Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: Potential significance for tau protein phosphorylation

Jin G. Sheng, Richard A. Jones, Xue Q. Zhou, John M. McGinness, Linda J. Van Eldik, Robert E. Mrak, W. Sue T. Griffin

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138 Citations (SciVal)


Activated (phosphorylated) mitogen-activated protein kinase p38 (MAPK-p38) and interleukin-1 (IL-1) have both been implicated in the hyperphosphorylation of tau, a major component of the neurofibrillary tangles in Alzheimer's disease. This, together with findings showing that IL-1 activates MAPK-p38 in vitro and is markedly overexpressed in Alzheimer brain, suggest a role for IL-1-induced MAPK-p38 activation in the genesis of neurofibrillary pathology in Alzheimer's disease. We found frequent colocalization of hyperphosphorylated tau protein (AT8 antibody) and activated MAPK-p38 in neurons and in dystrophic neurites in Alzheimer brain, and frequent association of these structures with activated microglia overexpressing IL-1. Tissue levels of IL-1 mRNA as well as of both phosphorylated and non-phosphorylated isoforms of tau were elevated in these brains. Significant correlations were found between the numbers of AT8- and MAPK-p38-immunoreactive neurons, and between the numbers of activated microglia overexpressing IL-1 and the numbers of both AT8- and MAPK-p38-immunoreactive neurons. Furthermore, rats bearing IL-1-impregnated pellets showed a six- to seven-fold increase in the levels of MAPK-p38 mRNA, compared with rats with vehicle-only pellets (P<0.0001). These results suggest that microglial activation and IL-1 overexpression are part of a feedback cascade in which MAPK-p38 overexpression and activation leads to tau hyperphosphorylation and neurofibrillary pathology in Alzheimer's disease.

Original languageEnglish
Pages (from-to)341-348
Number of pages8
JournalNeurochemistry International
Issue number5-6
StatePublished - 2001

Bibliographical note

Funding Information:
The authors thank S. Woodward for technical assistance, P. Free for secretarial assistance, and P. Green for reviewing the manuscript. This research was supported in part by NIH AG13939, NIH AG15501, NIH AG12411, and the Donald W. Reynolds Foundation.


  • AT8
  • Alzheimer's disease
  • Interleukin-1
  • MAPK-p38
  • Tau phosphorylation

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience
  • Cell Biology


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