Downregulation of GABA Transporter 3 (GAT3) is Associated with Deficient Oxidative GABA Metabolism in Human Induced Pluripotent Stem Cell-Derived Astrocytes in Alzheimer's Disease

Salcedo, Claudia; Wagner, Antonie; Andersen, Jens V.; Vinten, Kasper Tore; Waagepetersen, Helle S.; Schousboe, Arne; Freude, Kristine; Aldana, Blanca I.

doi:10.1007/s11064-021-03276-3

Cited by 17 publications

(13 citation statements)

References 69 publications

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“…The astrocytes were differentiated based on a modified protocol by Shaltouki et al (2013), described elsewhere (Salcedo et al, 2021). Briefly, when the NPCs reached 70% confluency, they were plated on Matrigel in an astrocytic maintenance medium (AMM), which promotes the generation of astrocyte progenitor cells (APCs).…”

Section: Astrocytic Differentiationmentioning

confidence: 99%

“…Reconstituted extracts were used for the quantification of amino acid amounts, by reverse phase high-performance liquid chromatography using 1260 Infinity (Agilent Technologies, Sta. Clara, CA, United States), as described elsewhere (Salcedo et al, 2021). Amino acid separation and detection were performed by precolumn o-phthalaldehyde (OPA) online derivatization and fluorescent detection (λex = 338 nm, 10-nm bandwidth; λem = 390 nm, 20-nm bandwidth).…”

Section: Quantitative Analysis Of Amino Acid Amounts Performed By High Performance Liquid Chromatography (Hplc)mentioning

confidence: 99%

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Functional Metabolic Mapping Reveals Highly Active Branched-Chain Amino Acid Metabolism in Human Astrocytes, Which Is Impaired in iPSC-Derived Astrocytes in Alzheimer's Disease

Salcedo

Andersen

Vinten

et al. 2021

Front. Aging Neurosci.

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The branched-chain amino acids (BCAAs) leucine, isoleucine, and valine are important nitrogen donors for synthesis of glutamate, the main excitatory neurotransmitter in the brain. The glutamate carbon skeleton originates from the tricarboxylic acid (TCA) cycle intermediate α-ketoglutarate, while the amino group is derived from nitrogen donors such as the BCAAs. Disturbances in neurotransmitter homeostasis, mainly of glutamate, are strongly implicated in the pathophysiology of Alzheimer's disease (AD). The divergent BCAA metabolism in different cell types of the human brain is poorly understood, and so is the involvement of astrocytic and neuronal BCAA metabolism in AD. The goal of this study is to provide the first functional characterization of BCAA metabolism in human brain tissue and to investigate BCAA metabolism in AD pathophysiology using astrocytes and neurons derived from human-induced pluripotent stem cells (hiPSCs). Mapping of BCAA metabolism was performed using mass spectrometry and enriched [15N] and [13C] isotopes of leucine, isoleucine, and valine in acutely isolated slices of surgically resected cerebral cortical tissue from human brain and in hiPSC-derived brain cells carrying mutations in either amyloid precursor protein (APP) or presenilin-1 (PSEN-1). We revealed that both human astrocytes of acutely isolated cerebral cortical slices and hiPSC-derived astrocytes were capable of oxidatively metabolizing the carbon skeleton of BCAAs, particularly to support glutamine synthesis. Interestingly, hiPSC-derived astrocytes with APP and PSEN-1 mutations exhibited decreased amino acid synthesis of glutamate, glutamine, and aspartate derived from leucine metabolism. These results clearly demonstrate that there is an active BCAA metabolism in human astrocytes, and that leucine metabolism is selectively impaired in astrocytes derived from the hiPSC models of AD. This impairment in astrocytic BCAA metabolism may contribute to neurotransmitter and energetic imbalances in the AD brain.

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Section: Astrocytic Differentiationmentioning

confidence: 99%

Section: Quantitative Analysis Of Amino Acid Amounts Performed By High Performance Liquid Chromatography (Hplc)mentioning

confidence: 99%

Functional Metabolic Mapping Reveals Highly Active Branched-Chain Amino Acid Metabolism in Human Astrocytes, Which Is Impaired in iPSC-Derived Astrocytes in Alzheimer's Disease

Salcedo

Andersen

Vinten

et al. 2021

Front. Aging Neurosci.

