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/...

Cells latently infected with HIV represent a currently insurmountable barrier to viral eradication in infected patients. Using the J‐Lat human T‐cell model of HIV latency, we have investigated the role of host factor binding to the κB enhancer elements of the HIV long terminal repeat (LTR) in the maintenance of viral latency. We show that NF‐κB p50–HDAC1 complexes constitutively bind the latent HIV LTR and induce histone deacetylation and repressive changes in chromatin structure of the HIV LTR, changes that impair recruitment of RNA polymerase II and transcriptional initiation. Knockdown of p50 expression with specific small hairpin RNAs reduces HDAC1 binding to the latent HIV LTR and induces RNA polymerase II recruitment. Similarly, inhibition of histone deacetylase (HDAC) activity with trichostatin A promotes binding of RNA polymerase II to the latent HIV LTR. This bound polymerase complex, however, remains non‐processive, generating only short viral transcripts. Synthesis of full‐length viral transcripts can be rescued under these conditions by expression of Tat. The combination of HDAC inhibitors and Tat merits consideration as a new strategy for purging latent HIV proviruses from their cellular reservoirs.

No abstract

No abstract