Pub Date : 2008-01-01DOI: 10.1101/087969784.52.159
G. Kempermann, Hongjun Song, F. Gage
As noted previously in this volume, adult neurogenesis is a process, not an event. Adult neurogenesis comprises a series of sequential developmental events that are all necessary for the generation of new neurons under the conditions of the adult brain. In the original publications on adult neurogenesis, the precursor cell population from which neurogenesis originates was identified only by the detection of proliferative activity and the absence of mature neuronal markers (Altman and Das 1965; Kaplan and Hinds 1977; Cameron et al. 1993; Kuhn et al. 1996). The new neurons, in contrast, were identified by the presence of mature neuronal markers in cells that had been birthmarked with the thymidineoder BrdU (bromodeoxyuridine) method (see Chapters 2 and 3) a couple of weeks earlier. The expression of the polysialilated neural cell adhesion molecule (PSA-NCAM) with neurogenesis has been noted early but could not be clearly linked to either proliferation or mature stage (Seki and Arai 1993a,b). PSA-NCAM expression was the first indication of the developmental events that take place, filling the gaps between the start and endpoint of development. Today, we have quite detailed knowledge about the course of neuronal development in the adult hippocampus, and although many detailed questions remain open, a clear overall picture has emerged (Kempermann et al. 2004; Abrous et al. 2005; Ming and Song 2005; Lledo et al. 2006). Although we coarsely talk about neurogenesis in the hippocampus, it should be noted that neurogenesis occurs only in the dentate gyrus (DG), not other regions; in an...
如前所述，成人神经发生是一个过程，而不是一个事件。成人神经发生包括一系列连续的发育事件，这些事件都是在成人大脑条件下产生新神经元所必需的。在关于成人神经发生的原始出版物中，神经发生起源的前体细胞群仅通过检测增殖活性和缺乏成熟神经元标记物来识别(Altman和Das 1965;卡普兰和海因兹1977;Cameron et al. 1993;Kuhn et al. 1996)。相比之下，新神经元是通过在几周前用胸腺嘧啶生成的BrdU(溴脱氧尿苷)方法(见第2章和第3章)中存在的成熟神经元标记物来识别的。多唾液化神经细胞粘附分子(PSA-NCAM)在神经发生过程中的表达早被发现，但不能明确地将其与增殖或成熟阶段联系起来(Seki和Arai 1993a,b)。PSA-NCAM的表达是发育事件发生的第一个指示，填补了发育起点和终点之间的空白。今天，我们对成人海马体中神经元发育的过程有了相当详细的了解，尽管许多细节问题仍未解决，但一个清晰的总体图景已经出现(Kempermann et al. 2004;Abrous et al. 2005;明宋2005;Lledo et al. 2006)。虽然我们粗略地谈论海马中的神经发生，但应该注意的是，神经发生只发生在齿状回(DG)，而不是其他区域;在一个…
{"title":"9 Neurogenesis in the Adult Hippocampus","authors":"G. Kempermann, Hongjun Song, F. Gage","doi":"10.1101/087969784.52.159","DOIUrl":"https://doi.org/10.1101/087969784.52.159","url":null,"abstract":"As noted previously in this volume, adult neurogenesis is a process, not an event. Adult neurogenesis comprises a series of sequential developmental events that are all necessary for the generation of new neurons under the conditions of the adult brain. In the original publications on adult neurogenesis, the precursor cell population from which neurogenesis originates was identified only by the detection of proliferative activity and the absence of mature neuronal markers (Altman and Das 1965; Kaplan and Hinds 1977; Cameron et al. 1993; Kuhn et al. 1996). The new neurons, in contrast, were identified by the presence of mature neuronal markers in cells that had been birthmarked with the thymidineoder BrdU (bromodeoxyuridine) method (see Chapters 2 and 3) a couple of weeks earlier. The expression of the polysialilated neural cell adhesion molecule (PSA-NCAM) with neurogenesis has been noted early but could not be clearly linked to either proliferation or mature stage (Seki and Arai 1993a,b). PSA-NCAM expression was the first indication of the developmental events that take place, filling the gaps between the start and endpoint of development. Today, we have quite detailed knowledge about the course of neuronal development in the adult hippocampus, and although many detailed questions remain open, a clear overall picture has emerged (Kempermann et al. 2004; Abrous et al. 2005; Ming and Song 2005; Lledo et al. 2006). Although we coarsely talk about neurogenesis in the hippocampus, it should be noted that neurogenesis occurs only in the dentate gyrus (DG), not other regions; in an...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"25 1","pages":"159-174"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83345851","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-01DOI: 10.1101/087969824.51.427
G. Lithgow, Richard A. Miller
This chapter explores the hypothesis that declines in aging rate, whether produced by evolutionary adaptations, single gene mutations, or dietary interventions, reflect alterations in a stress resistance pathway that increases cellular resistance to multiple forms of stress. We argue that such a stress resistance pathway evolved early in the eukaryotic lineage to allow small short-lived organisms to adjust their life history styles to intermittent environmental fluctuations and that as multicellular organisms evolved, they linked regulated stress-response mechanisms to a variety of hormonal and nutritional triggers specific for their own environmental niche. We believe that this model, although surely oversimplified, helps to explain much of the experimental data on stress and aging. We will try to show that the model provides a helpful heuristic framework for developing new experimental approaches to learn about the connections linking stress resistance, developmental biology, and endocrine controls to the aging process and, ultimately, to modulation of life span and most if not all of the diseases of aging. We must start with working definitions of two key terms: aging and stress. By “aging” we mean the process that gradually transforms healthy and vigorous adults into older adults with diminished ability to meet a wide range of physiological challenges and, concomitantly, increased susceptibility to multiple forms of illness, injury, and death. This definition emphasizes the process of aging, rather than its outcome, the aged individual, in order to highlight the changes that occur, even in young and middle-aged adults, and lead eventually to infirmity. In this...
