No abstract

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.

Vascular endothelial growth factor (VEGF) is an angiogenic protein with therapeutic potential in ischemic disorders, including stroke. VEGF confers neuroprotection and promotes neurogenesis and cerebral angiogenesis, but the manner in which these effects may interact in the ischemic brain is poorly understood. We produced focal cerebral ischemia by middle cerebral artery occlusion for 90 minutes in the adult rat brain and measured infarct size, neurological function, BrdU labeling of neuroproliferative zones, and vWF-immunoreactive vascular profiles, without and with intracerebroventricular administration of VEGF on days 1-3 of reperfusion. VEGF reduced infarct size, improved neurological performance, enhanced the delayed survival of newborn neurons in the dentate gyrus and subventricular zone, and stimulated angiogenesis in the striatal ischemic penumbra, but not the dentate gyrus. We conclude that in the ischemic brain VEGF exerts an acute neuroprotective effect, as well as longer latency effects on survival of new neurons and on angiogenesis, and that these effects appear to operate independently. VEGF may, therefore, improve histological and functional outcome from stroke through multiple mechanisms.

No abstract

Experimental stroke in rodents stimulates neurogenesis and migration of newborn neurons from their sites of origin into ischemic brain regions. We report that in patients with stroke, cells that express markers associated with newborn neurons are present in the ischemic penumbra surrounding cerebral cortical infarcts, where these cells are preferentially localized in the vicinity of blood vessels. These findings suggest that stroke-induced compensatory neurogenesis may occur in the human brain, where it could contribute to postischemic recovery and represent a target for stroke therapy.ischemia ͉ stem cells ͉ penumbra ͉ infarct ͉ vascular niche

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...

Vascular endothelial growth factor (VEGF) is an angiogenic protein with therapeutic potential in ischemic disorders, including stroke. VEGF confers neuroprotection and promotes neurogenesis and cerebral angiogenesis, but the manner in which these effects may interact in the ischemic brain is poorly understood. We produced focal cerebral ischemia by middle cerebral artery occlusion for 90 minutes in the adult rat brain and measured infarct size, neurological function, BrdU labeling of neuroproliferative zones, and vWF-immunoreactive vascular profiles, without and with intracerebroventricular administration of VEGF on days 1-3 of reperfusion. VEGF reduced infarct size, improved neurological performance, enhanced the delayed survival of newborn neurons in the dentate gyrus and subventricular zone, and stimulated angiogenesis in the striatal ischemic penumbra, but not the dentate gyrus. We conclude that in the ischemic brain VEGF exerts an acute neuroprotective effect, as well as longer latency effects on survival of new neurons and on angiogenesis, and that these effects appear to operate independently. VEGF may, therefore, improve histological and functional outcome from stroke through multiple mechanisms.

SummaryNeurogenesis, which may contribute to the ability of the adult brain to function normally and adapt to disease, nevertheless declines with advancing age. Adult neurogenesis can be enhanced by administration of growth factors, but whether the aged brain remains responsive to these factors is unknown. We compared the effects of intracerebroventricular fibroblast growth factor (FGF)-2 and heparin-binding epidermal growth factor-like growth factor (HB-EGF) on neurogenesis in the hippocampal dentate subgranular zone (SGZ) and the subventricular zone (SVZ) of young adult (3-month) and aged (20-month) mice. Neurogenesis, measured by labelling with bromodeoxyuridine (BrdU) and by expression of doublecortin, was reduced by ∼ ∼ ∼ ∼ 90% in SGZ and by ∼ ∼ ∼ ∼ 50% in SVZ of aged mice. HB-EGF increased BrdU labelling in SGZ at 3 months by ∼ ∼ ∼ ∼ 60% and at 20 months by ∼ ∼ ∼ ∼ 450%, which increased the number of BrdU-labelled cells in SGZ of aged mice to ∼ ∼ ∼ ∼ 25% of that in young adults. FGF-2 also stimulated BrdU labelling in SGZ, by ∼ ∼ ∼ ∼ 25% at 3 months and by ∼ ∼ ∼ ∼ 250% at 20 months, increasing the number of newborn neurones in older mice to ∼ ∼ ∼ ∼ 20% of that in younger mice. In SVZ, HB-EGF and FGF-2 increased BrdU incorporation by ∼ ∼ ∼ ∼ 140% at 3 months and ∼ ∼ ∼ ∼ 170% at 20 months, so the number of BrdU-labelled cells was comparable in untreated 3-month-old and growth factor-treated 20-month-old mice. These results demonstrate that the aged brain retains the capacity to respond to exogenous growth factors with increased neurogenesis, which may have implications for the therapeutic potential of neurogenesis enhancement in age-associated neurological disorders.