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Presenilin-1 Dependent Neurogenesis Regulates Hippocampal Learning and Memory.

Bonds JA, Kuttner-Hirshler Y, Bartolotti N, Tobin MK, Pizzi M, Marr R, Lazarov O - PLoS ONE (2015)

Bottom Line: New granule neurons expressing reduced PS1 levels exhibit decreased dendritic branching and dendritic spines.Further, they exhibit reduced survival.Lastly, we show that PS1 effect on neurogenesis is mediated via β-catenin phosphorylation and notch signaling.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Neuroscience, University of Illinois at Chicago, Chicago, Illinois, 60612, United States of America; Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, 60612, United States of America.

ABSTRACT
Presenilin-1 (PS1), the catalytic core of the aspartyl protease γ-secretase, regulates adult neurogenesis. However, it is not clear whether the role of neurogenesis in hippocampal learning and memory is PS1-dependent, or whether PS1 loss of function in adult hippocampal neurogenesis can cause learning and memory deficits. Here we show that downregulation of PS1 in hippocampal neural progenitor cells causes progressive deficits in pattern separation and novelty exploration. New granule neurons expressing reduced PS1 levels exhibit decreased dendritic branching and dendritic spines. Further, they exhibit reduced survival. Lastly, we show that PS1 effect on neurogenesis is mediated via β-catenin phosphorylation and notch signaling. Together, these observations suggest that impairments in adult neurogenesis induce learning and memory deficits and may play a role in the cognitive deficits observed in Alzheimer's disease.

No MeSH data available.


Related in: MedlinePlus

Downregulation of PS1 expression in adult neural progenitor cells induces the expression of differentiation markers.Quantitation of Western blot analysis reported as percentage of control values all normalized to actin. Western blot analysis (A) and quantification (B) of neurogenic signals in neural progenitor cell culture infected with lentiviral vectors expressing either control RL shRNA or PS1 shRNA. (Bi-iii). Expression of PS1-NTF (i), and Nestin (ii) are significantly reduced, while expression of Cyclin D1 (iii) and epidermal growth factor receptor (EGFR, iv) are slightly reduced following PS1 downregulation in protein extract of neurosphere cultures infected with lentivirus expressing PS1 shRNA. This suggests that reduced PS1 expression decreases proliferation and progenitor phase. Expression of Neurofilament-L (v) increased in neural progenitors infected with PS1 shRNA, supporting enhanced premature neuronal differentiation following PS1 downregulation in these cells. Levels of platelet derived growth factor receptor α (PDGFRα, vi) were not significantly different. Unpaired t-test with Welch’s correction, *P<0.05, **P<0.005. Error bars indicate ±SEM.
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pone.0131266.g006: Downregulation of PS1 expression in adult neural progenitor cells induces the expression of differentiation markers.Quantitation of Western blot analysis reported as percentage of control values all normalized to actin. Western blot analysis (A) and quantification (B) of neurogenic signals in neural progenitor cell culture infected with lentiviral vectors expressing either control RL shRNA or PS1 shRNA. (Bi-iii). Expression of PS1-NTF (i), and Nestin (ii) are significantly reduced, while expression of Cyclin D1 (iii) and epidermal growth factor receptor (EGFR, iv) are slightly reduced following PS1 downregulation in protein extract of neurosphere cultures infected with lentivirus expressing PS1 shRNA. This suggests that reduced PS1 expression decreases proliferation and progenitor phase. Expression of Neurofilament-L (v) increased in neural progenitors infected with PS1 shRNA, supporting enhanced premature neuronal differentiation following PS1 downregulation in these cells. Levels of platelet derived growth factor receptor α (PDGFRα, vi) were not significantly different. Unpaired t-test with Welch’s correction, *P<0.05, **P<0.005. Error bars indicate ±SEM.

Mentions: To examine the signaling pathways involved in PS1 regulation of neurogenesis, hippocampal neurospheres were infected with lentivirus expressing either PS1 shRNA or RL shRNA. Examination of PS1 protein expression 4 days after infection showed a significant reduction in expression of PS1-NTF by approximately 30% (Fig 6a and 6bi). Levels of nestin were significantly reduced, suggesting exit of NPCs from the progenitor stage following reduced PS1 expression (Fig 6a and 6bii). In addition, levels of cyclin D1 (Fig 6a and 6biii) and EGFR (Fig 6a and 6biv) appear reduced, albeit not statistically significant. Levels of neurofilament-L, as an indicator of neuronal differentiation, are significantly increased (Fig 6a and 6bv). Interestingly, levels of PDGFRα were reduced, but did not reach significance (Fig 6a and 6bvi). These results support the phenotype we observed in vivo, in which following downregulation of PS1 in NPCs, they exit the cell cycle and differentiate into neurons and glia [13].


Presenilin-1 Dependent Neurogenesis Regulates Hippocampal Learning and Memory.

