Intracellular amyloid-␤ peptide (A␤) has been implicated in neuronal death associated with Alzheimer's disease. Although A␤ is predominantly secreted into the extracellular space, mechanisms of A␤ transport at the level of the neuronal cell membrane remain to be fully elucidated. We demonstrate that receptor for advanced glycation end products (RAGE) contributes to transport of A␤ from the cell surface to the intracellular space. Mouse cortical neurons exposed to extracellular human A␤ subsequently showed detectable peptide intracellularly in the cytosol and mitochondria by confocal microscope and immunogold electron microscopy. Pretreatment of cultured neurons from wild-type mice with neutralizing antibody to RAGE, and neurons from RAGE knockout mice displayed decreased uptake of A␤ and protection from A␤-mediated mitochondrial dysfunction. A␤ activated p38 MAPK, but not SAPK/JNK, and then stimulated intracellular uptake of A␤-RAGE complex. Similar intraneuronal co-localization of A␤ and RAGE was observed in the hippocampus of transgenic mice overexpressing mutant amyloid precursor protein. These findings indicate that RAGE contributes to mechanisms involved in the translocation of A␤ from the extracellular to the intracellular space, thereby enhancing A␤ cytotoxicity.is a progressive neurodegenerative process characterized by senile plaques, neurofibrillary tangles, and neuronal loss (1, 2). Deposition of amyloid-␤ peptide (A␤), a 39-43-amino acid peptide derived from the transmembrane amyloid precursor protein (APP), is found in extracellular senile plaque cores and is associated with neurodegeneration in later stages of AD. In contrast, recent studies suggest that accumulation of intraneuronal A␤ may be an early event in the pathogenesis of AD (3-16). Addition of A␤ to human neuronal-like cells caused significant mitochondrial damage (17). Furthermore, our recent study revealed that binding of A␤ to A␤-binding alcohol dehydrogenase (ABAD) or cyclophilin D (10, 11) intracellularly triggered events leading to neuronal apoptosis through a mitochondrial pathway (12,13,18,19). However, mechanisms through which A␤ produced at the plasma membrane and released into the extracellular space reaches the intracellular milieu remain to be elucidated.Receptor for advanced glycation end products (RAGE) is a multiligand receptor of the Ig superfamily of cell surface molecules (20)(21)(22). RAGE acts as a counter-receptor for several quite distinct classes of ligands, such as AGEs, S100/calgranulins, HMG1 (high mobility group 1 or amphoterin), and the family of crossed ␤-sheet fibrils/macromolecular assemblies, which activate receptormediated signal transduction pathways. These ligand-receptor interactions are believed to exert pathogenic effects through sustained cellular perturbation in a range of chronic disorders, including the secondary complications of diabetes, inflammation, and neurodegenerative processes (23,24). RAGE, a cell surface binding site for A␤ (25), is expressed at higher levels in an A␤-rich environment (...

Experiences during brain development may influence the pathogenesis of developmental disorders. Thus, social isolation (SI) rearing after weaning is a useful animal model for studying the pathological mechanisms of such psychiatric diseases. In this study, we examined the effect of SI on neurogenesis in the hippocampal dentate gyrus (DG) relating to memory and emotion-related behaviors. When newly divided cells were labeled with 5-bromo-2'-deoxyuridine (BrdU) before SI, the number of BrdU-positive cells and the rate of differentiation into neurons were significantly decreased after 4-week SI compared with those in group-housed mice. Repeated treatment of fluoxetine prevented the SI-induced impairment of survival of newly divided cells and ameliorated spatial memory impairment and part of aggression in SI mice. Furthermore, we investigated the changes in gene expression in the DG of SI mice by using DNA microarray and real-time PCR. We finally found that SI reduced the expression of development-related genes Nurr1 and Npas4. These findings suggest that communication in juvenile is important in the survival and differentiation of newly divided cells, which may be associated with memory and aggression, and raise the possibility that the reduced expression of Nurr1 and/or Npas4 may contribute to the impairment of neurogenesis and memory and aggression induced by SI.

FUS is an RNA/DNA-binding protein involved in multiple steps of gene expression and is associated with amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD). However, the specific disease-causing and/or modifying mechanism mediated by FUS is largely unknown. Here we evaluate intrinsic roles of FUS on synaptic functions and animal behaviours. We find that FUS depletion downregulates GluA1, a subunit of AMPA receptor. FUS binds GluA1 mRNA in the vicinity of the 3′ terminus and controls poly (A) tail maintenance, thus regulating stability. GluA1 reduction upon FUS knockdown reduces miniature EPSC amplitude both in cultured neurons and in vivo. FUS knockdown in hippocampus attenuates dendritic spine maturation and causes behavioural aberrations including hyperactivity, disinhibition and social interaction defects, which are partly ameliorated by GluA1 reintroduction. These results highlight the pivotal role of FUS in regulating GluA1 mRNA stability, post-synaptic function and FTLD-like animal behaviours.