PMID- 33551720
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240330
IS  - 1662-4548 (Print)
IS  - 1662-453X (Electronic)
IS  - 1662-453X (Linking)
VI  - 14
DP  - 2020
TI  - Presenilin-Deficient Neurons and Astrocytes Display Normal Mitochondrial 
      Phenotypes.
PG  - 586108
LID - 10.3389/fnins.2020.586108 [doi]
LID - 586108
AB  - Presenilin 1 (PS1) and Presenilin 2 (PS2) are predominantly known as the 
      catalytic subunits of the gamma-secretase complex that generates the amyloid-beta (Abeta) 
      peptide, the major constituent of the senile plaques found in the brain of 
      Alzheimer's disease (AD) patients. Apart from their role in gamma-secretase activity, 
      a growing number of cellular functions have been recently attributed to PSs. 
      Notably, PSs were found to be enriched in mitochondria-associated membranes 
      (MAMs) where mitochondria and endoplasmic reticulum (ER) interact. PS2 was more 
      specifically reported to regulate calcium shuttling between these two organelles 
      by controlling the formation of functional MAMs. We have previously demonstrated 
      in mouse embryonic fibroblasts (MEF) an altered mitochondrial morphology along 
      with reduced mitochondrial respiration and increased glycolysis in PS2-deficient 
      cells (PS2KO). This phenotype was restored by the stable re-expression of human 
      PS2. Still, all these results were obtained in immortalized cells, and one 
      bottom-line question is to know whether these observations hold true in central 
      nervous system (CNS) cells. To that end, we carried out primary cultures of PS1 
      knockdown (KD), PS2KO, and PS1KD/PS2KO (PSdKO) neurons and astrocytes. They were 
      obtained from the same litter by crossing PS2 heterozygous; PS1 floxed (PS2(+/-); 
      PS1(flox/flox)) animals. Genetic downregulation of PS1 was achieved by lentiviral 
      expression of the Cre recombinase in primary cultures. Strikingly, we did not 
      observe any mitochondrial phenotype in PS1KD, PS2KO, or PSdKO primary cultures in 
      basal conditions. Mitochondrial respiration and membrane potential were similar 
      in all models, as were the glycolytic flux and NAD(+)/NADH ratio. Likewise, 
      mitochondrial morphology and content was unaltered by PS expression. We further 
      investigated the differences between results we obtained here in primary nerve 
      cells and those previously reported in MEF cell lines by analyzing PS2KO primary 
      fibroblasts. We found no mitochondrial dysfunction in this model, in line with 
      observations in PS2KO primary neurons and astrocytes. Together, our results 
      indicate that the mitochondrial phenotype observed in immortalized PS2-deficient 
      cell lines cannot be extrapolated to primary neurons, astrocytes, and even to 
      primary fibroblasts. The PS-dependent mitochondrial phenotype reported so far 
      might therefore be the consequence of a cell immortalization process and should 
      be critically reconsidered regarding its relevance to AD.
CI  - Copyright (c) 2021 Contino, Suelves, Vrancx, Vadukul, Payen, Stanga, Bertrand and 
      Kienlen-Campard.
FAU - Contino, Sabrina
AU  - Contino S
AD  - Alzheimer Research Group, Molecular and Cellular Division (CEMO), Institute of 
      Neuroscience, Universite Catholique de Louvain, Brussels, Belgium.
FAU - Suelves, Nuria
AU  - Suelves N
AD  - Alzheimer Research Group, Molecular and Cellular Division (CEMO), Institute of 
      Neuroscience, Universite Catholique de Louvain, Brussels, Belgium.
FAU - Vrancx, Celine
AU  - Vrancx C
AD  - Alzheimer Research Group, Molecular and Cellular Division (CEMO), Institute of 
      Neuroscience, Universite Catholique de Louvain, Brussels, Belgium.
FAU - Vadukul, Devkee M
AU  - Vadukul DM
AD  - Alzheimer Research Group, Molecular and Cellular Division (CEMO), Institute of 
      Neuroscience, Universite Catholique de Louvain, Brussels, Belgium.
FAU - Payen, Valery L
AU  - Payen VL
AD  - Laboratory of Advanced Drug Delivery and Biomaterial (ADDB), Louvain Drug 
      Research Institute (LDRI), Universite Catholique de Louvain, Brussels, Belgium.
FAU - Stanga, Serena
AU  - Stanga S
AD  - Neuroscience Institute Cavalieri Ottolenghi, Department of Neuroscience, 
      University of Torino, Torino, Italy.
FAU - Bertrand, Luc
AU  - Bertrand L
AD  - Pole of Cardiovascular Research, Institute of Experimental and Clinical Research, 
      Universite Catholique de Louvain, Brussels, Belgium.
FAU - Kienlen-Campard, Pascal
AU  - Kienlen-Campard P
AD  - Alzheimer Research Group, Molecular and Cellular Division (CEMO), Institute of 
      Neuroscience, Universite Catholique de Louvain, Brussels, Belgium.
LA  - eng
PT  - Journal Article
DEP - 20210122
PL  - Switzerland
TA  - Front Neurosci
JT  - Frontiers in neuroscience
JID - 101478481
PMC - PMC7862347
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - OXPHOS
OT  - astrocyte
OT  - mitochondria
OT  - neuron
OT  - presenilins
COIS- The authors declare that the research was conducted in the absence of any 
      commercial or financial relationships that could be construed as a potential 
      conflict of interest.
EDAT- 2021/02/09 06:00
MHDA- 2021/02/09 06:01
PMCR- 2020/01/01
CRDT- 2021/02/08 05:35
PHST- 2020/07/22 00:00 [received]
PHST- 2020/12/14 00:00 [accepted]
PHST- 2021/02/08 05:35 [entrez]
PHST- 2021/02/09 06:00 [pubmed]
PHST- 2021/02/09 06:01 [medline]
PHST- 2020/01/01 00:00 [pmc-release]
AID - 10.3389/fnins.2020.586108 [doi]
PST - epublish
SO  - Front Neurosci. 2021 Jan 22;14:586108. doi: 10.3389/fnins.2020.586108. 
      eCollection 2020.