Acrylamide induces cell death in neural progenitor cells and impairs hippocampal neurogenesis

Mutations in Presenilin-1 (PS1) are a major cause of familial Alzheimer's disease. Our previous studies showed that PS1 is required for murine neural development. Here we report that lack of PS1 leads to premature differentiation of neural progenitor cells, indicating a role for PS1 in a cell fate decision between postmitotic neurons and neural progenitor cells. Neural proliferation and apoptotic cell death during neurogenesis are unaltered in PS1(−/−) mice, suggesting that the reduction in the neural progenitor cells observed in the PS1(−/−) brain is due to premature differentiation of progenitor cells, rather than to increased apoptotic cell death or decreased cell proliferation. In addition, the premature neuronal differentiation in the PS1(−/−) brain is associated with aberrant neuronal migration and disorganization of the laminar architecture of the developing cerebral hemisphere. In the ventricular zone of PS1(−/−) mice, expression of the Notch1 downstream effector gene Hes5 is reduced and expression of the Notch1 ligand Dll1 is elevated, whereas expression of Notch1 is unchanged. The level of Dll1 transcripts is also increased in the presomitic mesoderm of PS1(−/−) embryos, while the level of Notch1 transcripts is unchanged, in contrast to a previous report (Wong et al., 1997, Nature 387, 288–292). These results provide direct evidence that PS1 controls neuronal differentiation in association with the downregulation of Notch signalling during neurogenesis.

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Differential responses of Trans-Resveratrol on proliferation of neural progenitor cells and aged rat hippocampal neurogenesis

Scientific Reports ◽

10.1038/srep28142 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 25

Author(s):

Vivek Kumar ◽

Ankita Pandey ◽

Sadaf Jahan ◽

Rajendra Kumar Shukla ◽

Dipak Kumar ◽

...

Keyword(s):

Progenitor Cells ◽

Neural Progenitor Cells ◽

Neural Progenitor ◽

Hippocampal Neurogenesis ◽

Aged Rat ◽

Differential Responses

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Mitochondrial dysfunction-induced KDM5A degradation impairs adult hippocampal neurogenesis in Alzheimer’s disease

10.21203/rs.3.rs-114597/v1 ◽

2020 ◽

Author(s):

Dong Kyu Kim ◽

Hyobin Jeong ◽

Jingi Bae ◽

Moon-Yong Cha ◽

Moonkyung Kang ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Mitochondrial Dysfunction ◽

Progenitor Cells ◽

Neuronal Differentiation ◽

Neural Progenitor Cells ◽

Neural Progenitor ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Amyloid Pathology ◽

Neural Stem Progenitor Cells

Abstract Background Adult hippocampal neurogenesis (AHN) is a process of continuously generating functional mature neurons from neural stem cells in the dentate gyrus. In Alzheimer’s disease (AD) brains, amyloid pathology has deleterious effects on AHN, but molecular mechanisms for dysregulated AHN are unclear. Mitochondria of neural stem/progenitor cells play crucial roles in determining cell fate. Since mitochondrial dysfunction by amyloid pathology is the typical symptom of AD pathogenesis, we aim to study whether mitochondrial dysfunction of neural stem/progenitor cells by amyloid pathology causes the impairment of AHN, and elucidate the molecular mechanism of the phenomenon. Methods To investigate the effect of mitochondrial dysfunction of neural stem/progenitor cells on neuronal differentiation, we expressed mitochondria-targeted amyloid beta (mitoAβ) in neural stem/progenitor cells in vitro and in vivo. Proteomic analysis of the hippocampal tissue implicated mitochondrial dysfunction by mitoAβ as a cause of AHN deficits. We identified epigenetic regulators of neural progenitor cells that are regulated by mitoAβ expression or drug-induced mitochondrial toxicity and proposed a link between mitochondria and AHN. Results Amyloid pathology characteristically inhibited the neuronal differentiation stage, not the proliferation of neural stem/progenitor cells during AHN in early AD model mice. Mitochondrial dysfunction in neural stem/progenitor cells by expressing mitoAβ inhibited the neuronal differentiation and AHN with cognitive impairment. Mechanistic studies revealed that lysine demethylase 5A (KDM5A) was involved in the neuronal differentiation and could be degraded by mitochondrial dysfunction in neural progenitor cells, thereby inhibiting the differentiation and cognitive functions. Conclusions These results reveal the new role of KDM5A as a mediator of retrograde signaling, reflecting mitochondrial status, and that the decrease of KDM5A in neural progenitor cells by mitochondrial dysfunction impairs the neuronal differentiation and AHN, finally leading to memory deficits. These findings and its relationship to mitochondrial dysfunction suggest that mitochondrial failure in neural progenitor cells by amyloid pathology closely associates with reduced AHN in AD.

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Expression of progenitor cell/immature neuron markers does not present definitive evidence for adult neurogenesis

Molecular Brain ◽

10.1186/s13041-019-0522-8 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 3

Author(s):

Hideo Hagihara ◽

Tomoyuki Murano ◽

Koji Ohira ◽

Miki Miwa ◽

Katsuki Nakamura ◽

...

Keyword(s):

Progenitor Cells ◽

Neural Progenitor Cells ◽

Adult Life ◽

Neural Progenitor ◽

Hippocampal Neurogenesis ◽

Adult Hippocampal Neurogenesis ◽

Mature Adult ◽

Neuronal Markers ◽

Definitive Evidence ◽

Immature Neurons

AbstractIt is agreed upon that adult hippocampal neurogenesis (AHN) occurs in the dentate gyrus (DG) in rodents. However, the existence of AHN in humans, particularly in elderly individuals, remains to be determined. Recently, several studies reported that neural progenitor cells, neuroblasts, and immature neurons were detected in the hippocampus of elderly humans, based on the expressions of putative markers for these cells, claiming that this provides evidence of the persistence of AHN in humans. Herein, we briefly overview the phenomenon that we call “dematuration,” in which mature neurons dedifferentiate to a pseudo-immature status and re-express the molecular markers of neural progenitor cells and immature neurons. Various conditions can easily induce dematuration, such as inflammation and hyper-excitation of neurons, and therefore, the markers for neural progenitor cells and immature neurons may not necessarily serve as markers for AHN. Thus, the aforementioned studies have not presented definitive evidence for the persistence of hippocampal neurogenesis throughout adult life in humans, and we would like to emphasize that those markers should be used cautiously when presented as evidence for AHN. Increasing AHN has been considered as a therapeutic target for Alzheimer’s disease (AD); however, given that immature neuronal markers can be re-expressed in mature adult neurons, independent of AHN, in various disease conditions including AD, strategies to increase the expression of these markers in the DG may be ineffective or may worsen the symptoms of such diseases.

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