Gene expression correlates of neurofibrillary tangles in Alzheimer's disease

Travis Dunckley, Thomas G. Beach, Keri E. Ramsey, Andrew Grover, Diego Mastroeni, Douglas G. Walker, Bonnie J. LaFleur, Keith D. Coon, Kevin M. Brown, Richard Caselli, Walter Kukull, Roger Higdon, Daniel McKeel, John C. Morris, Christine Hulette, Donald Schmechel, Eric M. Reiman, Joseph Rogers, Dietrich A. Stephan

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1359-1371
Number of pages13
JournalNeurobiology of Aging
Volume27
Issue number10
DOIs
StatePublished - Oct 2006

Keywords

  • Alzheimer's disease
  • Dementia
  • Gene expression
  • Laser capture microdissection
  • Microarray
  • NFT
  • Neurodegeneration
  • Neurofibrillary tangles

ASJC Scopus subject areas

  • Neuroscience(all)
  • Aging
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

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    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. (2006). Gene expression correlates of neurofibrillary tangles in Alzheimer's disease. Neurobiology of Aging, 27(10), 1359-1371. https://doi.org/10.1016/j.neurobiolaging.2005.08.013