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Interleukin-1 promotion of MAPK-p38 overexpression in experimental animals and in Alzheimer's disease: potential significance for tau protein phosphorylation |
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| Authors: | Sheng J G Jones R A Zhou X Q McGinness J M Van Eldik L J Mrak R E Griffin W S |
| Affiliation: | a The Donald W. Reynolds Department of Geriatrics, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA b The Department of Pathology, University of Arkansas for Medical Sciences, 4301 W. Markham Street, Little Rock, AR 72205, USA c The Geriatric Research Department, Clinical Center, VA Medical Center, 4300 W. 7th Street, Little Rock, AR 72205, USA d Northwestern Drug Discovery Program and Department of Cell and Molecular Biology, Northwestern University, Chicago, IL, USA e Department of Neurology, Rui-Jin Hospital, Shanghai Second Medical University, Shanghai 200025, People's Republic of China |
| 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. |
| Keywords: | Alzheimer's disease Interleukin-1 MAPK-p38 AT8 Tau phosphorylation |
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