neurogenic niche
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Pharmaceutics ◽  
2022 ◽  
Vol 14 (1) ◽  
pp. 200
Author(s):  
Sebastian Peters ◽  
Eva Wirkert ◽  
Sabrina Kuespert ◽  
Rosmarie Heydn ◽  
Siw Johannesen ◽  
...  

The capability of the adult central nervous system to self-repair/regenerate was demonstrated repeatedly throughout the last decades but remains in debate. Reduced neurogenic niche activity paralleled by a profound neuronal loss represents fundamental hallmarks in the disease course of neurodegenerative disorders. We and others have demonstrated the endogenous TGFβ system to represent a potential pathogenic participant in disease progression, of amyotrophic lateral sclerosis (ALS) in particular, by generating and promoting a disequilibrium of neurodegenerative and neuroregenerative processes. The novel human/primate specific LNA Gapmer Antisense Oligonucleotide “NVP-13”, targeting TGFBR2, effectively reduced its expression and lowered TGFβ signal transduction in vitro and in vivo, paralleled by boosting neurogenic niche activity in human neuronal progenitor cells and nonhuman primate central nervous system. Here, we investigated NVP-13 in vivo pharmacology, safety, and tolerability following repeated intrathecal injections in nonhuman primate cynomolgus monkeys for 13 weeks in a GLP-toxicology study approach. NVP-13 was administered intrathecally with 1, 2, or 4 mg NVP-13/animal within 3 months on days 1, 15, 29, 43, 57, 71, and 85 in the initial 13 weeks. We were able to demonstrate an excellent local and systemic tolerability, and no adverse events in physiological, hematological, clinical chemistry, and microscopic findings in female and male Cynomolgus Monkeys. Under the conditions of this study, the no observed adverse effect level (NOAEL) is at least 4 mg/animal NVP-13.


2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Mainá Bitar ◽  
Christin Weissleder ◽  
Hayley F. North ◽  
Misaki S. Clearwater ◽  
Oressia Zalucki ◽  
...  

AbstractThe generation of new neurons within the mammalian forebrain continues throughout life within two main neurogenic niches, the subgranular zone (SGZ) of the hippocampal dentate gyrus, and the subependymal zone (SEZ) lining the lateral ventricles. Though the SEZ is the largest neurogenic niche in the adult human forebrain, our understanding of the mechanisms regulating neurogenesis from development through aging within this region remains limited. This is especially pertinent given that neurogenesis declines dramatically over the postnatal lifespan. Here, we performed transcriptomic profiling on the SEZ from human post-mortem tissue from eight different life-stages ranging from neonates (average age ~ 2 months old) to aged adults (average age ~ 86 years old). We identified transcripts with concomitant profiles across these decades of life and focused on three of the most distinct profiles, namely (1) genes whose expression declined sharply after birth, (2) genes whose expression increased steadily with age, and (3) genes whose expression increased sharply in old age in the SEZ. Critically, these profiles identified neuroinflammation as becoming more prevalent with advancing age within the SEZ and occurring with time courses, one gradual (starting in mid-life) and one sharper (starting in old age).


2022 ◽  
Author(s):  
Zhechun Hu ◽  
Jiao Ma ◽  
Huimin Yue ◽  
Xiaofang Li ◽  
Chao Wang ◽  
...  

Hippocampal neurogenesis declines with aging. Wnt ligands and antagonists within the hippocampal neurogenic niche regulate the proliferation of neural progenitor cells and the development of new neurons, and the changes of their levels in the niche mediate aging-associated decline of neurogenesis. We found that RNA-binding protein Lin28a remained existent in neural progenitor cells and granule neurons in the adult hippocampus, and decreased with aging. Loss of Lin28a inhibited the responsiveness of neural progenitor cells to niche Wnt agonist and reduced neurogenesis, thus impairing pattern separation. Overexpression of Lin28a increased the proliferation of neural progenitor cells, promoted the functional integration of newborn neurons, restored neurogenesis in Wnt-deficient dentate gyrus, and rescued the impaired pattern separation in aging mice. Our data suggest that Lin28a regulates adult hippocampal neurogenesis as an intracellular mechanism by responding to niche Wnt signals, and its decrease is involved in aging-associated decline of hippocampal neurogenesis as well as related cognitive functions.