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“…A loss of GABAergic neurons in the cerebral cortex, decreased GAD enzyme activity in the hippocampal neurons and increased concentration of GABA in cortical astrocytes were all discovered in AD autopsies. According to in vitro research, the downregulation of GAT3 expression might prevent astrocytes from reabsorbing GABA and disrupt the GABA metabolism, which may cause an imbalance between excitatory and inhibitory transmission in AD patients’ brains and pathological modifications caused by the disease [ 70 ]. GABA was markedly downregulated at both the protein and mRNA levels in the hippocampus and cortex of six-month-old APP/PS1 mice, and the density of GABA receptors was reduced near amyloid deposits [ 71 ].…”

Section: Neurotransmitter Abnormalities and Cognitive Dysfunctionmentioning

confidence: 99%

Neurotransmitters in Prevention and Treatment of Alzheimer’s Disease

Yang

Zou

Wang

2023

IJMS

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Alzheimer’s disease (AD) is the most frequent cause of cognitive impairment in middle-aged and older populations. There is a lack of drugs that demonstrate significant efficacy in AD, so the study of the pathogenesis of AD is of great importance. More efficacious interventions are needed, as reflected by our population’s fast aging. Synaptic plasticity is the capacity of neurons to adjust their connections, and it is strongly tied to learning and memory, cognitive function, and brain injury recovery. Changes in synaptic strength, such as long-term potentiation (LTP) or inhibition (LTD), are thought to represent the biological foundation of the early stages of learning and memory. The results of numerous studies confirm that neurotransmitters and their receptors play an important role in the regulation of synaptic plasticity. However, so far, there is no definite correlation between the function of neurotransmitters in aberrant neural oscillation and AD-related cognitive impairment. We summarized the AD process to understand the impact of neurotransmitters in the progression and pathogenesis of AD, including the current status of neurotransmitter target drugs, and the latest evidence of neurotransmitters’ function and changes in the AD process.

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“…GABA metabolism in astrocytes is perturbed in neurological disorders. GABA metabolism has been found to be downregulated in astrocytes with APP or PSEN-1 mutations, which was associated with the decline of GAT-3 expression and GABA uptake (Salcedo et al, 2021). In cortical astrocytes, both the nitrogen and carbon skeleton of GABA can be used for glutamine synthesis (Andersen et al, 2020).…”

Section: Gaba Regulates the Differentiation Metabolism And Functions ...mentioning

confidence: 99%

“…GABA neurotransmission disorders have been reported in various neurological diseases. For instance, the decline of GABA uptake and metabolism in AD astrocytes leads to GATs expression reduction, hereby contributing to neurotransmitter disturbances and cognitive impairment (Salcedo et al, 2021). In mouse models of early Parkinson's disease, the downregulated GATs expression in the dorsal striatum also reduces the co-release of DA and GABA in DA axons, enhancing tonic inhibition of DA release and accelerating disease progression (Roberts et al, 2020).…”

Section: Gaba-stimulated Astrocytes Contribute To Neurological Disordersmentioning

confidence: 99%

Astrocytes: GABAceptive and GABAergic Cells in the Brain

Liu

Feng²,

Wang³

et al. 2022

Front. Cell. Neurosci.

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Astrocytes, the most numerous glial cells in the brain, play an important role in preserving normal neural functions and mediating the pathogenesis of neurological disorders. Recent studies have shown that astrocytes are GABAceptive and GABAergic astrocytes express GABAA receptors, GABAB receptors, and GABA transporter proteins to capture and internalize GABA. GABAceptive astrocytes thus influence both inhibitory and excitatory neurotransmission by controlling the levels of extracellular GABA. Furthermore, astrocytes synthesize and release GABA to directly regulate brain functions. In this review, we highlight recent research progresses that support astrocytes as GABAceptive and GABAergic cells. We also summarize the roles of GABAceptive and GABAergic astrocytes that serve as an inhibitory node in the intercellular communication in the brain. Besides, we discuss future directions for further expanding our knowledge on the GABAceptive and GABAergic astrocyte signaling.

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Downregulation of GABA Transporter 3 (GAT3) is Associated with Deficient Oxidative GABA Metabolism in Human Induced Pluripotent Stem Cell-Derived Astrocytes in Alzheimer's Disease

Cited by 17 publications

References 69 publications

Functional Metabolic Mapping Reveals Highly Active Branched-Chain Amino Acid Metabolism in Human Astrocytes, Which Is Impaired in iPSC-Derived Astrocytes in Alzheimer's Disease

Functional Metabolic Mapping Reveals Highly Active Branched-Chain Amino Acid Metabolism in Human Astrocytes, Which Is Impaired in iPSC-Derived Astrocytes in Alzheimer's Disease

Neurotransmitters in Prevention and Treatment of Alzheimer’s Disease

Astrocytes: GABAceptive and GABAergic Cells in the Brain

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