{"title":"16 Determination of Aging Rate by Coordinated Resistance to Multiple Forms of Stress","authors":"G. Lithgow, Richard A. Miller","doi":"10.1101/087969824.51.427","DOIUrl":"https://doi.org/10.1101/087969824.51.427","url":null,"abstract":"This chapter explores the hypothesis that declines in aging rate, whether produced by evolutionary adaptations, single gene mutations, or dietary interventions, reflect alterations in a stress resistance pathway that increases cellular resistance to multiple forms of stress. We argue that such a stress resistance pathway evolved early in the eukaryotic lineage to allow small short-lived organisms to adjust their life history styles to intermittent environmental fluctuations and that as multicellular organisms evolved, they linked regulated stress-response mechanisms to a variety of hormonal and nutritional triggers specific for their own environmental niche. We believe that this model, although surely oversimplified, helps to explain much of the experimental data on stress and aging. We will try to show that the model provides a helpful heuristic framework for developing new experimental approaches to learn about the connections linking stress resistance, developmental biology, and endocrine controls to the aging process and, ultimately, to modulation of life span and most if not all of the diseases of aging. We must start with working definitions of two key terms: aging and stress. By “aging” we mean the process that gradually transforms healthy and vigorous adults into older adults with diminished ability to meet a wide range of physiological challenges and, concomitantly, increased susceptibility to multiple forms of illness, injury, and death. This definition emphasizes the process of aging, rather than its outcome, the aged individual, in order to highlight the changes that occur, even in young and middle-aged adults, and lead eventually to infirmity. In this...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"51 1","pages":"427-481"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87924128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-01DOI: 10.1101/087969752.50.151
J. Wrana, B. Ozdamar, C. Roy, H. Benchabane
Transforming growth factor-β (TGF-β) is the prototypical member of a family of structurally related cytokines that function as secreted morphogens to control cell fate throughout development and during homeostasis. TGF-β-related molecules are expressed in all metazoan organisms investigated to date and include TGF-βs, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins, inhibins, Mullerian inhibiting substance (MIS, also termed anti-Mullerian hormone, AMH), nodal, and leftys (de Caestecker 2004). In multicellular organisms, extracellular cues are critical to allow the specialization of cell function and the establishment of complex tissues. Transmembrane signaling receptors are the primary conduit whereby extracellular polypeptide cues regulate cell function. Broad classes of signaling receptors have been defined for a range of extracellular factors, including multipass transmembrane receptors, such as G-protein-coupled receptors; Frizzleds, which transduce Wnt signals; and Smoothened and Patched, which regulate Hedgehog signals. A broad range of structurally diverse receptors with single transmembrane regions have also been defined. Their intracellular regions can harbor catalytic domains, such as the receptor tyrosine kinases (RTKs), or can serve as scaffolds that mediate the assembly of large, multicomponent signaling complexes, usually in response to ligand-induced receptor clustering. Finally, coreceptors can promote binding of extracellular factors to their appropriate signaling receptors and thus have a critical role in mediating high-affinity and high-specificity interactions. For example, the glycosaminoglycan heparin sulfate, which is found in the extracellular environment, is required for fibroblast growth factor (FGF) binding to its cognate RTK signaling receptors. Coreceptors can also be tethered to the membrane via glycosylphosphatidylinositol...
