Phosphorylation of the eukaryotic initiation factor 2 α subunit (eIF2α) is increased in the brains of Alzheimer's disease patients and model mice. Here the authors show that knocking down two kinases that phosphorylate eIF2α, PERK and GCN2, rescues protein synthesis, synaptic plasticity and behavioral deficits in Alzheimer's disease model mice. Expression of long-lasting synaptic plasticity and long-term memory requires protein synthesis, which can be repressed by phosphorylation of eukaryotic initiation factor 2 α-subunit (eIF2α). Elevated phosphorylation of eIF2α has been observed in the brains of Alzheimer's disease patients and Alzheimer's disease model mice. Therefore, we tested whether suppressing eIF2α kinases could alleviate synaptic plasticity and memory deficits in Alzheimer's disease model mice. Genetic deletion of eIF2α kinase PERK prevented enhanced phosphorylation of eIF2α and deficits in protein synthesis, synaptic plasticity and spatial memory in mice that express familial Alzheimer's disease–related mutations in APP and PSEN1. Similarly, deletion of another eIF2α kinase, GCN2, prevented impairments of synaptic plasticity and defects in spatial memory exhibited by the Alzheimer's disease model mice. Our findings implicate aberrant eIF2α phosphorylation as a previously unidentified molecular mechanism underlying Alzheimer's disease–related synaptic pathophysioloy and memory dysfunction and suggest that PERK and GCN2 are potential therapeutic targets for treatment of individuals with Alzheimer's disease.

The p38 mitogen‐activated protein kinase (MAPK) pathway, like the c‐Jun N‐terminal kinase (JNK) MAPK pathway, is activated in response to cellular stress and inflammation and is involved in many fundamental biological processes. To study the role of the p38 MAPK pathway in vivo , we have used homologous recombination in mice to inactivate the Mkk3 gene, one of the two specific MAPK kinases (MAPKKs) that activate p38 MAPK. Mkk3−/− mice were viable and fertile; however, they were defective in interleukin‐12 (IL‐12) production by macrophages and dendritic cells. Interferon‐γ production following immunization with protein antigens and in vitro differentiation of naive T cells is greatly reduced, suggesting an impaired type I cytokine immune response. The effect of the p38 MAPK pathway on IL‐12 expression is at least partly transcriptional, since inhibition of this pathway blocks IL‐12 p40 promoter activity in macrophage cell lines and IL‐12 p40 mRNA is reduced in MKK3‐deficient mice. We conclude that the p38 MAP kinase, activated through MKK3, is required for the production of inflammatory cytokines by both antigen‐presenting cells and CD4+ T cells.

In response to Toll-like receptor ligands, dendritic cells (DCs) dramatically enhance their antigen presentation capacity by stabilizing at the cell-surface MHC II molecules. We demonstrate here that, in human monocyte-derived DCs, the RING-CH ubiquitin E3 ligase, membrane-associated RING-CH I (MARCH I), promotes the ubiquitination of the HLA-DR β-chain. Thus, in nonactivated DCs, MARCH I induces the surface internalization of mature HLA-DR complexes, therefore reducing their stability and levels. We further demonstrate that the maturation-dependent down-regulation of MARCH I is a key event in MHC class II up-regulation at the surface of LPS-activated DCs. MARCH I is, therefore, a major regulator of HLA-DR traffic, and its loss contributes to the acquisition of the potent immunostimulatory properties of mature human DCs.

Sec1 is a hydrophilic protein that plays an essential role in exocytosis from the yeast Saccharomyces cerevisiae. Two high copy suppressors of mutations in the Sec1 gene, SSO1 and SSO2, were recently identified that encode proteins of the syntaxin family. Syntaxin (a T-SNARE), together with SNAP-25 and synaptobrevin/VAMP (a T- and a V-SNARE, respectively), is thought to form the core of the docking-fusion complex in synaptic vesicle exocytosis. Proteins that exhibit similarity to Sec1 were identified in the nervous system of Drosophila melanogaster (Rop) and Caenorhabditis elegans (UNC18). Based on the amino acid sequence alignment of Sec1, Rop, and UNC18, we have used a PCR-based approach to isolate a rat brain cDNA encoding a Sec1 homologue. The cDNA hybridizes to a 3.5-kb brain-specific mRNA by Northern blot analysis and encodes a protein of 593 amino acids (rbSec1). Antibodies raised against a central portion of rbSec1 recognize a 67.5-kDa protein in total homogenates of rat brain but not of nonneuronal tissues. When incubated with a Triton X-100 brain extract, rbSec1-glutathione S-transferase (GST) fusion protein, but not GST protein alone, specifically interacts with syntaxin but not with SNAP-25 or synaptobrevin/VAMP. We conclude that the function of proteins of the Sec1 family in membrane fusion involves an interaction with a T-SNARE.