TY - JOUR
T1 - Rapid initiation of cell cycle reentry processes protects neurons from amyloid-β toxicity
AU - Ippati, Stefania
AU - Deng, Yuanyuan
AU - Hoven, Julia van der
AU - Heu, Celine
AU - Hummel, Annika van
AU - Chua, Sook Wern
AU - Paric, Esmeralda
AU - Chan, Gabriella
AU - Feiten, Astrid
AU - Fath, Thomas
AU - Ke, Yazi D.
AU - Haass, Nikolas K.
AU - Ittner, Lars M.
PY - 2021/3/23
Y1 - 2021/3/23
N2 - Neurons are postmitotic cells. Reactivation of the cell cycle by neurons has been reported in Alzheimer’s disease (AD) brains and models. This gave rise to the hypothesis that reentering the cell cycle renders neurons vulnerable and thus contributes to AD pathogenesis. Here, we use the fluorescent ubiquitination-based cell cycle indicator (FUCCI) technology to monitor the cell cycle in live neurons. We found transient, self-limited cell cycle reentry activity in naive neurons, suggesting that their postmitotic state is a dynamic process. Furthermore, we observed a diverse response to oligomeric amyloid-β (oAβ) challenge; neurons without cell cycle reentry activity would undergo cell death without activating the FUCCI reporter, while neurons undergoing cell cycle reentry activity at the time of the oAβ challenge could maintain and increase FUCCI reporter signal and evade cell death. Accordingly, we observed marked neuronal FUCCI positivity in the brains of human mutant Aβ precursor protein transgenic (APP23) mice together with increased neuronal expression of the endogenous cell cycle control protein geminin in the brains of 3-mo-old APP23 mice and human AD brains. Taken together, our data challenge the current view on cell cycle in neurons and AD, suggesting that pathways active during early cell cycle reentry in neurons protect from Aβ toxicity.
AB - Neurons are postmitotic cells. Reactivation of the cell cycle by neurons has been reported in Alzheimer’s disease (AD) brains and models. This gave rise to the hypothesis that reentering the cell cycle renders neurons vulnerable and thus contributes to AD pathogenesis. Here, we use the fluorescent ubiquitination-based cell cycle indicator (FUCCI) technology to monitor the cell cycle in live neurons. We found transient, self-limited cell cycle reentry activity in naive neurons, suggesting that their postmitotic state is a dynamic process. Furthermore, we observed a diverse response to oligomeric amyloid-β (oAβ) challenge; neurons without cell cycle reentry activity would undergo cell death without activating the FUCCI reporter, while neurons undergoing cell cycle reentry activity at the time of the oAβ challenge could maintain and increase FUCCI reporter signal and evade cell death. Accordingly, we observed marked neuronal FUCCI positivity in the brains of human mutant Aβ precursor protein transgenic (APP23) mice together with increased neuronal expression of the endogenous cell cycle control protein geminin in the brains of 3-mo-old APP23 mice and human AD brains. Taken together, our data challenge the current view on cell cycle in neurons and AD, suggesting that pathways active during early cell cycle reentry in neurons protect from Aβ toxicity.
KW - Alzheimer
KW - cell cycle
KW - postmitotic neurons
KW - FUCCI
UR - http://purl.org/au-research/grants/nhmrc/1081916
UR - http://purl.org/au-research/grants/nhmrc/1123564
UR - http://purl.org/au-research/grants/nhmrc/1132524
UR - http://purl.org/au-research/grants/nhmrc/1136241
UR - http://purl.org/au-research/grants/nhmrc/1143848
UR - http://purl.org/au-research/grants/arc/DP150104321
UR - http://www.scopus.com/inward/record.url?scp=85103230714&partnerID=8YFLogxK
U2 - 10.1073/pnas.2011876118
DO - 10.1073/pnas.2011876118
M3 - Article
C2 - 33737393
VL - 118
SP - 1
EP - 9
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 12
M1 - e2011876118
ER -