Adverse effect of a presenilin-1 mutation in microglia results in enhanced nitric oxide and inflammatory cytokine responses to immune challenge in the brain.
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.
Lee
Jaewon
J
laboratory of Neurosciences, National Institute on Aging Gerontology Research Center, Baltimore, MD 21224, USA.
Chan
Sic L
SL
Mattson
Mark P
MP
D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics* / Q000517:prevention & control; D019943:Amino Acid Substitution; D016564:Amyloid beta-Protein Precursor / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D003062:Codon / Q000235:genetics; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D004790:Enzyme Induction; D018628:Gene Dosage; D020869:Gene Expression Profiling; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D017628:Microglia / Q000201:enzymology / Q000378:metabolism*; D020125:Mutation, Missense; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis*; D052247:Nitric Oxide Synthase Type II; D009928:Organ Specificity; D053764:Presenilin-1; D012333:RNA, Messenger / Q000096:biosynthesis; D012795:Sialoglycoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D014612:Vaccines
D016564:Amyloid beta-Protein Precursor; D003062:Codon; D016207:Cytokines; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D015850:Interleukin-6; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012333:RNA, Messenger; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha; D014612:Vaccines; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse