inflammatory cytokine responses to immune challenge in the brain.

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1: Neuromolecular Med. 2002;2(1):29-45. Related Articles, Links

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Adverse effect of a presenilin-1 mutation in microglia results in

enhanced nitric oxide and inflammatory cytokine responses to immune

challenge in the brain.

Lee J, Chan SL, Mattson MP.

laboratory of Neurosciences, National Institute on Aging Gerontology

Research Center, Baltimore, MD 21224, USA.

Inflammatory processes involving glial cell activation are associated

with amyloid plaques and neurofibrillary tangles, the cardinal

neuropathological lesions in the brains of Alzheimer's disease (AD)

patients, However, it is unclear whether these inflammatory processes occur

as a response to neuronal degeneration or might represent more seminal

events in the disease process. Some cases of AD are caused by mutations in

presenilin-1 (PS1), and it has been shown that PS1 mutations perturb

neuronal calcium homeostasis, promote increased production of amyloid

beta-peptide (Abeta), and render neurons vulnerable to synaptic dysfunction,

excitotoxicity, and apoptosis. Although glial cells express PS1, it is not

known if PS1 mutations alter glial cell functions. We now report on studies

of glial cells in PS1 mutant knockin mice that demonstrate an adverse effect

PS1 mutations in microglial cells. Specifically, PS1 mutant mice exhibit an

enhanced inflammatory cytokine response to immune challenge with bacterial

lipopolysaccharide (LPS). LPS-induced levels of mRNAs encoding tumor

necrosis fctor-alpha (TNFalpha), interleukin (IL)-1alpha, IL-1beta, IL-1

receptor antagonist, and IL-6 are significantly greater in the hippocampus

and cerebral cortex of PS1 mutant mice as compared to wild-type mice. In

contrast, the cytokine responses to LPS in the spleen is unaffected by the

PS1 mutation. Studies of cultured microglia from PS1 mutant and wild-type

mice reveal that PS1 is expressed in microglia and that the PS1 mutation

confers a heightened sensitivity to LPS, as indicated by superinduction of

inducible nitric oxide synthase (NOS) and activation of mitogen-activated

protein kinase (MAPK). These findings demonstrate an adverse effect of PS1

mutations on microglial cells that results in their hyperactivation under

pro-inflammatory conditions, which may, together with direct effects of

mutant PS1 in neurons, contribute to the neurodegenerative process in AD.

These findings also have important implications for development of a

" vaccine " for the prevention or treatment of AD.

PMID: 12230303 [PubMed - indexed for MEDLINE]