Integrated biology approach reveals molecular and pathological interactions among Alzheimer’s Aβ42, Tau, TREM2, and TYROBP in Drosophila models
Open accessAbstract
BACKGROUND: Cerebral amyloidosis, neuroinflammation, and tauopathy are key features of Alzheimer's disease (AD), but interactions among these features remain poorly understood. Our previous multiscale molecular network models of AD revealed TYROBP as a key driver of an immune- and microglia-specific network that was robustly associated with AD pathophysiology. Recent genetic studies of AD further identified pathogenic mutations in both TREM2 and TYROBP. METHODS: In this study, we systematically examined molecular and pathological interactions among Aβ, tau, TREM2, and TYROBP by integrating signatures from transgenic Drosophila models of AD and transcriptome-wide gene co-expression networks from two human AD cohorts. RESULTS: Glial expression of TREM2/TYROBP exacerbated tau-mediated neurodegeneration and synergistically affected pathways underlying late-onset AD pathology, while neuronal Aβ42 and glial TREM2/TYROBP synergistically altered expression of the genes in synaptic function and immune modules in AD. CONCLUSIONS: The comprehensive pathological and molecular data generated through this study strongly validate the causal role of TREM2/TYROBP in driving molecular networks in AD and AD-related phenotypes in flies.
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Up to one-third of patients with a clinical diagnosis of AD have no accumulation of Aβ.
“For instance, up to one-third of patients with a clinical diagnosis of AD have no accumulation of Aβ (4)”
From Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets (2021) · cites this paper as [4]
The Background states that up to one-third of patients with clinically diagnosed AD have no evidence of amyloidosis on brain amyloid imaging. That supports the proportion and clinical-diagnosis qualifier, but an imaging result does not establish that they have no Aβ accumulation at all. No page number is provided in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAD is a heterogeneous disease caused by various pathophysiologic mechanisms beyond the typical dogma.
“However, an increasingly growing body of evidence has demonstrated that AD is a heterogeneous disease caused by various pathophysiologic mechanisms beyond the typical dogma.”
From Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets (2021) · cites this paper as [4]
Cognitive impairment is neither dependent on nor fully assured by high levels of Aβ and tau accumulation.
“These findings are consistent with previous studies that have shown that cognitive impairment is neither dependent on nor fully assured by high levels of Aβ and tau accumulation (4, 5).”
From Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets (2021) · cites this paper as [4]
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Neuroinflammation and microglial activation in Alzheimer disease: where do we go from here?
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“13 of 17 nor fully assured by high levels of A and tau accumulation (4, 5).”
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Additional file 1 of Integrated analysis of the aging brain transcriptome and proteome in tauopathy
Mangleburg, C. G., Wu, T., Yalamanchili, H. K., Guo, C., Hsieh, Y.-C., Duong, D. M., Dammer, E. B., Jager, P. L. D., Seyfried, N. T., Liu, Z., et al. (2020) · Figshare · doi:10.6084/m9.figshare.13024037
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- Authors
- Sekiya, M., Wang, M., Fujisaki, N., Sakakibara, Y., Quan, X., Ehrlich, M. E., De Jager, P. L., Bennett, D. A., Schadt, E. E., Gandy, S., Ando, K., Zhang, B., & Iijima, K. M.
- Affiliations
- National Center for Geriatrics and Gerontology (JP)
- Icahn School of Medicine at Mount Sinai (US)
- Nagoya City University (JP)
- Rush University Medical Center (US)
- James J. Peters VA Medical Center (US)
- Tokyo Metropolitan University (JP)
- Corresponding author
- Zhang, Bin
- Iijima, Koichi M.
- ORCID
- Venue
- Genome Medicine
- Published
- 2018-03-29
- Volume
- 10
- Issue
- 1
- Pages
- 26-26
- ISSN
- 1756-994X (ISSN-L)
- PMC
- PMC5875009
- OpenAlex
- W2795614235
- Cited by
- 38
- References
- 82
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 9 · 2023: 5 · 2022: 4 · 2021: 4 · 2020: 6 · 2019: 1 · 2018: 1
- FWCI
- 2.05
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Genome Medicine (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute on Aging (U01AG046170, U01AG46152, P30AG10161, RF1AG15819, R01AG36836, RF1AG054014, RF1AG057440, R01AG057907, U01AG052411)
- National Center for Geriatrics and Gerontology (28-26)
- Takeda Science Foundation
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurobiology and Insect Physiology Research
- Keywords
- Alzheimer's disease, amyloid-beta 42, tau protein, TREM2, TYROBP, microglia, neuroinflammation, cerebral amyloidosis, tauopathy, Drosophila model, gene co-expression network, synaptic function, neurodegeneration, glial gene expression
- MeSH terms
- Alzheimer Disease, Animals, Brain, Disease Models, Animal, Drosophila melanogaster, Female, Gene Expression Regulation, Humans, Male, Membrane Glycoproteins, Membrane Proteins, Nerve Degeneration, Neuroglia, Neurons, Receptors, Immunologic, Synapses, Signal Transduction, Amyloid beta-Peptides, tau Proteins, Drosophila Proteins, Animals, Genetically Modified, Adaptor Proteins, Signal Transducing, Gene Regulatory Networks
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
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