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The Journal of Neuroscience, February 15, 2001, 21(4):1179-1188
 -Amyloid Stimulation of Microglia and Monocytes Results in
TNF -Dependent Expression of Inducible Nitric Oxide Synthase and
Neuronal Apoptosis
Colin K.
Combs,
J. Colleen
Karlo,
Shih-Chu
Kao, and
Gary
E.
Landreth
Alzheimer Research Laboratory, Departments of Neurosciences and
Neurology, Case Western Reserve University School of Medicine,
Cleveland, Ohio 44106
Reactive microglia associated with the  -amyloid plaques in
Alzheimer's disease (AD) brains initiate a sequence of inflammatory events integral to the disease process. We have observed that fibrillar
-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 TNF and IL1- was mediated by the
nonreceptor tyrosine kinase, Syk. Additionally, -amyloid stimulated
an NF B-dependent pathway in parallel that was required for cytokine
production. Importantly, TNF generated by the monocytes and
microglia was responsible for the majority of the neuorotoxic activity
secreted by these cells after -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 -amyloid-dependent activation of microglia and several
characteristic markers of neuronal death occurring in Alzheimer's
disease brains.
Key words:
Alzheimer's disease; -amyloid; microglia; THP-1
monocytes; signal transduction; tyrosine kinase; Lyn; Syk; inflammation; neurotoxicity; apoptosis; nitric oxide; nitrotyrosine; peroxynitrite; TNF; cytokines
Copyright © 2001 Society for Neuroscience 0270-6474/01/2141179-10$05.00/0
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