Bonds JA, Kuttner-Hirshler Y, Bartolotti N, Tobin MK, Pizzi M, Marr R, Lazarov O - PLoS ONE (2015)

Downregulation of PS1 expression in adult neural progenitor cells induces the expression of differentiation markers.Quantitation of Western blot analysis reported as percentage of control values all normalized to actin. Western blot analysis (A) and quantification (B) of neurogenic signals in neural progenitor cell culture infected with lentiviral vectors expressing either control RL shRNA or PS1 shRNA. (Bi-iii). Expression of PS1-NTF (i), and Nestin (ii) are significantly reduced, while expression of Cyclin D1 (iii) and epidermal growth factor receptor (EGFR, iv) are slightly reduced following PS1 downregulation in protein extract of neurosphere cultures infected with lentivirus expressing PS1 shRNA. This suggests that reduced PS1 expression decreases proliferation and progenitor phase. Expression of Neurofilament-L (v) increased in neural progenitors infected with PS1 shRNA, supporting enhanced premature neuronal differentiation following PS1 downregulation in these cells. Levels of platelet derived growth factor receptor α (PDGFRα, vi) were not significantly different. Unpaired t-test with Welch’s correction, *P<0.05, **P<0.005. Error bars indicate ±SEM.
© Copyright Policy
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4476567&req=5

pone.0131266.g006: Downregulation of PS1 expression in adult neural progenitor cells induces the expression of differentiation markers.Quantitation of Western blot analysis reported as percentage of control values all normalized to actin. Western blot analysis (A) and quantification (B) of neurogenic signals in neural progenitor cell culture infected with lentiviral vectors expressing either control RL shRNA or PS1 shRNA. (Bi-iii). Expression of PS1-NTF (i), and Nestin (ii) are significantly reduced, while expression of Cyclin D1 (iii) and epidermal growth factor receptor (EGFR, iv) are slightly reduced following PS1 downregulation in protein extract of neurosphere cultures infected with lentivirus expressing PS1 shRNA. This suggests that reduced PS1 expression decreases proliferation and progenitor phase. Expression of Neurofilament-L (v) increased in neural progenitors infected with PS1 shRNA, supporting enhanced premature neuronal differentiation following PS1 downregulation in these cells. Levels of platelet derived growth factor receptor α (PDGFRα, vi) were not significantly different. Unpaired t-test with Welch’s correction, *P<0.05, **P<0.005. Error bars indicate ±SEM.
Mentions: To examine the signaling pathways involved in PS1 regulation of neurogenesis, hippocampal neurospheres were infected with lentivirus expressing either PS1 shRNA or RL shRNA. Examination of PS1 protein expression 4 days after infection showed a significant reduction in expression of PS1-NTF by approximately 30% (Fig 6a and 6bi). Levels of nestin were significantly reduced, suggesting exit of NPCs from the progenitor stage following reduced PS1 expression (Fig 6a and 6bii). In addition, levels of cyclin D1 (Fig 6a and 6biii) and EGFR (Fig 6a and 6biv) appear reduced, albeit not statistically significant. Levels of neurofilament-L, as an indicator of neuronal differentiation, are significantly increased (Fig 6a and 6bv). Interestingly, levels of PDGFRα were reduced, but did not reach significance (Fig 6a and 6bvi). These results support the phenotype we observed in vivo, in which following downregulation of PS1 in NPCs, they exit the cell cycle and differentiate into neurons and glia [13].

Bottom Line: New granule neurons expressing reduced PS1 levels exhibit decreased dendritic branching and dendritic spines.Further, they exhibit reduced survival.Lastly, we show that PS1 effect on neurogenesis is mediated via β-catenin phosphorylation and notch signaling.

View Article: PubMed Central - PubMed

Affiliation: Graduate Program in Neuroscience, University of Illinois at Chicago, Chicago, Illinois, 60612, United States of America; Department of Anatomy and Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, 60612, United States of America.

ABSTRACT
Presenilin-1 (PS1), the catalytic core of the aspartyl protease γ-secretase, regulates adult neurogenesis. However, it is not clear whether the role of neurogenesis in hippocampal learning and memory is PS1-dependent, or whether PS1 loss of function in adult hippocampal neurogenesis can cause learning and memory deficits. Here we show that downregulation of PS1 in hippocampal neural progenitor cells causes progressive deficits in pattern separation and novelty exploration. New granule neurons expressing reduced PS1 levels exhibit decreased dendritic branching and dendritic spines. Further, they exhibit reduced survival. Lastly, we show that PS1 effect on neurogenesis is mediated via β-catenin phosphorylation and notch signaling. Together, these observations suggest that impairments in adult neurogenesis induce learning and memory deficits and may play a role in the cognitive deficits observed in Alzheimer's disease.

No MeSH data available.


Related in: MedlinePlus