{"title":"6 Signaling Receptors of the TGF-β Family","authors":"J. Wrana, B. Ozdamar, C. Roy, H. Benchabane","doi":"10.1101/087969752.50.151","DOIUrl":"https://doi.org/10.1101/087969752.50.151","url":null,"abstract":"Transforming growth factor-β (TGF-β) is the prototypical member of a family of structurally related cytokines that function as secreted morphogens to control cell fate throughout development and during homeostasis. TGF-β-related molecules are expressed in all metazoan organisms investigated to date and include TGF-βs, bone morphogenetic proteins (BMPs), growth and differentiation factors (GDFs), activins, inhibins, Mullerian inhibiting substance (MIS, also termed anti-Mullerian hormone, AMH), nodal, and leftys (de Caestecker 2004). In multicellular organisms, extracellular cues are critical to allow the specialization of cell function and the establishment of complex tissues. Transmembrane signaling receptors are the primary conduit whereby extracellular polypeptide cues regulate cell function. Broad classes of signaling receptors have been defined for a range of extracellular factors, including multipass transmembrane receptors, such as G-protein-coupled receptors; Frizzleds, which transduce Wnt signals; and Smoothened and Patched, which regulate Hedgehog signals. A broad range of structurally diverse receptors with single transmembrane regions have also been defined. Their intracellular regions can harbor catalytic domains, such as the receptor tyrosine kinases (RTKs), or can serve as scaffolds that mediate the assembly of large, multicomponent signaling complexes, usually in response to ligand-induced receptor clustering. Finally, coreceptors can promote binding of extracellular factors to their appropriate signaling receptors and thus have a critical role in mediating high-affinity and high-specificity interactions. For example, the glycosaminoglycan heparin sulfate, which is found in the extracellular environment, is required for fibroblast growth factor (FGF) binding to its cognate RTK signaling receptors. Coreceptors can also be tethered to the membrane via glycosylphosphatidylinositol...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"117 1","pages":"151-177"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87964106","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-01DOI: 10.1101/087969752.50.789
J. Letterio, F. Ruscetti
As in most systems, the three mammalian transforming growth factor-β (TGF-β) isoforms, TGF-β1, -β2, and -β3, have distinct but overlapping effects on hematopoiesis. The activity of each isoform is concentration dependent and invariably influenced by both the differentiation stage of the target cell and the local microenvironment (Ruscetti and Bartelmez 2001; Henckaerts et al. 2004). For example, TGF-β promotes or suppresses the proliferative, apoptotic, and differentiation responses in myeloid and lymphoid progenitors and can either inhibit or increase terminally differentiated cell function (Fig. 1). The molecular basis of these disparate responses is, in part, the result of cross-talk between the TGF-β signaling pathways and those of multiple other hematopoietic regulatory cytokines and may be related to the often indirect regulation of the function and differentiation of these cells, for example, through effects on the bone marrow microenvironment. In addition, the paracrine and autocrine actions of TGF-β have overlapping but distinct regulatory effects on hematopoietic stem/progenitor cells. Loss-of-function mutations affecting TGF-β signaling in hematopoietic stem cells (HSCs) have significant effects on hematopoiesis that frequently differ from those induced by a transient blockade of autocrine TGF-β1. Such differences, which are most apparent in assays of regulation of HSC quiescence by TGF-β, may be attributed to the activities of TGF-β at numerous steps in the hematopoietic cascade and suggest a therapeutic potential of transient neutralization of autocrine TGF-β in HSCs (Fortunel et al. 2000). During myeloid and lymphoid cell development, TGF-β1 and/or its Smad signals regulate the response of the progenitor cells to...
