Gene expression correlates of neurofibrillary tangles in Alzheimer's disease
Open accessAbstract
Neurofibrillary tangles (NFT) constitute one of the cardinal histopathological features of Alzheimer's disease (AD). To explore in vivo molecular processes involved in the development of NFTs, we compared gene expression profiles of NFT-bearing entorhinal cortex neurons from 19 AD patients, adjacent non-NFT-bearing entorhinal cortex neurons from the same patients, and non-NFT-bearing entorhinal cortex neurons from 14 non-demented, histopathologically normal controls (ND). Of the differentially expressed genes, 225 showed progressively increased expression (AD NFT neurons > AD non-NFT neurons > ND non-NFT neurons) or progressively decreased expression (AD NFT neurons < AD non-NFT neurons < ND non-NFT neurons), raising the possibility that they may be related to the early stages of NFT formation. Immunohistochemical studies confirmed that many of the implicated proteins are dysregulated and preferentially localized to NFTs, including apolipoprotein J, interleukin-1 receptor-associated kinase 1, tissue inhibitor of metalloproteinase 3, and casein kinase 2, beta. Functional validation studies are underway to determine which candidate genes may be causally related to NFT neuropathology, thus providing therapeutic targets for the treatment of AD.
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Re-analysis of transcriptional data from AD brain tissue showed that neurons with high tau were enriched for signatures of DNA damage and senescence.
“This dataset was later re‐analyzed to show that neurons with high levels of tau were enriched for signatures of DNA damage and senescence (Dunckley et al, 2006; Musi et al, 2018).”
From Mechanisms of DNA damage-mediated neurotoxicity in neurodegenerative disease (2022) · cites this paper as Dunckley et al, 2006
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- Authors
- Dunckley, T., Beach, T. G., Ramsey, K. E., Grover, A., Mastroeni, D., Walker, D. G., LaFleur, B. J., Coon, K. D., Brown, K. M., Caselli, R., Kukull, W., Higdon, R., McKeel, D., Morris, J. C., Hulette, C., Schmechel, D., Reiman, E. M., Rogers, J., & Stephan, D. A.
- Affiliations
- Translational Genomics Research Institute (US)
- Vanderbilt University (US)
- Mayo Clinic (US)
- National Alzheimer's Coordinating Center (US)
- Duke University (US)
- Corresponding author
- Stephan, Dietrich A.
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2006-10
- Volume
- 27
- Issue
- 10
- Pages
- 1359-1371
- ISSN
- 0197-4580 (ISSN-L)
- PMC
- PMC2259291
- OpenAlex
- W2005889734
- Cited by
- 177
- References
- 35
- Citations by year
- 2026: 2 · 2025: 8 · 2024: 8 · 2023: 14 · 2022: 11 · 2021: 10 · 2020: 15 · 2019: 10 · 2018: 10 · 2017: 5 · 2016: 9 · 2015: 12 · 2014: 10 · 2013: 9 · 2012: 9
- FWCI
- 3.60
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (1k01ag024079-01a2)
- National Institute on Aging (P30-AG-19610, AG05 128, R01AG023193, 1-RO1-AG023193, U01AG016976, K01-AG-024079, P50AG005128, P 50 AG05681, P50AG005681, P30AG019610, P01 AG0 3991, P01AG003991)
- 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
- neurofibrillary tangles, Alzheimer's disease, gene expression profiling, differentially expressed genes, clusterin, TIMP-3, casein kinase 2, therapeutic target
- MeSH terms
- Aged, 80 and over, Female, Humans, Male, Nerve Tissue Proteins, Gene Expression, Neurofibrillary Tangles, Entorhinal Cortex, Gene Expression Profiling
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