hippocampus. They support using transcriptional signatures to investigate tau-related changes across brain regions, but do not establish region-specific expression of tau itself. The Aβ and immune-response clauses are attributed to other citations, not Castanho et al. (LLM, conf=0.78)
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Wan, Y.-W., Al-Ouran, R., Mangleburg, C. G., Perumal, T. M., Lee, T. V., Allison, K., Swarup, V., Funk, C. C., Gaiteri, C., Allen, M., et al. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.107908 · Cited by 295 · see citing works
“These investigations have similarly highlighted the potential importance of immune or inflammatory and neuronal or synaptic changes (Boisvert et al., 2018; Castanho et al., 2020; Cummings et al., 2015; Gjoneska et al., 2015; Matarin et al., 2015; Rothman et al., 2018; Stephenson et al., 2018; Swartzlander et al., 2018…”
BackgroundSelf-citationDiverse human astrocyte and microglial transcriptional responses to Alzheimer’s pathology
Smith, A. M., Davey, K., Tsartsalis, S., Khozoie, C., Fancy, N., Tang, S. S., Liaptsi, E., Weinert, M., McGarry, A., Muirhead, R. C. J., et al. (2022) · Acta Neuropathologica · doi:10.1007/s00401-021-02372-6 · Cited by 209 · see citing works
“Our analytical approach for addressing heterogeneity in the samples also differs from most prior studies (although it is not without similar precedents [7, 41]).”
ResultChen, Y.-A., Lu, C.-H., Ke, C.-C., Chiu, S.-J., Jeng, F.-S., Chang, C.-W., Yang, B.-H., & Liu, R.-S. (2021) · Biomedicines · doi:10.3390/biomedicines9060594 · Cited by 167 · see citing works
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Tsumagari, K., Sato, Y., Shimozawa, A., Aoyagi, H., Okano, H., & Kuromitsu, J. (2022) · iScience · doi:10.1016/j.isci.2022.104832 · Cited by 15 · see citing works
Integrative network analysis reveals novel moderators of Aβ-Tau interaction in Alzheimer's disease
Kitani, A., Matsui, Y., & Initiative, F. T. A. D. N. (2025) · Alzheimer's Research & Therapy · doi:10.1186/s13195-025-01705-x · Cited by 6 · see citing works
Network analysis identifies strain-dependent response to tau and tau seeding-associated genes
Acri, D. J., You, Y., Tate, M. D., Karahan, H., Martinez, P., McCord, B., Sharify, A. D., John, S., Kim, B., Dabin, L. C., et al. (2023) · Journal of Experimental Medicine · doi:10.1084/jem.20230180 · Cited by 3 · see citing works
- Authors
- Castanho, I., Murray, T. K., Hannon, E., Jeffries, A., Walker, E., Laing, E., Baulf, H., Harvey, J., Bradshaw, L., Randall, A., Moore, K., O’Neill, P., Lunnon, K., Collier, D. A., Ahmed, Z., O’Neill, M. J., & Mill, J.
- Affiliations
- University of Exeter (GB)
- Eli Lilly (United Kingdom) (GB)
- Corresponding author
- Mill, Jonathan
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2020-02
- Volume
- 30
- Issue
- 6
- Pages
- 2040-2054.e5
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC7016505
- OpenAlex
- W3005955078
- Cited by
- 62
- References
- 16
- Citations by year
- 2026: 3 · 2025: 6 · 2024: 8 · 2023: 11 · 2022: 8 · 2021: 14 · 2020: 11 · 2019: 1
- FWCI
- 6.62
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Open Research Exeter (University of Exeter) (submittedVersion, cc-by)
- Royal Devon and Exeter Research Repository (Royal Devon and Exeter) (submittedVersion, cc-by)
- Funders
- Medical Research Council (MC_PC_14127)
- Biotechnology and Biological Sciences Research Council (BB/K003240/1)
- Alzheimer's Society
- AbbVie
- Alzheimer’s Research UK (ARUK-PG2018B-016)
- Garfield Weston Foundation (231, MR/M008924/1)
- Wellcome Trust (WT097835MF, WT101650MA)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, tau hyperphosphorylation, amyloid-beta, rTg4510 mice, entorhinal cortex, transcriptome, gene co-expression network, immune response, transgenic mouse model
- MeSH terms
- Alzheimer Disease, Animals, Disease Models, Animal, Humans, Mice, Transgenic, Amyloid beta-Peptides, tau Proteins, Disease Progression, Mice
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