Brain environment and Alzheimer's disease mutations affect the survival, migration and differentiation of neural progenitor cells
Abstract
Enhancement of neurogenesis and stem cell transplantation are potential therapies for neurodegenerative diseases. In Alzheimer's disease (AD) newborn neural cells and the transplanted cells encounter a diseased brain where the accumulation of toxic amyloid-β (Aβ) peptides disturbs normal functions and interactions of brain cells. In addition, ADlinked mutatations in newborn neurons or autologously transplanted neural progenitor cells (NPCs) are likely to affect the fate of these cells. Here we analyzed the effect of AD-linked APdE9 mutant on NPCs in culture and by isolating NPCs from APdE9 transgenic mice and transplanting them into APdE9 and wild type mouse brain. We show that the brain environment in APdE9 mutant mice reduced astrocytic differentiation but increased the survival and migration of NPCs in vivo. APdE9 mutation of NPCs increased neuronal differentiation also in vitro. Instead extracellular Aβ(42) peptide decreased the survival, neuronal differentiation and migration of NPCs in vitro, whereas Aβ(40) had an opposite effect. NPC transplantation induced brain neurogenesis, which was not altered in Aβ burdened APdE9 brain or by APdE9 mutant in NPCs. Thus, AD-linked mutations in newborn neural cells or NPCs do not compromise the utilization of enhanced neurogenesis or autologous NPC transplantation as potential therapies. The results suggest that combining the treatments resulting in reduced Aβ(42) and enhanced neurogenesis may be one therapeutic approach to be explored in AD.
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Loss of supportive function by impaired astrocytes has been implicated in neurodegenerative diseases via neuronal death.
“Loss of supportive function by impaired astrocytes has been implicated in neurodegenerative diseases via neuronal death [21,22].”
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Park, M. W., Cha, H. W., Kim, J., Kim, J. H., Yang, H., Yoon, S., Boonpraman, N., Yi, S. S., Yoo, I. D., & Moon, J.-S. (2021) · Redox Biology · doi:10.1016/j.redox.2021.101947 · Cited by 683 · see citing works
Oksanen, M., Lehtonen, Š., Jaronen, M., Goldsteins, G., Hämäläinen, R. H., & Koıstınaho, J. (2019) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-019-03111-7 · Cited by 156 · see citing works
“Primary astrocyte defects have been implicated to impact neurodegenerative diseases, and both a loss of their normal supportive function as well as a gain of toxic functions are thought to underlie the neuronal death in acute or chronic brain diseases [2, 3].”
BackgroundSelf-citationNrf2 Regulates Neurogenesis and Protects Neural Progenitor Cells Against Aβ Toxicity
Kärkkäinen, V., Pomeshchik, Y., Savchenko, E., Dhungana, H., Kurronen, A., Lehtonen, Š., Naumenko, N. V., Tavi, P., Levonen, A., Yamamoto, M. P., et al. (2014) · Stem Cells · doi:10.1002/stem.1666 · Cited by 128 · see citing works
Self-citationPodda, M. V., Leone, L., Barbati, S. A., Mastrodonato, A., Puma, D. D. L., Piacentini, R., & Grassi, C. (2013) · European Journal of Neuroscience · doi:10.1111/ejn.12465 · Cited by 71 · see citing works
“As a result, several physiological, environmental and pharmacological stimuli have been described that positively affect the complex process of adult hippocampal neurogenesis as a whole or in its specific steps (Van Praag et al., 1999; Brown et al., 2003; Corvino et al., 2012; Kempermann, 2012).”
BackgroundStem‐Cell Challenges in the Treatment of Alzheimer's Disease: A Long Way from Bench to Bedside
Fan, X., Sun, D., Tang, X., Cai, Y., Yin, Z. Q., & Xu, H. (2014) · Medicinal Research Reviews · doi:10.1002/med.21309 · Cited by 66 · see citing works
Ryu, J., Hong, B.-H., Kim, Y., Yang, E.-J., Choi, M., Kim, H., Ahn, S., Baik, T.-K., Woo, R.-S., & Hs, K. (2016) · Cell Death and Disease · doi:10.1038/cddis.2016.30 · Cited by 64 · see citing works
“Oligomeric Aβ1-42 has been reported to reduce neural differentiation in fetal neural stem cells.(32) Here, we examined whether NRG1 affected the neural differentiation impair-”
BackgroundAmyloid-β oligomers regulate the properties of human neural stem cells through GSK-3β signaling
Lee, I.-S., Jung, K., Kim, I., & Park, K. I. (2013) · Experimental & Molecular Medicine · doi:10.1038/emm.2013.125 · Cited by 62 · see citing works
PPARβ/δ‐agonist GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes
Konttinen, H., Gureviciene, I., Oksanen, M., Grubman, A., Loppi, S. H., Huuskonen, M. T., Korhonen, P., Lampinen, R., Keuters, M. H., Belaya, I., et al. (2018) · Glia · doi:10.1002/glia.23534 · Cited by 52 · see citing works
Self-citationKim, J., Lim, J., Yoo, I. D., Park, S., & Moon, J. (2023) · Redox Biology · doi:10.1016/j.redox.2023.102735 · Cited by 37 · see citing works
Kirschen, G. W., Kéry, R., & Ge, S. (2017) · Brain Plasticity · doi:10.3233/bpl-170055 · Cited by 28 · see citing works
“However, A isolated from human AD patients decreases NPC survival, migration and differentiation in vitro [141].”
