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The nuclear function of the heterodimeric NF-kB transcription factor is regulated in part through reversible acetylation of its RelA subunit. We now demonstrate that the p300 and CBP acetyltransferases play a major role in the in vivo acetylation of RelA, principally targeting lysines 218, 221 and 310 for modi®cation. Analysis of the functional properties of hypoacetylated RelA mutants containing lysine-toarginine substitutions at these sites and of wild-type RelA co-expressed in the presence of a dominantly interfering mutant of p300 reveals that acetylation at lysine 221 in RelA enhances DNA binding and impairs assembly with IkBa. Conversely, acetylation of lysine 310 is required for full transcriptional activity of RelA in the absence of effects on DNA binding and IkBa assembly. Together, these ®nd-ings highlight how site-speci®c acetylation of RelA differentially regulates distinct biological activities of the NF-kB transcription factor complex.

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Accumulating evidence suggests that neurodegeneration induced by pathogenic proteins depends on contributions from surrounding glia. Here we demonstrate that NF-B signaling in microglia is critically involved in neuronal death induced by amyloid-␤ (A␤) peptides, which are widely presumed to cause Alzheimer disease. Constitutive inhibition of NF-B signaling in microglia by expression of the nondegradable IB␣ superrepressor blocked neurotoxicity, indicating a pivotal role for microglial NF-B signaling in mediating A␤ toxicity. Stimulation of microglia with A␤ increased acetylation of RelA/p65 at lysine 310, which regulates the NF-B pathway. Overexpression of SIRT1 deacetylase and the addition of the SIRT1 agonist resveratrol markedly reduced NF-B signaling stimulated by A␤ and had strong neuroprotective effects. Our results support a glial loop hypothesis by demonstrating a critical role for microglial NF-B signaling in A␤-dependent neurodegeneration. They also implicate SIRT1 in this pathway and highlight the therapeutic potential of resveratrol and other sirtuin-activating compounds in Alzheimer disease.Neurodegenerative diseases appear to be caused by pathogenic proteins that affect neurons directly or contribute to neuronal death by engaging neurotoxic pathways in surrounding glia (1-3). In Alzheimer disease (AD), 3 neurodegeneration may be exacerbated by chronic inflammatory reactions of cells surrounding neuritic plaques, including microglia and astrocytes (4, 5). High concentrations of fibrillar A␤ can activate microglia, resulting in tumor necrosis factor-␣-dependent expression of inducible nitric-oxide synthase (iNOS) and neuronal apoptosis (6). Nonfibrillar A␤, which may be the major pathogenic form of A␤ in the early stages of AD, also stimulates microglia to induce neurodegeneration. Dimeric and trimeric assemblies of A␤-(1-42) isolated from amyloid deposits elicited profound neurotoxicity in hippocampal neurons but only in the presence of microglia (7). Stimulation with soluble A␤ caused microglia to secrete toxic factors, including cathepsin B, and mediated neurodegeneration (8). Inhibiting the induction of long term potentiation with soluble A␤ involves activation of microglia and stimulation of iNOS and superoxide (9).We hypothesized that the pathogenic engagement of microglia by A␤ involves activation of NF-B, a transcription factor that mediates immune and inflammatory responses (10) and controls the expression of both iNOS and cathepsin B (11, 12). In AD brains, RelA/p65 immunoreactivity is greater in neurons and astrocytes surrounding amyloid plaques, raising the possibility of a role for NF-B in AD pathogenesis (13). In cultured neurons and glia, A␤ stimulation led to NF-B activation (12-15). However, it remains unclear whether NF-B signaling actually contributes to AD-related neurodegeneration.To test our hypothesis, we took advantage of the fact that NF-B activation is tightly regulated by inhibitory proteins, such as IB␣ (16). In response to stimuli, IB␣ is degraded to release the NF-B p50/...