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

Neurochem Int. Nov-Dec 2001;39(5-6):341-8. doi: 10.1016/s0197-0186(01)00041-9.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Aged
  • Aged, 80 and over
  • Alzheimer Disease / metabolism*
  • Animals
  • Blotting, Western
  • Brain / enzymology
  • Female
  • Humans
  • Interleukin-1 / genetics
  • Interleukin-1 / metabolism
  • Interleukin-1 / pharmacology
  • Interleukin-1 / physiology*
  • Male
  • Middle Aged
  • Mitogen-Activated Protein Kinases / metabolism*
  • Phosphorylation
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Reverse Transcriptase Polymerase Chain Reaction
  • p38 Mitogen-Activated Protein Kinases
  • tau Proteins / metabolism

Substances

  • Interleukin-1
  • RNA, Messenger
  • tau Proteins
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases