Age-dependent effects of TWEAK/Fn14 receptor activation on neural progenitor cells

TWEAK/Fn14 signaling regulates progenitor cell proliferation, differentiation, and survival in multiple organ systems. This study examined the effects of TWEAK (tumor necrosis factor-like weak inducer of apoptosis) treatment on cultured mouse neural progenitor cells. The receptor for TWEAK is expressed by neural progenitor cells from the early embryonic stages through postnatal development. Although embryonic day 12 (E12) and postnatal day 1 (PN1) neural progenitor cells both express the receptor for TWEAK, TWEAK treatment of cultured E12 and PN1 progenitor cells resulted in age-dependent effects on proliferation and on neurite extension by neuronal progeny. TWEAK treatment did not alter proliferation of E12 neural progenitor cells but shifted PN1 progenitor cells toward cell-cycle phases G0 and G1 and reduced the rate at which they incorporated CldU. Conversely, the effects of TWEAK on axon elongation were more prominent in the earlier developmental stage. TWEAK induced extensive neurite outgrowth by the neuronal progeny of E12 but not PN1 progenitors. Treatment of the E12 progenitor cells with a TWEAK-neutralizing antibody repressed neurite extension, indicating that endogenous activation of this pathway may be required for neurite extension by the embryonic neuronal progeny. These studies indicate that TWEAK/Fn14 receptor activation exerts different effects on neural progenitor cells and their progeny depending on the developmental stage of the cells.     

Coupling of angiogenesis and neurogenesis in cultured endothelial cells and neural progenitor cells after stroke.

Angiogenesis and neurogenesis are coupled processes. Using a coculture system, we tested the hypothesis that cerebral endothelial cells activated by ischemia enhance neural progenitor cell proliferation and differentiation, while neural progenitor cells isolated from the ischemic subventricular zone promote angiogenesis. Coculture of neural progenitor cells isolated from the subventricular zone of the adult normal rat with cerebral endothelial cells isolated from the stroke boundary substantially increased neural progenitor cell proliferation and neuronal differentiation and reduced astrocytic differentiation. Conditioned medium harvested from the stroke neural progenitor cells promoted capillary tube formation of normal cerebral endothelial cells. Blockage of vascular endothelial growth factor receptor 2 suppressed the effect of the endothelial cells activated by stroke on neurogenesis as well as the effect of the supernatant obtained from stroke neural progenitor cells on angiogenesis. These data suggest that angiogenesis couples to neurogenesis after stroke and vascular endothelial growth factor likely mediates this coupling.     

A nitric oxide donor induces neurogenesis and reduces functional deficits after stroke in rats.

The adult rodent brain is capable of generating neuronal progenitor cells in the subventricular zone, and in the dentate gyrus of the hippocampus, throughout the life of the animal. Signals that regulate progenitor cell proliferation, differentiation, and migration are not well known. We report that administration of a nitric oxide donor, (Z)-1-[N-(2-aminoethyl)-N-(2-ammonioethyl) aminio]diazen-1-ium-1,2-diolate (DETA/NONOate), to young adult rats significantly increases cell proliferation and migration in the subventricular zone and the dentate gyrus. Treatment with DETA/ NONOate also increases neurogenesis in the dentate gyrus. Furthermore, administration of DETA/NONOate to rats subjected to embolic middle cerebral artery occlusion significantly increases cell proliferation and migration in the subventricular zone and the dentate gyrus, and these rats exhibit significant improvements of neurological outcome during recovery from ischemic stroke. Administration of DETA/NONOate significantly increases cortical levels of guanosine monophosphate both in ischemic and nonischemic rats, supporting the role of nitric oxide in promoting cell proliferation and neurogenesis. Thus, our data indicate that nitric oxide is involved in the regulation of progenitor cells and neurogenesis in the adult brain. This suggests that nitric oxide delivered to the brain well after stroke may have therapeutic benefits.     

GABA sets the tempo for activity-dependent adult neurogenesis

GABA, a major inhibitory neurotransmitter in the adult brain, activates synaptic and extrasynaptic GABA(A) receptors, causing hyperpolarization of mature neurons. As in the embryonic nervous system, GABA depolarizes neural progenitors and immature neurons in the adult brain. Several recent studies have suggested that GABA has crucial roles in regulating different steps of adult neurogenesis, including proliferation of neural progenitors, migration and differentiation of neuroblasts, and synaptic integration of newborn neurons. Here, we review recent findings on how GABA regulates adult neurogenesis in the subventricular zone of the lateral ventricles and in the dentate gyrus of the hippocampus. We also discuss an emerging view that GABA serves as a key mediator of neuronal activity in setting the tempo of adult neurogenesis.     

