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

Activated (phosphorylated) mitogen-activated protein kinase p38 (MAPK-p38) and interleukin-1 (IL-1) have both been implicated in the hyperphosphorylat ion 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 path ology in Alzheimer's disease, We found frequent colocalization of hyperphos phorylated tau protein (AT8 antibody) and activated MAPK-p38 in neurons and in dystrophic neurites in Alzheimer brain. and frequent association of the se structures with activated microglia overexpressing IL-1. Tissue levels o f IL-1 mRNA as well as of both phosphorylated and non-phosphorylated isofor ms of tau were elevated in these brains. Significant correlations were foun d between the numbers of AT8- and MAPK-p38-immunoreactive neurons, and betw een 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 level s of MAPK-p38 mRNA, compared with rats with vehicle-only pellets (P < 0.000 1). These results suggest that microglial activation and IL-1 overexpressio n are part of a feedback cascade in which MAPK-p38 overexpression and activ ation leads to tau hyperphosphorylation and neurofibrillary pathology in Al zheimer's disease. (C) 2001 Published by Elsevier Science Ltd.