Journal
NEUROCHEMICAL RESEARCH
Volume 46, Issue 10, Pages 2676-2686Publisher
SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s11064-021-03276-3
Keywords
GAT3; Glutamine; Glutamate; Energy metabolism; APP; PSEN-1
Categories
Funding
- National Council of Science and Technology (CONACYT) [2018-000009-01EXTF-00121]
- Innovation Fund Denmark Brainstem [4108-00008B]
- Tommerhandler Vilhelm Bangs Fond
- Torben & Alice Frimodts Fond
- Ludvig Tegners' Legat
- Innovation Fund Denmark NeuroStem
Ask authors/readers for more resources
This study investigated astrocytic GABA metabolism in Alzheimer's disease pathology using human induced pluripotent stem cell-derived astrocytes. The results showed alterations in GABA uptake and metabolism in AD astrocytes linked to reduced GABA transporter expression, contributing further to neurotransmitter disturbances.
Alterations in neurotransmitter homeostasis, primarily of glutamate and GABA, is strongly implicated in the pathophysiology of Alzheimer's disease (AD). Homeostasis at the synapse is maintained by neurotransmitter recycling between neurons and astrocytes. Astrocytes support neuronal transmission through glutamine synthesis, which can be derived from oxidative metabolism of GABA. However, the precise implications of astrocytic GABA metabolism in AD remains elusive. The aim of this study was to investigate astrocytic GABA metabolism in AD pathology implementing human induced pluripotent stem cells derived astrocytes. Metabolic mapping of GABA was performed with [U-C-13]GABA stable isotopic labeling using gas chromatography coupled to mass spectrometry (GC-MS). Neurotransmitter and amino acid content was quantified via high performance liquid chromatography (HPLC) and protein expression was investigated by Western blot assay. Cell lines carrying mutations in either amyloid precursor protein (APP) or presenilin1 (PSEN-1) were used as AD models and were compared to a control cell line of the same genetic background. AD astrocytes displayed a reduced oxidative GABA metabolism mediated by a decreased uptake capacity of GABA, as GABA transporter 3 (GAT3) was downregulated in AD astrocytes compared to the controls. Interestingly, the carbon backbone of GABA in AD astrocytes was utilized to a larger extent to support glutamine synthesis compared to control astrocytes. The results strongly indicate alterations in GABA uptake and metabolism in AD astrocytes linked to reduced GABA transporter expression, hereby contributing further to neurotransmitter disturbances.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available