Visualization of neurogenesis in the central nervous system using nestin promoter-GFP transgenic mice

Neurons are generated from neural progenitor cells not only during development but also in the mature brain. To develop an in vivo system for analyzing neurogenesis, we generated transgenic mice expressing green fluorescent protein (GFP) under the control of regulatory regions of the nestin gene. GFP fluorescence was observed in areas and during periods connected with neurogenesis, including embryonic neuroepithelium, neonatal cerebellum, and hippocampal dentate gyrus and rostral migratory pathway from the subventricular zone to the olfactory bulb in the adult. GFP-positive cells in the adult brain included immature neuronal cells expressing polysialylated NCAM. BrdU labeling experiments revealed that newly generated interneurons which migrated rostrally from the subventricular zone expressed GFP until they reached the olfactory bulb. These results indicate that nestin promoter-GFP transgenic mice can be utilized to visualize the regions of neurogenesis throughout the life of the animals and to follow the migration and differentiation of newly generated neurons.     

Disruption of neurogenesis in the subventricular zone of adult mice,and in human cortical neuronal precursor cells in culture,by amyloid beta-peptide: implications for the pathogenesis of Alzheimer's disease

The adult mammalian brain contains populations of stem cells that can proliferate and then differentiate into neurons or glia. The highest concentration of such neural progenitor cells (NPC) is located in the subventricular zone (SVZ) and these cells can produce new olfactory bulb and cerebral cortical neurons. NPC may provide a cellular reservoir for replacement of cells lost during normal cell turnover and after brain injury. However, neurogenesis does not compensate for neuronal loss in age-related neurodegenerative disorders such as Alzheimer's disease (AD), suggesting the possibility that impaired neurogenesis contributes to the pathogenesis of such disorders. We now report that amyloid beta-peptide (Abeta), a self-aggregating neurotoxic protein thought to cause AD, can impair neurogenesis in the SVZ/cerebral cortex of adult mice and in human cortical NPC in culture. The proliferation and migration of NPC in the SVZ of amyloid precursor protein (APP) mutant mice, and in mice receiving an intraventricular infusion of Abeta, were greatly decreased compared to control mice. Studies of NPC neurosphere cultures derived from human embryonic cerebral cortex showed that Abeta can suppress NPC proliferation and differentiation, and can induce apoptosis. The adverse effects of Abeta on neurogenesis were associated with a disruption of calcium regulation in the NPC. Our data show that Abeta can impair cortical neurogenesis, and suggest that this adverse effect of Abeta contributes to the depletion of neurons and the resulting olfactory and cognitive deficits in AD.     

Induction of the cytokine TWEAK and its receptor Fn14 in ischemic stroke

Stroke outcome is determined by delayed neuronal cell death and edema formation. TWEAK, a cytokine of the TNF superfamily, and its membrane receptor Fn14 promote ischemia-induced neuronal apoptosis and leakage of the blood-brain barrier. Both TWEAK and Fn14 are upregulated in experimental stroke models. In this study, we investigated whether TWEAK and Fn14 are upregulated in stroke patients. We measured serum concentrations of TWEAK in stroke patients and matched control subjects by ELISA. Expression of Fn14 in the brain was evaluated by real-time RT-PCR and immunohistochemistry. TWEAK serum concentrations were elevated in stroke patients. In autopsy samples, we found elevated mRNA levels of the receptor Fn14 and a trend towards higher TWEAK mRNA levels. In the infarcted and peri-infarct tissue immunostaining for Fn14 was enhanced. These data show that the cytokine TWEAK and its membrane receptor Fn14 are upregulated in stroke and suggest that they contribute to stroke outcome.     

缺血性脑损伤与神经干细胞的再生

脑缺血可在成年哺乳动物脑内诱发神经再生,这可能有潜在的治疗价值。本文阐述了脑缺血后神经干细胞的增殖、迁移、分化和整合情况及血管微生态的重要作用,分析了侧脑室下区、齿状回和其他部位的神经再生情况以及老年脑神经再生的特点。     

Endogenous and exogenous ciliary neurotrophic factor enhances forebrain neurogenesis in adult mice

Neurogenesis in the adult mammalian CNS occurs in the subventricular zone (SVZ) and dentate gyrus. The receptor for ciliary neurotrophic factor (CNTF), CNTFRalpha, is expressed in the adult subventricular zone. Because the in vitro effects of CNTF on neural precursors have been varied, including proliferation and differentiation into neurons or glia, we investigated its role in vivo. Injection of CNTF in the adult C57BL/6 mice forebrain increased the number of cells labeled with ip BrdU in both neurogenic regions. In the dentate gyrus, CNTF also appeared to enhance differentiation of precursors into neurons, i.e., increased the proportion of NeuN+/BrdU+ cells from approximately 14 to approximately 29%, but did not affect differentiation into astrocytes (GFAP+) or oligodendrocytes (CNPase+). In the SVZ, CNTF increased the proportion of GFAP+/BrdU+ cells from approximately 1 to approximately 2%. CNTF enhanced the distance of migration of new neurons into the granule cell layer. Intraventricular injection of neutralizing anti-CNTF antibodies reduced the number of BrdU-labeled cells in the SVZ. These results suggest that endogenous CNTF regulates adult neurogenesis by increasing proliferation of neural stem cells and/or precursors. Alternatively, CNTF could maintain cells longer in the S-phase, resulting in increased BrdU labeling. In the neurogenic region of the SVZ, CNTFRalpha was exclusively present in GFAP-positive process-bearing cells, suggesting that CNTF affects neurogenesis indirectly via neighboring astroglia. Alternatively, these cells may be part of the neural precursor lineage. The restricted expression of CNTF within the nervous system makes it a potential selective drug target for cell replacement strategies.     

