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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
- Source :
- Neuromolecular medicine. 2(1)
- Publication Year :
- 2002
-
Abstract
- 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.
- Subjects :
- Lipopolysaccharides
Male
animal diseases
medicine.medical_treatment
Excitotoxicity
Gene Dosage
Nitric Oxide Synthase Type II
medicine.disease_cause
Amyloid beta-Protein Precursor
Mice
Cells, Cultured
Mutation
Vaccines
Microglia
Brain
Cytokine
medicine.anatomical_structure
Neurology
Organ Specificity
Enzyme Induction
Molecular Medicine
Cytokines
Tumor necrosis factor alpha
medicine.symptom
Cell activation
MAP Kinase Signaling System
Sialoglycoproteins
Mutation, Missense
Inflammation
Nerve Tissue Proteins
Biology
Presenilin
Cellular and Molecular Neuroscience
Alzheimer Disease
mental disorders
medicine
Presenilin-1
Animals
Humans
RNA, Messenger
Codon
Interleukin-6
Tumor Necrosis Factor-alpha
Gene Expression Profiling
Membrane Proteins
nervous system diseases
Interleukin 1 Receptor Antagonist Protein
nervous system
Amino Acid Substitution
Immunology
Cancer research
Nitric Oxide Synthase
Spleen
Interleukin-1
Subjects
Details
- ISSN :
- 15351084
- Volume :
- 2
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- Neuromolecular medicine
- Accession number :
- edsair.doi.dedup.....49edf224efd3b0b478e005330bd3b7bc