1. Amyloid beta-peptide stimulates nitric oxide production in astrocytes through an NFkappaB-dependent mechanism
K T Akama, C Albanese, R G Pestell, L J Van Eldik Proc Natl Acad Sci U S A. 1998 May 12;95(10):5795-800. doi: 10.1073/pnas.95.10.5795.
The major pathological features of Alzheimer's disease (AD) include amyloid plaques composed primarily of the beta-amyloid (Abeta) peptide, degenerating neurons and neurofibrillary tangles, and the presence of numerous activated astrocytes and microglia. Although extensive genetic data implicate Abeta in the neurodegenerative cascade of AD, the molecular mechanisms underlying its effects on neurons and glia and the relationship between glial activation and neuronal death are not well defined. Abeta has been shown to induce glial activation, and a growing body of evidence suggests that activated glia contribute to neurotoxicity through generation of inflammatory cytokines and neurotoxic free radicals, such as nitric oxide (NO), potent sources of oxidative stress known to occur in AD. It is therefore crucial to identify specific Abeta-induced molecular pathways mediating these responses in activated glia. We report that Abeta stimulates the activation of the transcription factor NFkappaB in rat astrocytes, that NFkappaB activation occurs selectively from p65 transactivation domain 2, and that Abeta-induced NO synthase expression and NO production occur through an NFkappaB-dependent mechanism. This demonstration of how Abeta couples an intracellular signal transduction pathway involving NFkappaB to a potentially neurotoxic response provides a key mechanistic link between Abeta and the generation of oxidative damage. Our results also suggest possible molecular targets upon which to focus future drug discovery efforts for AD.
2. Glial-derived proteins activate cultured astrocytes and enhance beta amyloid-induced glial activation
J Hu, L J Van Eldik Brain Res. 1999 Sep 18;842(1):46-54. doi: 10.1016/s0006-8993(99)01804-1.
A prominent feature of Alzheimer's disease (AD) pathology is an abundance of activated glia (astrocytes and microglia) in close proximity to the amyloid plaques. These activated glia overexpress a number of proteins that may participate in the progression of the disease, possibly by propagation of inflammatory and oxidative stress responses. The beta-amyloid peptide 1-42 (Abeta), a major constituent of neuritic plaques, can itself induce glial activation. However, little is known about whether other plaque components, especially the upregulated glial proteins, can induce glial activation or modulate the effects of Abeta on glia. In this study, we focused on four glial proteins that are abundant in amyloid plaques and/or that are known to interact with Abeta: alpha1-antichymotrypsin (ACT), interleukin-1beta (IL-1beta), S100beta, and butyrylcholinesterase (BChE). We examined the ability of these proteins to activate rat cortical astrocyte cultures and to influence the ability of Abeta to activate astrocytes. Treatment of astrocytes with ACT, IL-1beta, or S100beta resulted in glial activation, as assessed by reactive morphology, upregulation of IL-1beta, and production of inducible nitric oxide synthase and nitric oxide. The ability of Abeta to induce astrocyte activation was also enhanced in the presence of each of these three proteins. In contrast, BChE alone did not activate astrocytes and had no effect on Abeta-induced activation. These results suggest that certain proteins produced by activated glia may contribute to the chronic glial activation seen in AD through their ability to stimulate astrocytes directly or through their ability to modulate Abeta-induced activation.
3. Inducible nitric oxide synthase and argininosuccinate synthetase: co-induction in brain tissue of patients with Alzheimer's dementia and following stimulation with beta-amyloid 1-42 in vitro
Jürgen Haas, Brigitte Storch-Hagenlocher, Annette Biessmann, Brigitte Wildemann Neurosci Lett. 2002 Apr 5;322(2):121-5. doi: 10.1016/s0304-3940(02)00095-2.
In Alzheimer's disease (AD), amyloid plaques within the brain are surrounded by activated glial cells (microglia and astrocytes). The mechanisms of glial activation and its effect on disease progression are not fully understood. Growing evidence suggests that beta-amyloid (Abeta) peptide, a major constituent of the amyloid plaque, is critically involved in the induction of an inflammatory response. The goal of this study was to examine the role of Abeta in the pathogenesis of local inflammation and neuronal cell death. We found increased mRNA levels of inducible nitric oxide synthase (iNOS) and the arginine regenerating enzyme argininosuccinate synthetase (ASS) within cortices of AD patients suggesting high output NO production. In vitro, synthetic Abeta1-42 and to a lesser extent Abeta1-40 induced iNOS and ASS transcription with consecutive NO overproduction in mixed rat neuronal-glial cultures. Furthermore, Abeta-stimulation lead to an increased release of inflammatory cytokines interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha. Again, Abeta1-42 had a much more pronounced effect as compared to Abeta1-40. Our data suggest that Abeta1-42 is a key mediator of glial activation and via the induction of inflammatory mediators may be a critical component of the neurodegenerative process in AD.
