Cargando…
BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice
β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of β-amyloid (Aβ), one of the major pathogenic molecules of Alzheimer’s disease (AD), and is therefore being actively pursued as a drug target for AD. Adult hippocampal neurogenesis (AHN) is a lifelong process...
Autores principales: | , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Society for Neuroscience
2018
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073981/ https://www.ncbi.nlm.nih.gov/pubmed/30079376 http://dx.doi.org/10.1523/ENEURO.0067-18.2018 |
_version_ | 1783344313368838144 |
---|---|
author | Chatila, Zena K. Kim, Eunhee Berlé, Clara Bylykbashi, Enjana Rompala, Alexander Oram, Mary K. Gupta, Drew Kwak, Sang Su Kim, Young Hye Kim, Doo Yeon Choi, Se Hoon Tanzi, Rudolph E. |
author_facet | Chatila, Zena K. Kim, Eunhee Berlé, Clara Bylykbashi, Enjana Rompala, Alexander Oram, Mary K. Gupta, Drew Kwak, Sang Su Kim, Young Hye Kim, Doo Yeon Choi, Se Hoon Tanzi, Rudolph E. |
author_sort | Chatila, Zena K. |
collection | PubMed |
description | β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of β-amyloid (Aβ), one of the major pathogenic molecules of Alzheimer’s disease (AD), and is therefore being actively pursued as a drug target for AD. Adult hippocampal neurogenesis (AHN) is a lifelong process that is known to be important for learning and memory and may have the potential to regenerate damaged neural tissue. In this study, we examined whether BACE1 regulates AHN, which holds important implications for its suitability as a drug target in AD. Cohorts of 2-month-old wild-type (BACE1(+/+)), heterozygous, and homozygous BACE1 knockout mice (BACE1(+/–) and BACE1(–/–), respectively) were injected with 5-bromo-2′-deoxyuridine (BrdU) and sacrificed 1 day later to examine the impact of loss of BACE1 on neural precursor cell (NPC) proliferation in the adult brain. Parallel cohorts of mice were sacrificed 4 weeks after BrdU injection to determine the effects of BACE1 on survival and differentiation of newborn NPCs. We found that NPC proliferation was increased in BACE1(–/–) mice compared to BACE1(+/+) mice, while no difference was observed in NPC survival across genotypes. Differentiation of NPCs to neuronal lineage was impaired in BACE1(–/–) mice. However, no differences were observed in astrogenesis, the proportion of immature neurons, or the production of oligodendrocytes across genotypes. Importantly, corresponding with a decrease in neuronal differentiation in the absence of a complementary increase in an alternate cell fate, BACE1(–/–) mice were found to have a pool of undifferentiated NPCs in the hippocampus compared to BACE1(+/+) and BACE1(+/–) mice. |
format | Online Article Text |
id | pubmed-6073981 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Society for Neuroscience |
record_format | MEDLINE/PubMed |
spelling | pubmed-60739812018-08-03 BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice Chatila, Zena K. Kim, Eunhee Berlé, Clara Bylykbashi, Enjana Rompala, Alexander Oram, Mary K. Gupta, Drew Kwak, Sang Su Kim, Young Hye Kim, Doo Yeon Choi, Se Hoon Tanzi, Rudolph E. eNeuro New Research β-Site amyloid precursor protein cleaving enzyme 1 (BACE1) is required for the production of β-amyloid (Aβ), one of the major pathogenic molecules of Alzheimer’s disease (AD), and is therefore being actively pursued as a drug target for AD. Adult hippocampal neurogenesis (AHN) is a lifelong process that is known to be important for learning and memory and may have the potential to regenerate damaged neural tissue. In this study, we examined whether BACE1 regulates AHN, which holds important implications for its suitability as a drug target in AD. Cohorts of 2-month-old wild-type (BACE1(+/+)), heterozygous, and homozygous BACE1 knockout mice (BACE1(+/–) and BACE1(–/–), respectively) were injected with 5-bromo-2′-deoxyuridine (BrdU) and sacrificed 1 day later to examine the impact of loss of BACE1 on neural precursor cell (NPC) proliferation in the adult brain. Parallel cohorts of mice were sacrificed 4 weeks after BrdU injection to determine the effects of BACE1 on survival and differentiation of newborn NPCs. We found that NPC proliferation was increased in BACE1(–/–) mice compared to BACE1(+/+) mice, while no difference was observed in NPC survival across genotypes. Differentiation of NPCs to neuronal lineage was impaired in BACE1(–/–) mice. However, no differences were observed in astrogenesis, the proportion of immature neurons, or the production of oligodendrocytes across genotypes. Importantly, corresponding with a decrease in neuronal differentiation in the absence of a complementary increase in an alternate cell fate, BACE1(–/–) mice were found to have a pool of undifferentiated NPCs in the hippocampus compared to BACE1(+/+) and BACE1(+/–) mice. Society for Neuroscience 2018-08-03 /pmc/articles/PMC6073981/ /pubmed/30079376 http://dx.doi.org/10.1523/ENEURO.0067-18.2018 Text en Copyright © 2018 Chatila et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed. |
spellingShingle | New Research Chatila, Zena K. Kim, Eunhee Berlé, Clara Bylykbashi, Enjana Rompala, Alexander Oram, Mary K. Gupta, Drew Kwak, Sang Su Kim, Young Hye Kim, Doo Yeon Choi, Se Hoon Tanzi, Rudolph E. BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice |
title | BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice |
title_full | BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice |
title_fullStr | BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice |
title_full_unstemmed | BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice |
title_short | BACE1 Regulates Proliferation and Neuronal Differentiation of Newborn Cells in the Adult Hippocampus in Mice |
title_sort | bace1 regulates proliferation and neuronal differentiation of newborn cells in the adult hippocampus in mice |
topic | New Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6073981/ https://www.ncbi.nlm.nih.gov/pubmed/30079376 http://dx.doi.org/10.1523/ENEURO.0067-18.2018 |
work_keys_str_mv | AT chatilazenak bace1regulatesproliferationandneuronaldifferentiationofnewborncellsintheadulthippocampusinmice AT kimeunhee bace1regulatesproliferationandneuronaldifferentiationofnewborncellsintheadulthippocampusinmice AT berleclara bace1regulatesproliferationandneuronaldifferentiationofnewborncellsintheadulthippocampusinmice AT bylykbashienjana bace1regulatesproliferationandneuronaldifferentiationofnewborncellsintheadulthippocampusinmice AT rompalaalexander bace1regulatesproliferationandneuronaldifferentiationofnewborncellsintheadulthippocampusinmice AT orammaryk bace1regulatesproliferationandneuronaldifferentiationofnewborncellsintheadulthippocampusinmice AT guptadrew bace1regulatesproliferationandneuronaldifferentiationofnewborncellsintheadulthippocampusinmice AT kwaksangsu bace1regulatesproliferationandneuronaldifferentiationofnewborncellsintheadulthippocampusinmice AT kimyounghye bace1regulatesproliferationandneuronaldifferentiationofnewborncellsintheadulthippocampusinmice AT kimdooyeon bace1regulatesproliferationandneuronaldifferentiationofnewborncellsintheadulthippocampusinmice AT choisehoon bace1regulatesproliferationandneuronaldifferentiationofnewborncellsintheadulthippocampusinmice AT tanzirudolphe bace1regulatesproliferationandneuronaldifferentiationofnewborncellsintheadulthippocampusinmice |