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The Journal of Neuroscience, March 1, 2003, 23(5):1605
Interleukin-1 Mediates Pathological Effects of Microglia on Tau
Phosphorylation and on Synaptophysin Synthesis in Cortical Neurons
through a p38-MAPK Pathway
Yuekui
Li1,
Ling
Liu1,
Steven W.
Barger1, 2, 3, 4, and
W. Sue T.
Griffin1, 2, 3, 4, 5
Departments of 1 Geriatrics and 2 Anatomy,
University of Arkansas for Medical Sciences, and
3 Department of Veterans Affairs Medical Center and
4 Geriatric and 5 Mental Illness Research
Education Clinical Centers, Little Rock, Arkansas 72205
The presence of tangles of abnormally phosphorylated tau is a
characteristic of Alzheimer's disease (AD), and the loss of synapses
correlates with the degree of dementia. In addition, the overexpression
of interleukin-1 (IL-1) has been implicated in tangle formation in AD.
As a direct test of the requirement for IL-1 in tau phosphorylation and
synaptophysin expression, IL-1 actions in neuron-microglia cocultures
were manipulated. Activation of microglia with secreted  -amyloid
precursor protein or lipopolysaccharide elevated their expression of
IL-1 , IL-1, and tumor necrosis factor (TNF) mRNA. When
such activated microglia were placed in coculture with primary
neocortical neurons, a significant increase in the phosphorylation of
neuronal tau was accompanied by a decline in synaptophysin levels.
Similar effects were evoked by treatment of neurons with recombinant
IL-1. IL-1 receptor antagonist (IL-1ra) as well as anti-IL-1
antibody attenuated the influence of activated microglia on neuronal
tau and synaptophysin, but anti-TNF antibody was ineffective. Some
effects of microglial activation on neurons appear to be mediated by
activation of p38 mitogen-activated protein kinase (p38-MAPK), because
activated microglia stimulated p38-MAPK phosphorylation in neurons, and an inhibitor of p38-MAPK reversed the influence of IL-1 on tau phosphorylation and synaptophysin levels. Our results, together with
previous observations, suggest that activated microglia may contribute
to neurofibrillary pathology in AD through their production of IL-1,
activation of neuronal p38-MAPK, and resultant changes in neuronal
cytoskeletal and synaptic elements.
Key words:
Alzheimer's disease; -amyloid precursor
protein; cortical neuron; interleukin-1; microglia; mitogen-activated
protein kinase; synaptophysin; phosphorylated tau
Copyright © 2003 Society for Neuroscience 0270-6474/03/2351605-07$05.00/0
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