PMID- 37569690
OWN - NLM
STAT- MEDLINE
DCOM- 20230814
LR  - 20230814
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 24
IP  - 15
DP  - 2023 Aug 1
TI  - The Role of Intracellular Ca(2+) and Mitochondrial ROS in Small Abeta(1-42) 
      Oligomer-Induced Microglial Death.
LID - 10.3390/ijms241512315 [doi]
LID - 12315
AB  - Alzheimer's disease (AD) is the most common form of dementia worldwide, and it 
      contributes up to 70% of cases. AD pathology involves abnormal amyloid beta (Abeta) 
      accumulation, and the link between the Abeta(1-42) structure and toxicity is of 
      major interest. NMDA receptors (NMDAR) are thought to be essential in Abeta-affected 
      neurons, but the role of this receptor in glial impairment is still unclear. In 
      addition, there is insufficient knowledge about the role of Abeta species regarding 
      mitochondrial redox states in neurons and glial cells, which may be critical in 
      developing Abeta-caused neurotoxicity. In this study, we investigated whether 
      different Abeta(1-42) species-small oligomers, large oligomers, insoluble fibrils, 
      and monomers-were capable of producing neurotoxic effects via microglial NMDAR 
      activation and changes in mitochondrial redox states in primary rat brain cell 
      cultures. Small Abeta(1-42) oligomers induced a concentration- and time-dependent 
      increase in intracellular Ca(2+) and necrotic microglial death. These changes 
      were partially prevented by the NMDAR inhibitors MK801, memantine, and 
      D-2-amino-5-phosphopentanoic acid (DAP5). Neither microglial intracellular Ca(2+) 
      nor viability was significantly affected by larger Abeta(1-42) species or monomers. 
      In addition, the small Abeta(1-42) oligomers caused mitochondrial reactive oxygen 
      species (mtROS)-mediated mitochondrial depolarization, glutamate release, and 
      neuronal cell death. In microglia, the Abeta(1-42)-induced mtROS overproduction was 
      mediated by intracellular calcium ions and Abeta-binding alcohol dehydrogenase 
      (ABAD). The data suggest that the pharmacological targeting of microglial NMDAR 
      and mtROS may be a promising strategy for AD therapy.
FAU - Jekabsone, Aiste
AU  - Jekabsone A
AD  - Neuroscience Institute, Lithuanian University of Health Sciences, LT-50162 
      Kaunas, Lithuania.
AD  - Faculty of Pharmacy, Lithuanian University of Health Sciences, LT-50162 Kaunas, 
      Lithuania.
FAU - Jankeviciute, Silvija
AU  - Jankeviciute S
AD  - Neuroscience Institute, Lithuanian University of Health Sciences, LT-50162 
      Kaunas, Lithuania.
FAU - Pampuscenko, Katryna
AU  - Pampuscenko K
AD  - Neuroscience Institute, Lithuanian University of Health Sciences, LT-50162 
      Kaunas, Lithuania.
FAU - Borutaite, Vilmante
AU  - Borutaite V
AD  - Neuroscience Institute, Lithuanian University of Health Sciences, LT-50162 
      Kaunas, Lithuania.
FAU - Morkuniene, Ramune
AU  - Morkuniene R
AD  - Neuroscience Institute, Lithuanian University of Health Sciences, LT-50162 
      Kaunas, Lithuania.
AD  - Faculty of Pharmacy, Lithuanian University of Health Sciences, LT-50162 Kaunas, 
      Lithuania.
LA  - eng
GR  - LIG-04/2012/Lietuvos Mokslo Taryba/
PT  - Journal Article
DEP - 20230801
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (amyloid beta-protein (1-42))
RN  - 0 (Amyloid beta-Peptides)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (Peptide Fragments)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
SB  - IM
MH  - Rats
MH  - Animals
MH  - *Amyloid beta-Peptides/metabolism
MH  - Microglia/metabolism
MH  - Reactive Oxygen Species/metabolism
MH  - *Alzheimer Disease/metabolism
MH  - Peptide Fragments/pharmacology/metabolism
MH  - Receptors, N-Methyl-D-Aspartate/metabolism
PMC - PMC10418347
OTO - NOTNLM
OT  - Alzheimer's disease
OT  - NMDA receptors
OT  - amyloid-beta
OT  - cell death
OT  - glutamate
OT  - microglia
OT  - mitochondrial ROS
COIS- Authors have no conflict of interest.
EDAT- 2023/08/12 10:45
MHDA- 2023/08/14 06:42
PMCR- 2023/08/01
CRDT- 2023/08/12 01:10
PHST- 2023/06/30 00:00 [received]
PHST- 2023/07/27 00:00 [revised]
PHST- 2023/07/29 00:00 [accepted]
PHST- 2023/08/14 06:42 [medline]
PHST- 2023/08/12 10:45 [pubmed]
PHST- 2023/08/12 01:10 [entrez]
PHST- 2023/08/01 00:00 [pmc-release]
AID - ijms241512315 [pii]
AID - ijms-24-12315 [pii]
AID - 10.3390/ijms241512315 [doi]
PST - epublish
SO  - Int J Mol Sci. 2023 Aug 1;24(15):12315. doi: 10.3390/ijms241512315.