Cells ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 135
Author(s):  
Rafał Płatek ◽  
Piotr Rogujski ◽  
Jarosław Mazuryk ◽  
Marta B. Wiśniewska ◽  
Leszek Kaczmarek ◽  
...  

In the adult brain, new neurons are constitutively derived from postnatal neural stem cells/progenitors located in two neurogenic regions: the subventricular zone (SVZ) of the lateral ventricles (migrating and differentiating into different subtypes of the inhibitory interneurons of the olfactory bulbs), and the subgranular layer of the hippocampal dentate gyrus. Cyclin D2 knockout (cD2-KO) mice exhibit reduced numbers of new hippocampal neurons; however, the proliferation deficiency and the dysregulation of adult neurogenesis in the SVZ required further investigation. In this report, we characterized the differentiation potential of each subpopulation of the SVZ neural precursors in cD2-KO mice. The number of newly generated cells in the SVZs was significantly decreased in cD2-KO mice compared to wild type mice (WT), and was not accompanied by elevated levels of apoptosis. Although the number of B1-type quiescent precursors (B1q) and the overall B1-type activated precursors (B1a) were not affected in the SVZ neurogenic niche, the number of transit-amplifying progenitors (TaPs) was significantly reduced. Additionally, the subpopulations of calbindin D28k and calretinin interneurons were diminished in the olfactory bulbs of cD2-KO mice. Our results suggest that cyclin D2 might be critical for the proliferation of neural precursors and progenitors in the SVZ—the transition of B1a into TaPs and, thereafter, the production of newly generated interneurons in the olfactory bulbs. Untangling regulators that functionally modulate adult neurogenesis provides a basis for the development of regenerative therapies for injuries and neurodegenerative diseases.


2021 ◽  
Vol 25 (2) ◽  
pp. 114-126
Author(s):  
E. A. Teplyashina ◽  
Y. K. Komleva ◽  
E. V. Lychkovskaya ◽  
A. S. Deikhina ◽  
A. B. Salmina

Brain development is a unique process characterized by mechanisms defined as neuroplasticity (synaptogenesis, synapse elimination, neurogenesis, and cerebral angiogenesis). Numerous neurodevelopmental disorders brain damage, and aging are manifested by neurological deficits that are caused by aberrant neuroplasticity. The presence of stem and progenitor cells in neurogenic niches of the brain is responsible for the formation of new neurons capable of integrating into preexisting synaptic assemblies. The determining factors for the cells within the neurogenic niche are the activity of the vascular scaffold and the availability of active regulatory molecules that establish the optimal microenvironment. It has been found that regulated intramembrane proteolysis plays an important role in the control of neurogenesis in brain neurogenic niches. Molecules generated by the activity of specific proteases can stimulate or suppress the activity of neural stem and progenitor cells, their proliferation and differentiation, migration and integration of newly formed neurons into synaptic networks. Local neoangiogenesis supports the processes of neurogenesis in neurogenic niches, which is guaranteed by the multivalent action of peptides formed from transmembrane proteins. Identification of new molecules regulating the neuroplasticity (neurogenesis and angiogenesis). i. e. enzymes, substrates, and products of intramembrane proteolysis, will ensure the development of protocols for detecting the neuroplasticity markers and targets for efficient pharmacological modulation.


2021 ◽  
Author(s):  
F. Javier Perez-Martinez ◽  
Manuel Cifuentes ◽  
Juan M. Luque

During development reelin sets the pace of neocortical neurogenesis enabling in turn newborn neurons to migrate, but whether and, if so, how reelin signaling affects the adult neurogenic niches remains uncertain. We show that reelin signaling, resulting in Dab1 phosphorylation, occurs in the ependymal-subependymal zone (EZ/SEZ) of the lateral ventricles where, along with its associated rostral migratory stream (RMS), the highest density of functional ApoER2 accumulates. Mice deficient for reelin, ApoER2 or Dab1 exhibit enlarged ventricles and dysplastic RMS. Moreover, while the conditional ablation of Dab1 in neural progenitor cells (NPCs) enlarges the ventricles and impairs neuroblasts clearance from the SEZ, the transgenic misexpression of reelin in NPCs of reelin-deficient mice normalizes the ventricular lumen and the density of ependymal cilia, ameliorating in turn neuroblasts migration; consistently, intraventricular infusion of reelin reroutes neuroblasts. These results demonstrate that reelin signaling persists sustaining the germinal niche of the lateral ventricles and influencing neuroblasts migration in the adult brain.


