Deficient astrocyte metabolism impairs glutamine synthesis and neurotransmitter homeostasis in a mouse model of Alzheimer's disease

Andersen, Jens V.; Christensen, Sofie K.; Westi, Emil W.; Diaz‐delCastillo, Marta; Tanila, Heikki; Schousboe, Arne; Aldana, Blanca I.

doi:10.1016/j.nbd.2020.105198

Cited by 70 publications

(43 citation statements)

References 72 publications

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“…We have previously described similar effects of MSO on metabolism of the well-known astrocytic substrate [1,2- 13 C]acetate [ 43 ], further supporting that astrocytes are the main cellular compartment of C8 and C10 metabolism. Furthermore, we have previously demonstrated that transfer of astrocyte-derived glutamine to neurons is maintained in our slice incubation set-up [ 43 , 60 ], implying that the decreased neuronal GABA synthesis in the presence of MSO is indeed caused by the absent astrocyte glutamine supply. Insufficient astrocyte glutamine synthesis can lead to seizures [ 24 ] and reduced expression of GS has been found in the epileptic hippocampus [ 23 ].…”

Section: Discussionmentioning

confidence: 98%

“…In addition to direct metabolic effects, C10 may serve several signaling purposes in the brain [ 59 , 64 ], and is able to directly inhibit AMPA receptors [ 65 ], suggesting multiple mechanisms underlying the anti-epileptic effects of C10. Finally, astrocyte dysfunction is gaining attention in several neurodegenerative diseases [ 66 ] and we have demonstrated inadequate astrocyte glutamine supply in mouse models of both Alzheimer’s and Huntington’s disease [ 25 , 60 ]. Interestingly, C8 and C10 supplementation has been shown to improve cognitive function in patients with mild cognitive impairment and Alzheimer’s disease [ 6 – 8 ] and are gaining attention in several other diseases [ 5 ].…”

Section: Discussionmentioning

confidence: 99%

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Astrocyte metabolism of the medium-chain fatty acids octanoic acid and decanoic acid promotes GABA synthesis in neurons via elevated glutamine supply

et al. 2021

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The medium-chain fatty acids octanoic acid (C8) and decanoic acid (C10) are gaining attention as beneficial brain fuels in several neurological disorders. The protective effects of C8 and C10 have been proposed to be driven by hepatic production of ketone bodies. However, plasma ketone levels correlates poorly with the cerebral effects of C8 and C10, suggesting that additional mechanism are in place. Here we investigated cellular C8 and C10 metabolism in the brain and explored how the protective effects of C8 and C10 may be linked to cellular metabolism. Using dynamic isotope labeling, with [U-13C]C8 and [U-13C]C10 as metabolic substrates, we show that both C8 and C10 are oxidatively metabolized in mouse brain slices. The 13C enrichment from metabolism of [U-13C]C8 and [U-13C]C10 was particularly prominent in glutamine, suggesting that C8 and C10 metabolism primarily occurs in astrocytes. This finding was corroborated in cultured astrocytes in which C8 increased the respiration linked to ATP production, whereas C10 elevated the mitochondrial proton leak. When C8 and C10 were provided together as metabolic substrates in brain slices, metabolism of C10 was predominant over that of C8. Furthermore, metabolism of both [U-13C]C8 and [U-13C]C10 was unaffected by etomoxir indicating that it is independent of carnitine palmitoyltransferase I (CPT-1). Finally, we show that inhibition of glutamine synthesis selectively reduced 13C accumulation in GABA from [U-13C]C8 and [U-13C]C10 metabolism in brain slices, demonstrating that the glutamine generated from astrocyte C8 and C10 metabolism is utilized for neuronal GABA synthesis. Collectively, the results show that cerebral C8 and C10 metabolism is linked to the metabolic coupling of neurons and astrocytes, which may serve as a protective metabolic mechanism of C8 and C10 supplementation in neurological disorders.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Astrocyte metabolism of the medium-chain fatty acids octanoic acid and decanoic acid promotes GABA synthesis in neurons via elevated glutamine supply

et al. 2021

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“…To further substantiate these results, we next assessed if hiPSC-derived astrocytes could metabolize BCAAs through 13 C-incorporation into the TCA cycle. Incubation with the three [U-13 C]BCAAs (Figure 4) is presented as the molecular carbon labeling (MCL), which is the average of the carbon labeling in a given molecule (Andersen et al, 2021a). 13 C-enrichment was recovered in all TCA cycle metabolites and amino acids from [U-13 C]BCAA metabolism, which demonstrates that human astrocytes are capable of introducing and metabolizing the carbon skeleton of leucine, isoleucine, and valine in the TCA cycle.…”

Section: Bcaa Oxidative Metabolism In Human Astrocytesmentioning

confidence: 99%

“…In the brain, glutamine synthesis is also the primary pathway of ammonia fixation and is strictly located in astrocytes (Norenberg and Martinez-Hernandez, 1979;Brusilow et al, 2010). Interestingly, AD has been associated with elevated cerebral levels of ammonia (Seiler, 2002), which may be caused by insufficient astrocyte glutamine synthesis (Smith et al, 1991;Olabarria et al, 2011;Andersen et al, 2021a). Since glutamine is derived from the TCA cycle intermediate α-ketoglutarate via glutamate, astrocyte TCA cycle function is crucial for glutamine synthesis (Swanson and Graham, 1994).…”

Section: Bcaa Metabolism In Admentioning

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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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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“…Not all studies agree that glutamate uptake is impaired in mouse models of AD or by exposure to toxic fragments of Aβ. For example, no evidence of impaired glutamate uptake was recently reported in the hippocampus of the 5xFAD model of AD (Andersen et al, 2021). In this study, the authors exposed cortical and hippocampal brain slices to exogenous radiolabeled glutamate for 60 min.…”

Section: Glutamate Uptake In Neurodegenerative Diseasementioning

confidence: 99%

Entering a new era of quantifying glutamate clearance in health and disease

Brymer

Barnes

Parsons

2021

J of Neuroscience Research

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Glutamate is the brain's primary excitatory neurotransmitter and is essential for rapid excitatory synaptic neurotransmission, neuronal survival, and synaptic plasticity. Paradoxically, glutamate can also act as a toxic chemical, and enhanced glutamate-induced excitotoxicity is heavily implicated in numerous central nervous system (CNS) diseases including Alzheimer disease (AD) and Huntington disease (HD), among others (Parsons & Raymond, 2014). As glutamate is not metabolized in the extracellular space, the CNS is equipped with highly efficient excitatory amino acid transporters (EAATs) that rapidly clear extracellular glutamate following neural activity. The majority of EAATs are located on astrocytes, with lower expression

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Deficient astrocyte metabolism impairs glutamine synthesis and neurotransmitter homeostasis in a mouse model of Alzheimer's disease

Cited by 70 publications

References 72 publications

Astrocyte metabolism of the medium-chain fatty acids octanoic acid and decanoic acid promotes GABA synthesis in neurons via elevated glutamine supply

Astrocyte metabolism of the medium-chain fatty acids octanoic acid and decanoic acid promotes GABA synthesis in neurons via elevated glutamine supply

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

Entering a new era of quantifying glutamate clearance in health and disease

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