Agrin-Lrp4-Ror2 signaling regulates adult hippocampal neurogenesis in mice

Adult neurogenesis in the hippocampus may represent a form of plasticity in brain functions including mood, learning and memory. However, mechanisms underlying neural stem/progenitor cells (NSPCs) proliferation are not well understood. We found that Agrin, a factor critical for neuromuscular junction formation, is elevated in the hippocampus of mice that are stimulated by enriched environment (EE). Genetic deletion of the Agrn gene in excitatory neurons decreases NSPCs proliferation and increases depressive-like behavior. Low-density lipoprotein receptor-related protein 4 (Lrp4), a receptor for Agrin, is expressed in hippocampal NSPCs and its mutation blocked basal as well as EE-induced NSPCs proliferation and maturation of newborn neurons. Finally, we show that Lrp4 interacts with and activates receptor tyrosine kinase-like orphan receptor 2 (Ror2); and Ror2 mutation impairs NSPCs proliferation. Together, these observations identify a role of Agrin-Lrp4-Ror2 signaling for adult neurogenesis, uncovering previously unexpected functions of Agrin and Lrp4 in the brain.

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Stress-Related Dysfunction of Adult Hippocampal Neurogenesis—An Attempt for Understanding Resilience?

International Journal of Molecular Sciences ◽

10.3390/ijms22147339 ◽

2021 ◽

Vol 22 (14) ◽

pp. 7339

Author(s):

Julia Leschik ◽

Beat Lutz ◽

Antonietta Gentile

Keyword(s):

Major Depression ◽

Adult Neurogenesis ◽

Current Knowledge ◽

Functional Relation ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Special Focus ◽

Extrinsic Cues ◽

Health And Disease ◽

Newborn Neurons

Newborn neurons in the adult hippocampus are regulated by many intrinsic and extrinsic cues. It is well accepted that elevated glucocorticoid levels lead to downregulation of adult neurogenesis, which this review discusses as one reason why psychiatric diseases, such as major depression, develop after long-term stress exposure. In reverse, adult neurogenesis has been suggested to protect against stress-induced major depression, and hence, could serve as a resilience mechanism. In this review, we will summarize current knowledge about the functional relation of adult neurogenesis and stress in health and disease. A special focus will lie on the mechanisms underlying the cascades of events from prolonged high glucocorticoid concentrations to reduced numbers of newborn neurons. In addition to neurotransmitter and neurotrophic factor dysregulation, these mechanisms include immunomodulatory pathways, as well as microbiota changes influencing the gut-brain axis. Finally, we discuss recent findings delineating the role of adult neurogenesis in stress resilience.

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Adult hippocampal neurogenesis: an important target associated with antidepressant effects of exercise

Reviews in the Neurosciences ◽

10.1515/revneuro-2016-0076 ◽

2017 ◽

Vol 28 (7) ◽

pp. 693-703 ◽

Cited By ~ 13

Author(s):

Lina Sun ◽

Qingshan Sun ◽

Jinshun Qi

Keyword(s):

Adult Neurogenesis ◽

Healthy Lifestyle ◽

Brain Plasticity ◽

Treatment Method ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Brain Functions ◽

Antidepressant Effects ◽

Exercise Activity ◽

The Brain

AbstractDepression is a prevalent devastating mental disorder that affects the normal life of patients and brings a heavy burden to whole society. Although many efforts have been made to attenuate depressive/anxiety symptoms, the current clinic antidepressants have limited effects. Scientists have long been making attempts to find some new strategies that can be applied as the alternative antidepressant therapy. Exercise, a widely recognized healthy lifestyle, has been suggested as a therapy that can relieve psychiatric stress. However, how exercise improves the brain functions and reaches the antidepressant target needs systematic summarization due to the complexity and heterogeneous feature of depression. Brain plasticity, especially adult neurogenesis in the hippocampus, is an important neurophysiology to facilitate animals for neurogenesis can occur in not only humans. Many studies indicated that an appropriate level of exercise can promote neurogenesis in the adult brains. In this article, we provide information about the antidepressant effects of exercise and its implications in adult neurogenesis. From the neurogenesis perspective, we summarize evidence about the effects of exercise in enhancing neurogenesis in the hippocampus through regulating growth factors, neurotrophins, neurotransmitters and metabolism as well as inflammations. Taken together, a large number of published works indicate the multiple benefits of exercise in the brain functions of animals, particularly brain plasticity like neurogenesis and synaptogenesis. Therefore, a new treatment method for depression therapy can be developed by regulating the exercise activity.