2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 198-199
Author(s):  
Amar Sahay

Abstract Memory imprecision is a hallmark of age-related cognitive decline and mild-cognitive impairment (MCI) and is characterized by increased memory interference and decreased stability of memory representations. Evidence from humans, non-human primates and rodents demonstrate reduced hippocampal neurogenesis, excitation-inhibition imbalance and inflexible hippocampal remapping during age-related cognitive decline and MCI. Developing strategies to reverse cognitive decline during aging and Mild Cognitive Impairment necessitates an understanding of molecular, cellular, circuit and network mechanisms that support memory functions of the hippocampus. Over the last decade we have built a multifaceted program grounded in basic neuroscience that is aimed at improving memory in aging and MCI. We have demonstrated how we can Rejuvenate the aged hippocampus by selectively increasing neurogenesis and how we can Re-engineer connectivity of aged inhibitory microcircuits to improve memory precision in aging. Ongoing efforts include strategies to Repairing neurogenic niche fitness by targeting intercellular communication in the aging hippocampus. In today’s talk I will present a fourth approach catalyzed by our discovery of the first transcriptional regulator of neural stem cell expansion in the adult hippocampus. We will present data in support of this claim and convey how this discovery may guide strategies to maintain cognitive reserve embodied in the pool of neural stem cells in the adult hippocampus.


Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3240
Author(s):  
Maria Sidorova ◽  
Golo Kronenberg ◽  
Susann Matthes ◽  
Markus Petermann ◽  
Rainer Hellweg ◽  
...  

Serotonin (5-hydroxytryptamine, 5-HT) is a crucial signal in the neurogenic niche of the hippocampus, where it is involved in antidepressant action. Here, we utilized a new transgenic rat model (TetO-shTPH2), where brain 5-HT levels can be acutely altered based on doxycycline (Dox)-inducible shRNA-expression. On/off stimulations of 5-HT concentrations might uniquely mirror the clinical course of major depression (e.g., relapse after discontinuation of antidepressants) in humans. Specifically, we measured 5-HT levels, and 5-HT metabolite 5-HIAA, in various brain areas following acute tryptophan hydroxylase 2 (Tph2) knockdown, and replenishment, and examined behavior and proliferation and survival of newly generated cells in the dentate gyrus. We found that decreased 5-HT levels in the prefrontal cortex and raphe nuclei, but not in the hippocampus of TetO-shTPH2 rats, lead to an enduring anxious phenotype. Surprisingly, the reduction in 5-HT synthesis is associated with increased numbers of BrdU-labeled cells in the dentate gyrus. At 3 weeks of Tph2 replenishment, 5-HT levels return to baseline and survival of newly generated cells is unaffected. We speculate that the acutely induced decrease in 5-HT concentrations and increased neurogenesis might represent a compensatory mechanism.


2021 ◽  
pp. 136343
Author(s):  
Ryan N. Sheehy ◽  
Luis J. Quintanilla ◽  
Juan Song

2021 ◽  
Vol 15 ◽  
Author(s):  
Aurelien Kerever ◽  
Eri Arikawa-Hirasawa

In the adult mammalian brain, new neurons are generated in a restricted region called the neurogenic niche, which refers to the specific regulatory microenvironment of neural stem cells (NSCs). Among the constituents of neurogenic niches, the extracellular matrix (ECM) has emerged as a key player in NSC maintenance, proliferation, and differentiation. In particular, heparan sulfate (HS) proteoglycans are capable of regulating various growth factor signaling pathways that influence neurogenesis. In this review, we summarize our current understanding of the ECM niche in the adult subventricular zone (SVZ), with a special focus on basement membrane (BM)-like structures called fractones, and discuss how fractones, particularly their composition of glycosaminoglycans (GAGs), may influence neurogenesis.


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