在大多数系统中，三种哺乳动物转化生长因子-β (TGF-β)亚型，TGF-β1， -β2和-β3，对造血有不同但重叠的作用。每种异构体的活性都是浓度依赖性的，并且总是受到目标细胞分化阶段和当地微环境的影响(Ruscetti和Bartelmez 2001;Henckaerts et al. 2004)。例如，TGF-β促进或抑制髓系和淋巴系祖细胞的增殖、凋亡和分化反应，并可以抑制或增加终分化细胞功能(图1)。这些不同反应的分子基础部分是:TGF-β信号通路与多种其他造血调节细胞因子的信号通路相互作用的结果，可能与这些细胞的功能和分化经常间接调节有关，例如通过对骨髓微环境的影响。此外，TGF-β的旁分泌和自分泌作用对造血干细胞/祖细胞具有重叠但不同的调节作用。影响造血干细胞(hsc)中TGF-β信号传导的功能缺失突变对造血功能有显著影响，这与短暂阻断自分泌TGF-β1诱导的造血功能不同。这种差异在TGF-β对HSC静止调节的实验中最为明显，这可能归因于TGF-β在造血级联的许多步骤中的活性，并表明在HSC中短暂中和自分泌TGF-β具有治疗潜力(Fortunel等人，2000)。在髓细胞和淋巴细胞发育过程中，TGF-β1和/或其Smad信号调节祖细胞对…
{"title":"25 TGF-β as a Regulator of Myeloid and Lymphoid Development and Function","authors":"J. Letterio, F. Ruscetti","doi":"10.1101/087969752.50.789","DOIUrl":"https://doi.org/10.1101/087969752.50.789","url":null,"abstract":"As in most systems, the three mammalian transforming growth factor-β (TGF-β) isoforms, TGF-β1, -β2, and -β3, have distinct but overlapping effects on hematopoiesis. The activity of each isoform is concentration dependent and invariably influenced by both the differentiation stage of the target cell and the local microenvironment (Ruscetti and Bartelmez 2001; Henckaerts et al. 2004). For example, TGF-β promotes or suppresses the proliferative, apoptotic, and differentiation responses in myeloid and lymphoid progenitors and can either inhibit or increase terminally differentiated cell function (Fig. 1). The molecular basis of these disparate responses is, in part, the result of cross-talk between the TGF-β signaling pathways and those of multiple other hematopoietic regulatory cytokines and may be related to the often indirect regulation of the function and differentiation of these cells, for example, through effects on the bone marrow microenvironment. In addition, the paracrine and autocrine actions of TGF-β have overlapping but distinct regulatory effects on hematopoietic stem/progenitor cells. Loss-of-function mutations affecting TGF-β signaling in hematopoietic stem cells (HSCs) have significant effects on hematopoiesis that frequently differ from those induced by a transient blockade of autocrine TGF-β1. Such differences, which are most apparent in assays of regulation of HSC quiescence by TGF-β, may be attributed to the activities of TGF-β at numerous steps in the hematopoietic cascade and suggest a therapeutic potential of transient neutralization of autocrine TGF-β in HSCs (Fortunel et al. 2000). During myeloid and lymphoid cell development, TGF-β1 and/or its Smad signals regulate the response of the progenitor cells to...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"28 1","pages":"789-817"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83597646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-01DOI: 10.1101/087969784.52.593
S. Goldman
The damaged brain has traditionally been thought to exhibit little significant structural repair after injury. In part, this appears to reflect the failure of the mature forebrain to generate new neurons, except for a few discrete, relatively archaic regions of the brain, the hippocampus and olfactory bulb (OB) (Altman and Das 1966; Bayer et al. 1982; for review, see Goldman 1998; Alvarez-Buylla and Garcia-Verdugo 2002; Gage 2002). The limitation on neuronal addition to the adult brain has clearly been selected, and thus comprises an adaptation of likely, if unclear, evolutionary benefit. Among other possibilities, the lack of persistent neurogenesis in most regions of the adult mammalian brain may be associated with the need to stabilize the retention of long-term memories and entrained behaviors (Rakic 2002). Perhaps as a result, the adult mammalian neocortex exhibits no constitutive neuronal addition, and little or none after injury, except for discrete experimental lesions of defined neuronal populations (Magavi et al. 2000). In contrast, the subcortical neostriatum retains the capacity to regenerate neurons after stroke and major traumatic injury (Arvidsson et al. 2002; Parent et al. 2002; Jin et al. 2003a; Parent 2003). However, the numbers of striatal neurons generated in response to stroke have thus far been described as comprising only a small fraction of the population lost to the ischemic insult and have not yet been demonstrated to contribute to functional recovery. In general terms, the lack of compensatory neuronal replacement in most adult brain regions has impeded not only the recovery of...
