beta-Amyloid stimulation of microglia and monocytes results in TNFalpha-dependent expression of inducible nitric oxide synthase and neuronal apoptosis.
Reactive microglia associated with the beta-amyloid plaques in Alzheimer's disease (AD) brains initiate a sequence of inflammatory events integral to the disease process. We have observed that fibrillar beta-amyloid peptides activate a tyrosine kinase-based signaling response in primary mouse microglia and the human monocytic cell line, THP-1, resulting in production of neurotoxic secretory products, proinflammatory cytokines, and reactive oxygen species. We report that most of the amyloid-induced tyrosine kinase activity was stimulated after activation of Src family members such as Lyn. However, transduction of the signaling response required for increased production of the cytokines TNFalpha and IL1-beta was mediated by the nonreceptor tyrosine kinase, Syk. Additionally, beta-amyloid stimulated an NFkappaB-dependent pathway in parallel that was required for cytokine production. Importantly, TNFalpha generated by the monocytes and microglia was responsible for the majority of the neuorotoxic activity secreted by these cells after beta-amyloid stimulation but must act in concert with other factors elaborated by microglia to elicit neuronal death. Moreover, we observed that the neuronal loss was apoptotic in nature and involved increased neuronal expression of inducible nitric oxide synthase and subsequent peroxynitrite production. Selective inhibitors of inducible nitric oxide synthase effectively protected cells from toxicity associated with the microglial and monocytic secretory products. This study demonstrates a functional linkage between beta-amyloid-dependent activation of microglia and several characteristic markers of neuronal death occurring in Alzheimer's disease brains.
Combs
C K
CK
Alzheimer Research Laboratory, Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
Karlo
J C
JC
Kao
S C
SC
Landreth
G E
GE
D000544:Alzheimer Disease / Q000276:immunology / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D000075202:Contraindications; D004792:Enzyme Precursors / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000072377:Syk Kinase; D014157:Transcription Factors / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
D016229:Amyloid beta-Peptides; D004792:Enzyme Precursors; D047908:Intracellular Signaling Peptides and Proteins; D016328:NF-kappa B; D010446:Peptide Fragments; D014157:Transcription Factors; D014409:Tumor Necrosis Factor-alpha; C078592:amyloid beta-protein (1-40); C075222:amyloid beta-protein (1-42); C074636:amyloid beta-protein (25-35); C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases