CD38, a transmembrane glycoprotein with ADP-ribosyl cyclase activity, catalyses the formation of Ca2+ signalling molecules, but its role in the neuroendocrine system is unknown. Here we show that adult CD38 knockout (CD38-/-) female and male mice show marked defects in maternal nurturing and social behaviour, respectively, with higher locomotor activity. Consistently, the plasma level of oxytocin (OT), but not vasopressin, was strongly decreased in CD38-/- mice. Replacement of OT by subcutaneous injection or lentiviral-vector-mediated delivery of human CD38 in the hypothalamus rescued social memory and maternal care in CD38-/- mice. Depolarization-induced OT secretion and Ca2+ elevation in oxytocinergic neurohypophysial axon terminals were disrupted in CD38-/- mice; this was mimicked by CD38 metabolite antagonists in CD38+/+ mice. These results reveal that CD38 has a key role in neuropeptide release, thereby critically regulating maternal and social behaviours, and may be an element in neurodevelopmental disorders.

A new gene, termed klotho, is associated with the suppression of several aging phenotypes. Because high expression of klotho gene was detected in the brain, it would be plausible that klotho gene is involved in the regulation of brain aging. We investigated the changes in mnemonic function accompanying aging in klotho mutant mice. Cognitive function measured by novel-object recognition and conditioned-fear tests in klotho mutant mice was normal at the age of 6 wk, but markedly impaired at the age of 7 wk. Lipid (malondialdehyde) and DNA (8-hydroxy-2'-deoxyguanosine) peroxide levels in the hippocampus of klotho mutant mice increased at the age of 5 wk, 2 wk before the development of cognition deficits. Pro-death Bax increased, whereas anti-death Bcl-2 and Bcl-XL decreased, and apoptotic TUNEL-positive cells were detected in the hippocampus of klotho mutant mice at the age of 7 wk. A potent antioxidant, a-tocopherol, prevented cognition impairment and lipid peroxide accumulation and decreased the number of apoptotic cells in klotho mutant mice. These results suggest that oxidative stress has a crucial role in the aging-associated cognition impairment in klotho mutant mice. Klotho protein may be involved in the regulation of antioxidative defense.

The present study examined the kinetics of glutathione (GSH) concentration during maturation and after fertilization in pig oocytes and its relevance to the ability of pig oocytes to form a male pronucleus after in vitro fertilization. The GSH concentration was significantly higher in pig oocytes matured in Waymouth medium than in pig oocytes matured in either modified (m) TCM-199 or mTLP media. The addition of 0.04-0.57 mM cysteine (CySH) to mTLP significantly increased both the GSH concentrations in oocytes matured in vitro and the rate of male pronucleus formation as compared to those in oocytes cultured in mTLP alone. When pig oocytes were cultured 12, 24, or 36 h in mTLP plus 0.14 mM CySH, their GSH concentrations were significantly higher than in uncultured oocytes. After fertilization, the GSH concentration in pig oocytes declined significantly. GSH concentrations in oocytes matured in vivo did not differ from those in oocytes matured in mTLP plus 0.14 or 0.57 mM CySH. The results indicate that 1) the composition of maturation medium affects the GSH concentration in pig oocytes; 2) the addition of CySH to maturation medium permits GSH synthesis by the pig oocytes; 3) GSH levels in pig oocytes change during maturation and after fertilization; and 4) GSH synthesis during oocyte maturation is an important factor for promoting their ability to form a male pronucleus after fertilization.

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 (...