传统上认为，受损的大脑在受伤后几乎没有明显的结构修复。在某种程度上，这似乎反映了成熟的前脑不能产生新的神经元，除了大脑中一些离散的、相对古老的区域，海马体和嗅球(OB) (Altman and Das 1966;Bayer et al. 1982;回顾，见Goldman 1998;Alvarez-Buylla和Garcia-Verdugo 2002;计2002)。对成年大脑神经元添加的限制显然是被选择的，因此包含了一种可能的(如果不清楚的话)进化益处的适应。在其他可能性中，在成年哺乳动物大脑的大多数区域缺乏持续的神经发生可能与需要稳定长期记忆的保留和被训练的行为有关(Rakic 2002)。也许正因为如此，成年哺乳动物的新皮层在损伤后没有出现构成性神经元的增加，除了特定神经元群的离散实验损伤外，几乎没有神经元的增加(Magavi et al. 2000)。相反，皮层下新纹状体在中风和重大创伤性损伤后仍保留再生神经元的能力(Arvidsson等，2002;Parent等人，2002;Jin et al. 2003a;父母2003年)。然而，迄今为止，对中风产生的纹状体神经元的数量被描述为仅占缺血性损伤损失的一小部分，尚未被证明有助于功能恢复。一般来说，大多数成人大脑区域缺乏代偿性神经元替代不仅阻碍了…
{"title":"28 Neurogenesis in the Adult Songbird: A Model for Inducible Striatal Neuronal Addition","authors":"S. Goldman","doi":"10.1101/087969784.52.593","DOIUrl":"https://doi.org/10.1101/087969784.52.593","url":null,"abstract":"The damaged brain has traditionally been thought to exhibit little significant structural repair after injury. In part, this appears to reflect the failure of the mature forebrain to generate new neurons, except for a few discrete, relatively archaic regions of the brain, the hippocampus and olfactory bulb (OB) (Altman and Das 1966; Bayer et al. 1982; for review, see Goldman 1998; Alvarez-Buylla and Garcia-Verdugo 2002; Gage 2002). The limitation on neuronal addition to the adult brain has clearly been selected, and thus comprises an adaptation of likely, if unclear, evolutionary benefit. Among other possibilities, the lack of persistent neurogenesis in most regions of the adult mammalian brain may be associated with the need to stabilize the retention of long-term memories and entrained behaviors (Rakic 2002). Perhaps as a result, the adult mammalian neocortex exhibits no constitutive neuronal addition, and little or none after injury, except for discrete experimental lesions of defined neuronal populations (Magavi et al. 2000). In contrast, the subcortical neostriatum retains the capacity to regenerate neurons after stroke and major traumatic injury (Arvidsson et al. 2002; Parent et al. 2002; Jin et al. 2003a; Parent 2003). However, the numbers of striatal neurons generated in response to stroke have thus far been described as comprising only a small fraction of the population lost to the ischemic insult and have not yet been demonstrated to contribute to functional recovery. In general terms, the lack of compensatory neuronal replacement in most adult brain regions has impeded not only the recovery of...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"75 1","pages":"593-617"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85252058","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-01DOI: 10.1101/087969824.51.371
P. Wong, D. Price, L. Bertram, R. E. Tanzi
Alzheimer’s disease (AD), manifest as progressive loss of memory and cognitive impairments, affects more than 4 million individuals in the United States (Brookmeyer et al. 1998; Mayeux 2003; Cummings 2004; Wong et al. 2006). The index case, a middle-aged woman with behavioral disturbances and dementia, was described more than 100 years ago (Goedert and Spillantini 2006a; Hardy 2006a; Roberson and Mucke 2006; Small and Gandy 2006; Mandkelkow et al. 2007). Due to the postwar baby boom and increased life expectancy, the elderly are the most rapidly growing segment of our society and the number of persons with AD is predicted to triple over the next several decades. Prevalence, cost of care, impact on individuals and caregivers, and lack of mechanism-based treatments make AD one of the most challenging diseases of this new century (Price et al. 1998; Wong et al. 2002, 2006; Selkoe and Schenk 2003; Citron 2004a,b; Cummings 2004; Walsh and Selkoe 2004). This dementia syndrome results from dysfunction and death of neurons in specific brain regions/circuits, particularly those populations of neurons participating in memory and cognitive functions (Whitehouse et al. 1982; Hyman et al. 1984; Braak and Braak 1991, 1994; West et al. 1994, 2000, 2004; Price et al. 1998). The characteristic neuropathology of AD includes intracellular accumulations of phosphorylated Tau assembled in paired helical filaments (PHFs) within neurofibrillary tangles (NFTs) and abnormal neuritis, as well as extracellular Aβ peptide oligomers that, as aggregates, are at the core of neuritic amyloid plaques and represent sites of synaptic disconnection...
