Amyloid beta-peptide stimulates nitric oxide production in astrocytes through an NFkappaB-dependent mechanism.
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.
Akama
K T
KT
Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, IL 60611-3008, USA.
Albanese
C
C
Pestell
R G
RG
Van Eldik
L J
LJ
D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002478:Cells, Cultured; D004790:Enzyme Induction; D008969:Molecular Sequence Data; D016328:NF-kappa B / Q000378:metabolism*; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D052247:Nitric Oxide Synthase Type II; D018384:Oxidative Stress; D051381:Rats
D016229:Amyloid beta-Peptides; D016328:NF-kappa B; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat