β-Amyloid Stimulation of Microglia and Monocytes Results in TNFα-Dependent Expression of Inducible Nitric Oxide Synthase and Neuronal Apoptosis

By Colin K. Combs, J. Karlo, Shih-Chu Kao, G. Landreth. Journal of Neuroscience, 2001

633 citations recorded by the source corpus.

Reactive microglia associated with the β-amyloid plaques in Alzheimer's disease (AD) brains initiate a sequence of inflammatory events integral to the disease process. We have observed that fibrillar β-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 TNFα and IL1-β was mediated by the nonreceptor tyrosine kinase, Syk. Additionally, β-amyloid stimulated an NFκB-dependent pathway in parallel that was required for cytokine production. Importantly, TNFα generated by the monocytes and microglia was responsible for the majority of the neuorotoxic activity secreted by these cells after β-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 β-amyloid-dependent activation of microglia and several characteristic markers of neuronal death occurring in Alzheimer's disease brains.

Subfields: Clinical Biochemistry, Neurology, Physiology

View Paper: https://www.semanticscholar.org/paper/3940fdce9857e419ca64281cca69e4ae6834c951

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Citations in the corpus

Microglia promote the death of developing Purkinje cells. (2004, background): “Our study illustrates a mammalian form of en- cytokines (Combs et al., 2001), proteases (Flavin et al., gulfment-promoted cell death that links the execution 2000), free radicals (Chao et al., 1992; Thery et al., 1991), of neuron death to the scavenging of dead cells. or glutamate agonists (Piani…”
Microglia as a source and target of cytokines (2002, background): “Activated microglia clusters around plaques and microglial release products are thought to mediate a significant portion of the neurotoxic plaque potential (Yates et al., 2000; Bamberger and Landreth, 2001; Benveniste et al., 2001; Combs et al., 2001; Meda et al., 2001).”
A Cell Surface Receptor Complex for Fibrillar β-Amyloid Mediates Microglial Activation (2003, background): “It has previously been demonstrated that microglia secrete IL-1 as well as other cytokines on exposure to fibrillar A and other immune stimuli (Araujo and Cotman, 1992; Meda et al., 1995, 1996, 1999; Lorton et al., 1996; Fiala et al., 1998; Murphy et al., 1998; Combs et al., 2000, 2001).”
Rapid appearance and local toxicity of amyloid-β plaques in a mouse model of Alzheimer’s disease (2008, background): “Several studies have shown that microglia surround senile plaques both in patients with Alzheimer’s disease and transgenic mouse models 9,10 although their role remains elusive 11,12 .”
A Review: Inflammatory Process in Alzheimer's Disease, Role of Cytokines (2012, background): “Aβ is able to stimulate a nuclear factor-kappaB- (NFκB-) dependent pathway that is required for cytokine production [49].”
Inflammatory processes in Alzheimer's disease. (2007, neutral): “Additionally, Aβ is able to stimulate a NFκB-dependent pathway that is required for cytokine production (Combs et al., 2001).”