阿尔茨海默病(AD)表现为进行性记忆丧失和认知障碍，在美国影响了400多万人(Brookmeyer等人，1998;麦克斯2003;卡明斯2004;Wong et al. 2006)。索引病例是一位患有行为障碍和痴呆的中年妇女，早在100多年前就有记载(Goedert and Spillantini 2006a;哈迪2006;Roberson and Mucke 2006;Small and Gandy 2006;Mandkelkow et al. 2007)。由于战后婴儿潮和预期寿命的延长，老年人是我们社会中增长最快的部分，预计在未来几十年里，老年痴呆症患者的数量将增加两倍。患病率、护理费用、对个人和护理者的影响以及缺乏基于机制的治疗使阿尔茨海默病成为新世纪最具挑战性的疾病之一(Price et al. 1998;Wong et al. 2002, 2006;Selkoe and Schenk 2003;Citron 2004 a, b;卡明斯2004;Walsh and Selkoe 2004)。这种痴呆综合征是由特定脑区/回路的神经元功能障碍和死亡引起的，特别是那些参与记忆和认知功能的神经元群(Whitehouse et al. 1982;Hyman et al. 1984;Braak and Braak 1991,1994;West et al. 1994,2000,2004;Price et al. 1998)。阿尔茨海默病的特征性神经病理学包括在神经原纤维缠结(nft)内成对螺旋丝(PHFs)中组装的磷酸化Tau细胞内积聚和异常神经炎，以及作为聚集体的细胞外Aβ肽寡聚物，它们位于神经性淀粉样斑块的核心，代表突触断开的部位。
{"title":"14 Alzheimer’s Disease: Genetics, Pathogenesis, Models, and Experimental Therapeutics","authors":"P. Wong, D. Price, L. Bertram, R. E. Tanzi","doi":"10.1101/087969824.51.371","DOIUrl":"https://doi.org/10.1101/087969824.51.371","url":null,"abstract":"Alzheimer’s disease (AD), manifest as progressive loss of memory and cognitive impairments, affects more than 4 million individuals in the United States (Brookmeyer et al. 1998; Mayeux 2003; Cummings 2004; Wong et al. 2006). The index case, a middle-aged woman with behavioral disturbances and dementia, was described more than 100 years ago (Goedert and Spillantini 2006a; Hardy 2006a; Roberson and Mucke 2006; Small and Gandy 2006; Mandkelkow et al. 2007). Due to the postwar baby boom and increased life expectancy, the elderly are the most rapidly growing segment of our society and the number of persons with AD is predicted to triple over the next several decades. Prevalence, cost of care, impact on individuals and caregivers, and lack of mechanism-based treatments make AD one of the most challenging diseases of this new century (Price et al. 1998; Wong et al. 2002, 2006; Selkoe and Schenk 2003; Citron 2004a,b; Cummings 2004; Walsh and Selkoe 2004). This dementia syndrome results from dysfunction and death of neurons in specific brain regions/circuits, particularly those populations of neurons participating in memory and cognitive functions (Whitehouse et al. 1982; Hyman et al. 1984; Braak and Braak 1991, 1994; West et al. 1994, 2000, 2004; Price et al. 1998). The characteristic neuropathology of AD includes intracellular accumulations of phosphorylated Tau assembled in paired helical filaments (PHFs) within neurofibrillary tangles (NFTs) and abnormal neuritis, as well as extracellular Aβ peptide oligomers that, as aggregates, are at the core of neuritic amyloid plaques and represent sites of synaptic disconnection...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"13 1","pages":"371-407"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73839634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-01DOI: 10.1101/087969752.50.585
T. Watabe, K. Miyazono
Stem cells are defined as cells that have the ability to perpetuate themselves through self-renewal and to generate mature cells of a particular tissue through differentiation. Embryonic stem (ES) cells self-renew indefinitely and give rise to derivatives of all three primary germ layers. Somatic stem cells have also been identified in various adult organs, and in most cases, they exhibit limited abilities for self-renewal and differentiation. The capacity of ES cells and somatic stem cells for multilineage differentiation may yield replacement cell therapies for genetic, malignant, and degenerative diseases. The signaling cascades that govern stem cell renewal and differentiation have been the subject of extensive studies. The first half of this chapter describes how transforming growth factor-β (TGF-β) family signaling, in cooperation with other signaling cascades, maintains the self-renewal and pluripotency of human and mouse ES cells and induces their differentiation toward specific cell lineages. The second half of this chapter discusses the roles of TGF-β family signaling in the self-renewal and differentiation of somatic stem cells. TGF-β FAMILY SIGNALING IN ES CELLS Establishment of Mouse and Human ES Cells and Their Unique Features During early mouse embryogenesis, embryos are partitioned into extraembryonic and embryonic components. The embryonic component, referred to as the inner cell mass, is the source of all tissues of the developing embryo and fetus, and ultimately the adult organism. The inner cell mass also serves as the source of mouse ES cells. One of the defining features of mouse ES cells is their potential to undergo...