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Adult Hippocampal Neurogenesis in Alzheimer’s Disease: An Overview of Human and Animal Studies with Implications for Therapeutic Perspectives Aimed at Memory Recovery

Neural Plasticity ◽

10.1155/2022/9959044 ◽

2022 ◽

Vol 2022 ◽

pp. 1-18

Author(s):

Stefano Farioli-Vecchioli ◽

Valentina Ricci ◽

Silvia Middei

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Adult Neurogenesis ◽

Animal Studies ◽

Neurodegenerative Disorder ◽

Memory Loss ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Newborn Neurons ◽

Impaired Neurogenesis

The mammalian hippocampal dentate gyrus is a niche for adult neurogenesis from neural stem cells. Newborn neurons integrate into existing neuronal networks, where they play a key role in hippocampal functions, including learning and memory. In the ageing brain, neurogenic capability progressively declines while in parallel increases the risk for developing Alzheimer’s disease (AD), the main neurodegenerative disorder associated with memory loss. Numerous studies have investigated whether impaired adult neurogenesis contributes to memory decline in AD. Here, we review the literature on adult hippocampal neurogenesis (AHN) and AD by focusing on both human and mouse model studies. First, we describe key steps of AHN, report recent evidence of this phenomenon in humans, and describe the specific contribution of newborn neurons to memory, as evinced by animal studies. Next, we review articles investigating AHN in AD patients and critically examine the discrepancies among different studies over the last two decades. Also, we summarize researches investigating AHN in AD mouse models, and from these studies, we extrapolate the contribution of molecular factors linking AD-related changes to impaired neurogenesis. Lastly, we examine animal studies that link impaired neurogenesis to specific memory dysfunctions in AD and review treatments that have the potential to rescue memory capacities in AD by stimulating AHN.

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Effect of Opioid on Adult Hippocampal Neurogenesis

The Scientific World JOURNAL ◽

10.1155/2016/2601264 ◽

2016 ◽

Vol 2016 ◽

pp. 1-7 ◽

Cited By ~ 14

Author(s):

Yue Zhang ◽

Horace H. Loh ◽

Ping-Yee Law

Keyword(s):

Adult Neurogenesis ◽

Developmental Stages ◽

Opioid Addiction ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Future Directions ◽

Opiate Drugs ◽

Neural Stem Progenitor Cells ◽

Underlying Mechanisms

During the past decade, the study of the mechanisms and functional implications of adult neurogenesis has significantly progressed. Many studies focus on the factors that regulate proliferation and fate determination of adult neural stem/progenitor cells, including addictive drugs such as opioid. Here, we review the most recent works on opiate drugs’ effect on different developmental stages of adult hippocampal neurogenesis, as well as the possible underlying mechanisms. We conclude that opiate drugs in general cause a loss of newly born neural progenitors in the subgranular zone of dentate gyrus, by either modulating proliferation or interfering with differentiation and maturation. We also discuss the consequent impact of regulation of adult neurogenesis in animal’s opioid addiction behavior. We further look into the future directions in studying the convergence between the adult neurogenesis field and opioid addiction field, since the adult-born granular cells were shown to play a role in neuroplasticity and may help to reduce the vulnerability to drug craving and relapse.

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Inducible and Conditional Stimulation of Adult Hippocampal Neurogenesis Rescues Cadmium-Induced Impairments of Adult Hippocampal Neurogenesis and Hippocampus-Dependent Memory in Mice

Toxicological Sciences ◽

10.1093/toxsci/kfaa104 ◽

2020 ◽

Vol 177 (1) ◽

pp. 263-280 ◽

Cited By ~ 1

Author(s):

Hao Wang ◽

Megumi T Matsushita ◽

Liang Zhang ◽

Glen M Abel ◽

Brett C Mommer ◽

...

Keyword(s):

Adult Neurogenesis ◽

Mouse Strain ◽

Environmental Pollutant ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Mitogen Activated Protein Kinase ◽

Full Spectrum ◽

Neural Stem Progenitor Cells ◽

Cd Exposure ◽

Hippocampus Dependent Memory

Abstract Cadmium (Cd) is a heavy metal and an environmental pollutant. However, the full spectrum of its neurotoxicity and the underlying mechanisms are not completely understood. Our previous studies demonstrated that Cd exposure impairs adult hippocampal neurogenesis and hippocampus-dependent memory in mice. This study aims to determine if these adverse effects of Cd exposure can be mitigated by genetically and conditionally enhancing adult neurogenesis. To address this issue, we utilized the transgenic constitutive active MEK5 (caMEK5) mouse strain we previously developed and characterized. This mouse strain enables us to genetically and conditionally activate adult neurogenesis by administering tamoxifen to induce expression of a caMEK5 in adult neural stem/progenitor cells, which stimulates adult neurogenesis through activation of the endogenous extracellular signal-regulated kinase 5 mitogen-activated protein kinase pathway. The caMEK5 mice were exposed to 0.6 mg/l Cd through drinking water for 38 weeks. Once impairment of memory was confirmed, tamoxifen was administered to induce caMEK5 expression and to activate adult neurogenesis. Behavior tests were conducted at various time points to monitor hippocampus-dependent memory. Upon completion of the behavior tests, brain tissues were collected for cellular studies of adult hippocampal neurogenesis. We report here that Cd impaired hippocampus-dependent spatial memory and contextual fear memory in mice. These deficits were rescued by the tamoxifen induction of caMEK5 expression. Furthermore, Cd inhibition of adult hippocampal neurogenesis was also reversed. This rescue experiment provides strong evidence for a direct link between Cd-induced impairments of adult hippocampal neurogenesis and hippocampus-dependent memory.