BackgroundHaigh, C. L., Tumpach, C., Collins, S. J., & Drew, S. C. (2016) · Cell Biochemistry and Biophysics · doi:10.1007/s12013-016-0747-4 · Cited by 15 · see citing works
“In rodent models of Alzheimer's disease (AD), production of beta-amyloid, one hallmark of AD, changes the growth and differentiation of these cells [3,4,5,6,7].”
BackgroundHeikkinen, R., Malm, T., Heikkilä, J., Muona, A., Tanila, H., Koistinaho, M., & Koıstınaho, J. (2014) · Aging and Disease · doi:10.14336/ad.2014.050076 · Cited by 12 · see citing works
“While AD has been reported to reduce endogeneous neurogenesis in mouse models of AD [49-52], cerebral ischemia conversely triggers it in specific brain regions [28].”
BackgroundSelf-citationПолтавцева, Р. А., Samokhin, A. N., Бобкова, Н. В., et al. (2020) · Bulletin of Experimental Biology and Medicine · doi:10.1007/s10517-020-04758-0 · Cited by 11 · see citing works
Savchenko, E., Malm, T., Konttinen, H., Hämäläinen, R. H., Guerrero-Toro, C., Wojciechowski, S., Giniatullin, R. A., Koıstınaho, J., & Magga, J. M. (2016) · Frontiers in Cellular Neuroscience · doi:10.3389/fncel.2016.00279 · Cited by 9 · see citing works
“…the concentration of Aβ42 preparation which has been neurotoxic in our previous studies in primary hippocampal neurons and neural stem cells, including dose-response assays for cell viability and neural stem cell migration (Kanninen et al., 2008; Karkkainen et al., 2012; Kärkkäinen et al., 2014).”
MethodSelf-citationFrid, K., Binyamin, O., Usman, A., & Gabizon, R. (2020) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2020.07.030 · Cited by 9 · see citing works
“brain, which may change the fate and survival of transplanted NPCs (Giannakopoulou et al., 2011; Karkkainen et al., 2012).”
BackgroundFan, J., Yu, M., Zhao, Y., Guan, Y., Li, Z., Pan, L., Feng, Q., Yao, J., & Sun, C. (2022) · Chemical Biology & Drug Design · doi:10.1111/cbdd.14193 · Cited by 5 · see citing works
“Defects in astrocytes function are closely associated with the pathogenesis and development of various neurodegenerative diseases, and losing the supporting function and the acquisition of toxic functions in astrocytes leads to neuronal death in acute or chronic brain diseases (Karkkainen et al., 2012; Phatnani & Mani…”
Background
- Authors
- Karkkainen, V., Magga, J., Koistinaho, J., & Malm, T.
- Venue
- Current Alzheimer Research
- Publisher
- Bentham Science Publishers Ltd.
- Published
- 2012-10-01
- Volume
- 9
- Issue
- 9
- Pages
- 1030-1042
- ISSN
- 1567-2050 (ISSN-L)
- OpenAlex
- W2005847007
- Cited by
- 16
- References
- 0
- Citations by year
- 2023: 1 · 2022: 1 · 2021: 1 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 3 · 2014: 3 · 2013: 2
- FWCI
- 0.54
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Current Alzheimer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, neural progenitor cells, amyloid-beta, amyloid-beta 42, Aβ40, cell survival, cell migration, neuronal differentiation, astrocyte differentiation, neural stem cell transplantation, neurogenesis, autologous transplantation, transgenic mice, brain microenvironment
- MeSH terms
- Alzheimer Disease, Animals, Brain, Cell Differentiation, Cell Movement, Cell Survival, Immunohistochemistry, Mice, Transgenic, Mutation, Amyloid beta-Protein Precursor, In Situ Nick-End Labeling, Stem Cell Transplantation, Mice, Presenilin-1, Neural Stem Cells
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