{"title":"20 TGF-β Family Signaling in Stem Cell Renewal and Differentiation","authors":"T. Watabe, K. Miyazono","doi":"10.1101/087969752.50.585","DOIUrl":"https://doi.org/10.1101/087969752.50.585","url":null,"abstract":"Stem cells are defined as cells that have the ability to perpetuate themselves through self-renewal and to generate mature cells of a particular tissue through differentiation. Embryonic stem (ES) cells self-renew indefinitely and give rise to derivatives of all three primary germ layers. Somatic stem cells have also been identified in various adult organs, and in most cases, they exhibit limited abilities for self-renewal and differentiation. The capacity of ES cells and somatic stem cells for multilineage differentiation may yield replacement cell therapies for genetic, malignant, and degenerative diseases. The signaling cascades that govern stem cell renewal and differentiation have been the subject of extensive studies. The first half of this chapter describes how transforming growth factor-β (TGF-β) family signaling, in cooperation with other signaling cascades, maintains the self-renewal and pluripotency of human and mouse ES cells and induces their differentiation toward specific cell lineages. The second half of this chapter discusses the roles of TGF-β family signaling in the self-renewal and differentiation of somatic stem cells. TGF-β FAMILY SIGNALING IN ES CELLS Establishment of Mouse and Human ES Cells and Their Unique Features During early mouse embryogenesis, embryos are partitioned into extraembryonic and embryonic components. The embryonic component, referred to as the inner cell mass, is the source of all tissues of the developing embryo and fetus, and ultimately the adult organism. The inner cell mass also serves as the source of mouse ES cells. One of the defining features of mouse ES cells is their potential to undergo...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"67 1","pages":"585-611"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83589148","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
During development, neurogenesis is a multistep process that includes cell proliferation, cell cycle exit, a choice between survival and death, cell migration, cell differentiation, and cell-fate decisions, including neuron versus glia and neuronal cell class decisions (for review, see Nowakowski et al. 2002). The same multiple steps and associated decisions occur during adult neurogenesis but with several significant differences, the most important being that (1) there are fewer proliferating cells during adult neurogenesis and (2) the selection of neuronal cell classes produced is limited. With respect to the ultimate outcome—the production of functional neurons—each step in this multistep process is, in effect, a possible site of regulation. The complexity of these regulatory steps is described in the other chapters of this book. In this chapter, we deal with the early steps in the process of neurogenesis, i.e., cell proliferation and cell cycle exit. We discuss how the number of cells produced during neurogenesis is regulated by the proliferative capacity of a population of dividing cells. The proliferative capacity, in turn, is determined by the length of the cell cycle, the number of proliferating cells, and the proportion of daughter cells that exit versus reenter the cell cycle. In addition, we review some of the methods for measuring these properties and discuss some of the pitfalls that are commonly encountered. CELL CYCLE CHARACTERIZATION Neurogenesis is driven by cell proliferation, and the core process of cell proliferation is the cell cycle. Conceptually, the cell cycle is simple (Fig. 1A). It...
{"title":"2 Numerology of Neurogenesis: Characterizing the Cell Cycle of Neurostem Cells","authors":"R. Nowakowski, N. L. Hayes","doi":"10.1101/087969784.52.7","DOIUrl":"https://doi.org/10.1101/087969784.52.7","url":null,"abstract":"During development, neurogenesis is a multistep process that includes cell proliferation, cell cycle exit, a choice between survival and death, cell migration, cell differentiation, and cell-fate decisions, including neuron versus glia and neuronal cell class decisions (for review, see Nowakowski et al. 2002). The same multiple steps and associated decisions occur during adult neurogenesis but with several significant differences, the most important being that (1) there are fewer proliferating cells during adult neurogenesis and (2) the selection of neuronal cell classes produced is limited. With respect to the ultimate outcome—the production of functional neurons—each step in this multistep process is, in effect, a possible site of regulation. The complexity of these regulatory steps is described in the other chapters of this book. In this chapter, we deal with the early steps in the process of neurogenesis, i.e., cell proliferation and cell cycle exit. We discuss how the number of cells produced during neurogenesis is regulated by the proliferative capacity of a population of dividing cells. The proliferative capacity, in turn, is determined by the length of the cell cycle, the number of proliferating cells, and the proportion of daughter cells that exit versus reenter the cell cycle. In addition, we review some of the methods for measuring these properties and discuss some of the pitfalls that are commonly encountered. CELL CYCLE CHARACTERIZATION Neurogenesis is driven by cell proliferation, and the core process of cell proliferation is the cell cycle. Conceptually, the cell cycle is simple (Fig. 1A). It...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"435 1","pages":"7-23"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83620722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The term “adult neurogenesis” is used to describe the observation that, in the adult mammalian brain, new neurons are born from stem cells residing in discrete locations and these new neurons migrate, differentiate, and mature into newly integrated, functioning cells. By virtue of this definition, adult neurogenesis is a process, not an event, and as such, can be dissected and examined in evermore discrete components. In general, researchers seek a complete understanding of not only the details of these separate components but also the purpose and function of this process as a whole. Once the tools became available to monitor and measure adult neurogenesis, the interest in this process grew enormously, not the least because the birth and integration of new neurons in the adult brain constitute the most extreme cases of neuroplasticity in the adult brain. While the phenomenon is interesting enough to investigate and understand in the normal, healthy brain, the fact that this process is also disrupted in many disease states adds substantially to the numbers of those studying adult neurogenesis. As a result, a new way of looking at brain therapy has emerged that incorporates the potential of generating new neurons in the context of aging and disease into the search for a strategy for “self-repair.” The idea for this book originated from a meeting on adult neurogenesis in the adult brain held at the Banbury Conference Center at Cold Spring Harbor Laboratory in February 2006. In the secluded and intimate setting of this event, the