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Mitochondrial and Autophagic Regulation of Adult Neurogenesis in the Healthy and Diseased Brain

International Journal of Molecular Sciences ◽

10.3390/ijms22073342 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3342

Author(s):

Hansruedi Büeler

Keyword(s):

Stem Cell ◽

Mood Disorders ◽

Adult Neurogenesis ◽

Cell Function ◽

Natural Aging ◽

Hippocampal Neurogenesis ◽

Adult Brain ◽

Adult Hippocampal Neurogenesis ◽

Induced Mood ◽

Newborn Neurons

Adult neurogenesis is a highly regulated process during which new neurons are generated from neural stem cells in two discrete regions of the adult brain: the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus. Defects of adult hippocampal neurogenesis have been linked to cognitive decline and dysfunction during natural aging and in neurodegenerative diseases, as well as psychological stress-induced mood disorders. Understanding the mechanisms and pathways that regulate adult neurogenesis is crucial to improving preventative measures and therapies for these conditions. Accumulating evidence shows that mitochondria directly regulate various steps and phases of adult neurogenesis. This review summarizes recent findings on how mitochondrial metabolism, dynamics, and reactive oxygen species control several aspects of adult neural stem cell function and their differentiation to newborn neurons. It also discusses the importance of autophagy for adult neurogenesis, and how mitochondrial and autophagic dysfunction may contribute to cognitive defects and stress-induced mood disorders by compromising adult neurogenesis. Finally, I suggest possible ways to target mitochondrial function as a strategy for stem cell-based interventions and treatments for cognitive and mood disorders.

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The Role of the Low-Density Lipoprotein Receptor-Related Protein (LRP) in the Plasma Clearance and Liver Uptake of Recombinant Single-chain Urokinase-type Plasminogen Activator in Rats

Thrombosis and Haemostasis ◽

10.1055/s-0038-1656039 ◽

1997 ◽

Vol 77 (04) ◽

pp. 710-717 ◽

Cited By ~ 5

Author(s):

Marieke E van der Kaaden ◽

Dingeman C Rijken ◽

J Kar Kruijt ◽

Theo J C van Berkel ◽

Johan Kuiper

Keyword(s):

Plasminogen Activator ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Single Chain ◽

Liver Uptake ◽

Type Plasminogen Activator ◽

Parenchymal Liver ◽

Urokinase Type Plasminogen Activator ◽

Density Lipoprotein Receptor

SummaryUrokinase-type plasminogen activator (u-PA) is used as a thrombolytic agent in the treatment of acute myocardial infarction. In vitro, recombinant single-chain u-PA (rscu-PA) expressed in E.coli is recognized by the Low-Density Lipoprotein Receptor-related Protein (LRP) on rat parenchymal liver cells. In this study we investigated the role of LRP in the liver uptake and plasma clearance of rscu-PA in rats. A preinjection of the LRP inhibitor GST-RAP reduced the maximal liver uptake of 125I-rscu-PA at 5 min after injection from 50 to 30% of the injected dose and decreased the clearance of rscu-PA from 2.37 ml/min to 1.58 ml/min. Parenchymal, Kupffer and endothelial cells were responsible for 40, 50 and 10% of the liver uptake, respectively. The reduction in liver uptake of rscu-PA by the preinjection of GST-RAP was caused by a 91 % and 62% reduction in the uptake by parenchymal and Kupffer cells, respectively. In order to investigate the part of rscu-PA that accounted for the interaction with LRP, experiments were performed with a mutant of rscu-PA lacking residues 11-135 (= deltal25- rscu-PA). Deletion of residues 11-135 resulted in a 80% reduction in liver uptake and a 2.4 times slower clearance (0.97 ml/min). The parenchymal, Kupffer and endothelial cells were responsible for respectively 60, 33 and 7% of the liver uptake of 125I-deltal25-rscu-PA. Preinjection of GST-RAP completely reduced the liver uptake of delta 125-rscu-PA and reduced its clearance to 0.79 ml/min. Treatment of isolated Kupffer cells with PI-PLC reduced the binding of rscu-PA by 40%, suggesting the involvement of the urokinase-type Plasminogen Activator Receptor (u-PAR) in the recognition of rscu-PA. Our results demonstrate that in vivo LRP is responsible for more than 90% of the parenchymal liver cell mediated uptake of rscu-PA and for 60% of the Kupffer cell interaction. It is also suggested that u-PAR is involved in the Kupffer cell recognition of rscu-PA.

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