PMID- 38063257
OWN - NLM
STAT- MEDLINE
DCOM- 20240518
LR  - 20240518
IS  - 1471-4159 (Electronic)
IS  - 0022-3042 (Linking)
VI  - 168
IP  - 5
DP  - 2024 May
TI  - Increased glucose metabolism and impaired glutamate transport in human astrocytes 
      are potential early triggers of abnormal extracellular glutamate accumulation in 
      hiPSC-derived models of Alzheimer's disease.
PG  - 822-840
LID - 10.1111/jnc.16014 [doi]
AB  - Glutamate recycling between neurons and astrocytes is essential to maintain 
      neurotransmitter homeostasis. Disturbances in glutamate homeostasis, resulting in 
      excitotoxicity and neuronal death, have been described as a potential mechanism 
      in Alzheimer's disease (AD) pathophysiology. However, glutamate neurotransmitter 
      metabolism in different human brain cells, particularly astrocytes, has been 
      poorly investigated at the early stages of AD. We sought to investigate glucose 
      and glutamate metabolism in AD by employing human induced pluripotent stem cell 
      (hiPSC)-derived astrocytes and neurons carrying mutations in the amyloid 
      precursor protein (APP) or presenilin-1 (PSEN-1) gene as found in familial types 
      of AD (fAD). Methods such as live-cell bioenergetics and metabolic mapping using 
      [(13)C]-enriched substrates were used to examine metabolism in the early stages 
      of AD. Our results revealed greater glycolysis and glucose oxidative metabolism 
      in astrocytes and neurons with APP or PSEN-1 mutations, accompanied by an 
      elevated glutamate synthesis compared to control WT cells. Astrocytes with APP or 
      PSEN-1 mutations exhibited reduced expression of the excitatory amino acid 
      transporter 2 (EAAT2), and glutamine uptake increased in mutated neurons, with 
      enhanced glutamate release specifically in neurons with a PSEN-1 mutation. These 
      results demonstrate a hypermetabolic phenotype in astrocytes with fAD mutations 
      possibly linked to toxic glutamate accumulation. Our findings further identify 
      metabolic imbalances that may occur in the early phases of AD pathophysiology.
CI  - (c) 2023 International Society for Neurochemistry.
FAU - Salcedo, Claudia
AU  - Salcedo C
AD  - Department of Drug Design and Pharmacology, Faculty of Health and Medical 
      Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Pozo Garcia, Victoria
AU  - Pozo Garcia V
AD  - Department of Drug Design and Pharmacology, Faculty of Health and Medical 
      Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Garcia-Adan, Bernat
AU  - Garcia-Adan B
AD  - Department of Drug Design and Pharmacology, Faculty of Health and Medical 
      Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Ameen, Aishat O
AU  - Ameen AO
AUID- ORCID: 0000-0001-8235-9807
AD  - Department of Drug Design and Pharmacology, Faculty of Health and Medical 
      Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Gegelashvili, Georgi
AU  - Gegelashvili G
AD  - Department of Drug Design and Pharmacology, Faculty of Health and Medical 
      Sciences, University of Copenhagen, Copenhagen, Denmark.
AD  - Institute of Chemical Biology, Ilia State University, Tbilisi, Georgia.
FAU - Waagepetersen, Helle S
AU  - Waagepetersen HS
AUID- ORCID: 0000-0003-4583-8379
AD  - Department of Drug Design and Pharmacology, Faculty of Health and Medical 
      Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Freude, Kristine K
AU  - Freude KK
AD  - Department of Veterinary and Animal Sciences, Faculty of Health and Medical 
      Sciences, University of Copenhagen, Frederiksberg, Denmark.
FAU - Aldana, Blanca I
AU  - Aldana BI
AUID- ORCID: 0000-0002-5027-1218
AD  - Department of Drug Design and Pharmacology, Faculty of Health and Medical 
      Sciences, University of Copenhagen, Copenhagen, Denmark.
LA  - eng
GR  - Arvid Nilssons Fond/
GR  - PhD Grant No: 2018-000009-01EXTF-00121/Consejo Nacional de Ciencia y Tecnologia/
GR  - Eva og Henry Fraenkels Mindefond/
GR  - Grant No: 4108-00008B/Innovationsfonden/
GR  - Oda og Hans Svenningsens Fond/
GR  - Eva og Henry Fraenkels Mindefond/
PT  - Journal Article
DEP - 20231208
PL  - England
TA  - J Neurochem
JT  - Journal of neurochemistry
JID - 2985190R
RN  - 0 (PSEN1 protein, human)
SB  - IM
MH  - Humans
MH  - *Astrocytes/metabolism
MH  - *Alzheimer Disease/metabolism/pathology/genetics
MH  - *Glutamic Acid/metabolism
MH  - *Glucose/metabolism
MH  - *Induced Pluripotent Stem Cells/metabolism
MH  - *Presenilin-1/genetics/metabolism
MH  - Amyloid beta-Protein Precursor/metabolism/genetics
MH  - Cells, Cultured
MH  - Neurons/metabolism
MH  - Mutation
OTO - NOTNLM
OT  - APP
OT  - PSEN-1
OT  - energy metabolism
OT  - excitotoxicity
OT  - hiPSC astrocytes
OT  - hiPSC neurons
EDAT- 2023/12/08 12:42
MHDA- 2024/05/18 19:45
CRDT- 2023/12/08 07:48
PHST- 2023/10/27 00:00 [revised]
PHST- 2023/02/17 00:00 [received]
PHST- 2023/11/01 00:00 [accepted]
PHST- 2024/05/18 19:45 [medline]
PHST- 2023/12/08 12:42 [pubmed]
PHST- 2023/12/08 07:48 [entrez]
AID - 10.1111/jnc.16014 [doi]
PST - ppublish
SO  - J Neurochem. 2024 May;168(5):822-840. doi: 10.1111/jnc.16014. Epub 2023 Dec 8.