{"title":"Preface/Front Matter","authors":"F. Gage, G. Kempermann, Hongjun Song","doi":"10.1101/087969784.52.I","DOIUrl":"https://doi.org/10.1101/087969784.52.I","url":null,"abstract":"The term “adult neurogenesis” is used to describe the observation that, in the adult mammalian brain, new neurons are born from stem cells residing in discrete locations and these new neurons migrate, differentiate, and mature into newly integrated, functioning cells. By virtue of this definition, adult neurogenesis is a process, not an event, and as such, can be dissected and examined in evermore discrete components. In general, researchers seek a complete understanding of not only the details of these separate components but also the purpose and function of this process as a whole. Once the tools became available to monitor and measure adult neurogenesis, the interest in this process grew enormously, not the least because the birth and integration of new neurons in the adult brain constitute the most extreme cases of neuroplasticity in the adult brain. While the phenomenon is interesting enough to investigate and understand in the normal, healthy brain, the fact that this process is also disrupted in many disease states adds substantially to the numbers of those studying adult neurogenesis. As a result, a new way of looking at brain therapy has emerged that incorporates the potential of generating new neurons in the context of aging and disease into the search for a strategy for “self-repair.” The idea for this book originated from a meeting on adult neurogenesis in the adult brain held at the Banbury Conference Center at Cold Spring Harbor Laboratory in February 2006. In the secluded and intimate setting of this event, the","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84152338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2008-01-01DOI: 10.1101/087969784.52.341
G. Kempermann
Age and activity might be considered the two antagonistic key regulators of adult neurogenesis. Whereas adult neurogenesis declines with age, different kinds of “activities” positively regulate adult neurogenesis. An interaction between these two mechanisms exists. Aging influences aging, and activity affects aging processes. Aging is a principal determinant of life and as such cuts across all biological, psychological, and sociological research. The very essence of aging is difficult to conceptualize, because it is a uniquely omnipresent variable. Aging can thus only be addressed in an transdisciplinary approach, especially if the consequences of aging on complex brain functions are to be studied. In the context of neurogenesis research, “aging” has so far been largely equaled with the biology of long timescales. Implicit in this understanding is that age-dependent changes essentially reflect a unidirectional development in that everything builds on what has occurred before. In this sense, aging can also be seen as continued or lifelong development. This idea has limitations but is instructive with regard to adult neurogenesis because adult neurogenesis is neuronal development under the conditions of the adult brain. The age-related alterations of adult neurogenesis themselves have quantitative and qualitative components. So far, most research has focused on the quantitative aspects. But there can be little doubt that qualitative changes do not simply follow quantitative changes, for example, in cell or synapse numbers but emerge on a systems level and above, when an organism ages. The observation that adult neurogenesis is regulated by activity relates to this idea. From...
{"title":"17 Activity Dependency and Aging in the Regulation of Adult Neurogenesis","authors":"G. Kempermann","doi":"10.1101/087969784.52.341","DOIUrl":"https://doi.org/10.1101/087969784.52.341","url":null,"abstract":"Age and activity might be considered the two antagonistic key regulators of adult neurogenesis. Whereas adult neurogenesis declines with age, different kinds of “activities” positively regulate adult neurogenesis. An interaction between these two mechanisms exists. Aging influences aging, and activity affects aging processes. Aging is a principal determinant of life and as such cuts across all biological, psychological, and sociological research. The very essence of aging is difficult to conceptualize, because it is a uniquely omnipresent variable. Aging can thus only be addressed in an transdisciplinary approach, especially if the consequences of aging on complex brain functions are to be studied. In the context of neurogenesis research, “aging” has so far been largely equaled with the biology of long timescales. Implicit in this understanding is that age-dependent changes essentially reflect a unidirectional development in that everything builds on what has occurred before. In this sense, aging can also be seen as continued or lifelong development. This idea has limitations but is instructive with regard to adult neurogenesis because adult neurogenesis is neuronal development under the conditions of the adult brain. The age-related alterations of adult neurogenesis themselves have quantitative and qualitative components. So far, most research has focused on the quantitative aspects. But there can be little doubt that qualitative changes do not simply follow quantitative changes, for example, in cell or synapse numbers but emerge on a systems level and above, when an organism ages. The observation that adult neurogenesis is regulated by activity relates to this idea. From...","PeriodicalId":10493,"journal":{"name":"Cold Spring Harbor Monograph Archive","volume":"250 1","pages":"341-362"},"PeriodicalIF":0.0,"publicationDate":"2008-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73391077","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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