Meteorin is a chemokinetic factor in neuroblast migration and promotes stroke-induced striatal neurogenesis

Ischemic stroke affecting the adult brain causes increased progenitor proliferation in the subventricular zone (SVZ) and generation of neuroblasts, which migrate into the damaged striatum and differentiate to mature neurons. Meteorin (METRN), a newly discovered neurotrophic factor, is highly expressed in neural progenitor cells and immature neurons during development, suggesting that it may be involved in neurogenesis. Here, we show that METRN promotes migration of neuroblasts from SVZ explants of postnatal rats and stroke-subjected adult rats via a chemokinetic mechanism, and reduces N-methyl-D-asparate-induced apoptotic cell death in SVZ cells in vitro. Stroke induced by middle cerebral artery occlusion upregulates the expression of endogenous METRN in cells with neuronal phenotype in striatum. Recombinant METRN infused into the stroke-damaged brain stimulates cell proliferation in SVZ, promotes neuroblast migration, and increases the number of immature and mature neurons in the ischemic striatum. Our findings identify METRN as a new factor promoting neurogenesis both in vitro and in vivo by multiple mechanisms. Further work will be needed to translate METRN's actions on endogenous neurogenesis into improved recovery after stroke.     

Differential expression of nuclear lamin, the major component of nuclear lamina, during neurogenesis in two germinal regions of adult rat brain

Lamins are major structural proteins of the nuclear envelope. Three lamin subtypes, A/C, B1 and B2, predominate in mammalian somatic cells. While the expression levels of lamins in several tissues are known to change during cell differentiation, lamin expression is poorly understood in the nervous system. To investigate the expression of lamins during neuronal differentiation in the mammalian adult brain, we performed immunohistochemical studies on lamins A/C, B1 and B2 in two neurogenic regions of rat brain: the subgranular zone of the dentate gyrus and the subventricular zone of the lateral ventricle. In particular, three types of cells were analysed using confocal microscopy: GFAP-positive cells as primary progenitor (stem) cells, PSA-NCAM-positive cells as subsequent neuronal progenitor cells, and NeuN-positive mature neurons. GFAP-positive cells possesed lamin A/C (++), B1 (++) and B2 (++), PSA-NCAM-positive cells possessed lamin A/C (-), B1 (+++) and B2 (+), and mature neurons possessed lamin A/C (++), B1 (+) and B2 (+++), in both neurogenic regions. These observations showed that the compositions of expressing lamin subtypes are distinct in particular differentiation stages during neurogenesis in the adult rat brain. Our results suggest that the alteration of nuclear lamina structure is coupled with the progression of neuronal differentiation.     

Impaired neurogenesis is an early event in the etiology of familial Alzheimer's disease in transgenic mice

Formation of new neurons in the adult brain takes place in the subventricular zone and in the subgranule layer of the dentate gyrus throughout life. Neurogenesis is thought to play a role in hippocampus‐ and olfaction‐dependent learning and memory. However, whether impairments in neurogenesis take place in learning and memory disorders, such as Alzheimer's disease, is yet to be established. Importantly, it remains to be elucidated whether neurogenic impairments play a role in the course of the disease or are the result of extensive neuropathology. We now report that transgenic mice harboring familial Alzheimer's disease‐linked mutant APPswe/PS1ΔE9 exhibit severe impairments in neurogenesis that are evident as early as 2 months of age. These mice exhibit a significant reduction in the proliferation of neural progenitor cells and their neuronal differentiation. Interestingly, levels of hyperphosphorylated tau, the cytotoxic precursor of the Alzheimer's disease hallmark neurofibrillary tangles, are particularly high in the neurogenic niches. Isolation of neural progenitor cells in culture reveals that APPswe/PS1ΔE9‐expressing neurospheres exhibit impaired proliferation and tau hyperphosphorylation compared with wildtype neurospheres isolated from nontransgenic littermates. This study suggests that impaired neurogenesis is an early critical event in the course of Alzheimer's disease that may underlie memory impairments, at least in part, and exacerbate neuronal vulnerability in the hippocampal formation and olfaction circuits. Furthermore, impaired neurogenesis is the result of both intrinsic pathology in neural progenitor cells and extrinsic neuropathology in the neurogenic niches. Finally, hyperphosphorylation of the microtubule‐associated protein tau, a critical player in cell proliferation, neuronal maturation, and axonal transport, is a major contributor to impaired neurogenesis in Alzheimer's disease. © 2010 Wiley‐Liss, Inc.