Neurogenesis, which persists in the adult mammalian brain, may provide a basis for neuronal replacement therapy in neurodegenerative diseases like Alzheimer's disease (AD). Neurogenesis is increased in certain acute neurological disorders, such as ischemia and epilepsy, but the effect of more chronic neurodegenerations is uncertain, and some animal models of AD show impaired neurogenesis. To determine how neurogenesis is affected in the brains of patients with AD, we investigated the expression of immature neuronal marker proteins that signal the birth of new neurons in the hippocampus of AD patients. Compared to controls, Alzheimer's brains showed increased expression of doublecortin, polysialylated nerve cell adhesion molecule, neurogenic differentiation factor and TUC-4. Expression of doublecortin and TUC-4 was associated with neurons in the neuroproliferative (subgranular) zone of the dentate gyrus, the physiological destination of these neurons (granule cell layer), and the CA1 region of Ammon's horn, which is the principal site of hippocampal pathology in AD. These findings suggest that neurogenesis is increased in AD hippocampus, where it may give rise to cells that replace neurons lost in the disease, and that stimulating hippocampal neurogenesis might provide a new treatment strategy.

Alterations in Ca 2+ homeostasis and accumulation of unfolded proteins in the endoplasmic reticulum (ER) lead to an ER stress response. Prolonged ER stress may lead to cell death. Glucose-regulated protein (GRP) 78 (Bip) is an ER lumen protein whose expression is induced during ER stress. GRP78 is involved in polypeptide translocation across the ER membrane, and also acts as an apoptotic regulator by protecting the host cell against ER stress-induced cell death, although the mechanism by which GRP78 exerts its cytoprotective effect is not understood. The present study was carried out to determine whether one of the mechanisms of cell death inhibition by GRP78 involves inhibition of caspase activation. Our studies indicate that treatment of cells with ER stress inducers causes GRP78 to redistribute from the ER lumen with subpopulations existing in the cytosol and as an ER transmembrane protein. GRP78 inhibits cytochrome c-mediated caspase activation in a cell-free system, and expression of GRP78 blocks both caspase activation and caspase-mediated cell death. GRP78 forms a complex with caspase-7 and -12 and prevents release of caspase-12 from the ER. Addition of (d)ATP dissociates this complex and may facilitate movement of caspase-12 into the cytoplasm to set in motion the cytosolic component of the ER stressinduced apoptotic cascade. These results define a novel protective role for GRP78 in preventing ER stress-induced cell death. ß 2002 Published by Elsevier Science B.V. on behalf of the Federation of European Biochemical Societies.

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Neuroglobin (Ngb) is an O2-binding protein localized to cerebral neurons of vertebrates, including humans. Its physiological role is unknown but, like hemoglobin, myoglobin, and cytoglobin͞histo-globin, it may transport O 2, detoxify reactive oxygen species, or serve as a hypoxia sensor. We reported recently that hypoxia stimulates transcriptional activation of Ngb in cultured cortical neurons and that antisense inhibition of Ngb expression increases hypoxic neuronal injury, whereas overexpression of Ngb confers resistance to hypoxia. These findings are consistent with a role for Ngb in promoting neuronal survival after hypoxic insults in vitro. Here we report that in rats, intracerebroventricular administration of an Ngb antisense, but not sense, oligodeoxynucleotide increases infarct volume and worsens functional neurological outcome, whereas intracerebral administration of a Ngb-expressing adenoassociated virus vector reduces infarct size and improves functional outcome, after focal cerebral ischemia induced by occlusion of the middle cerebral artery. We conclude that Ngb acts as an endogenous neuroprotective factor in focal cerebral ischemia and may therefore represent a target for the development of new treatments for stroke.T he ability to sense and respond to hypoxia is a universal attribute of eukaryotic cells, but the role of this ability in protecting cells from ischemic insults and its potential for therapeutic application are unclear. One prominent feature of cellular adaptation to hypoxia or ischemia consists of the increased expression of hypoxia-inducible proteins (1), including proteins with the capacity to protect the brain from ischemic insults (2, 3). Examples include hypoxia-inducible factor-1 (4), erythropoietin (5), vascular endothelial growth factor (6), heme oxygenase-1 (7), and adrenomedullin (8). These proteins are likely to exert their neuroprotective effects through diverse mechanisms but their hypoxia-responsiveness depends ultimately on O 2 -binding proteins that can sense hypoxia and trigger appropriate cellular adaptations (9, 10).The globins are a family of heme proteins that can bind, transport, scavenge, detoxify, and sense gases like O 2 and NO (11). Four vertebrate globins have been identified. Hemoglobin, which differs from other vertebrate globins in occurring as a tetramer, is localized to erythrocytes and transports O 2 between the lungs and other tissues. Myoglobin (Mgb) is monomeric and is localized to the cytoplasm of skeletal and cardiac myocytes. Cytoglobin or histoglobin (12, 13) is expressed widely in both neural and nonneural vertebrate tissues, but its functions are unknown. The recent discovery of neuroglobin (Ngb; ref. 14), which is expressed primarily in cerebral neurons (15), is induced by neuronal hypoxia and cerebral ischemia (16) and protects neurons from hypoxia in vitro (16), suggests that this protein may have a role in sensing or responding to neuronal hypoxia, which could have implications for the pathophysiology and treatment of stroke.To test the hy...

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