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

Abstract

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.

Aberrant amino acid metabolism promotes neurovascular reactivity in rosacea

“…Downregulation of TP53 after doxycycline treatment may inhibit the release of glutamic acid synthesized by hepatocytes into the peripheral circulation, thereby reducing the serum glutamic acid concentration after treatment ( 27 ). Mutations in PSEN1 reduce the aspartic acid synthesis derived from leucine metabolism ( 28 ). Therefore, TP53 and PSEN1 were highlighted as the critical factors by which doxycycline may regulate glutamic acid or aspartic acid in patients with rosacea ( Figure 6H ).…”

“…PSEN1, belonging to the aspartyl proteases family, is generally recognized as being associated with Alzheimer’s disease. It is reported that the mutation of PSEN1 in astrocytes reduces the aspartic acid synthesis derived from leucine metabolism ( 28 ). Consistently, the expression of PSEN1 decreased after doxycycline treatment, as does the serum level of aspartic acid.…”

Detection of astrocytic slow oscillatory activity and response to seizurogenic compounds using planar microelectrode array

“…In addition to these methods, the evaluation of extracellular potential activity of astrocytes using the MEA method proposed here is expected to enable more detailed analysis of astrocyte activity. In recent years, the involvement of glia in various neurological diseases has been reported, and studies using patient iPSC-derived astrocytes for Rett syndrome, Alexander’s disease, Alzheimer’s disease, and autism spectrum disorder, in which astrocytes are thought to be involved, are actively conducted ( Williams et al, 2014 ; Kondo et al, 2016 ; Jones et al, 2017 ; Russo et al, 2018 ; Salcedo et al, 2021 ; Allen et al, 2022 ). We expect that the MEA-based system for assessing astrocyte activity will not only provide new insights into the mechanisms of neurological diseases, including epilepsy, but will also help in the evaluation of drug efficacy in the drug development for astrocyte related diseases.…”

Longitudinal analysis of UK Biobank participants suggests age and APOE-dependent alterations of energy metabolism in development of dementia

“…On the other hand, we identified an increased level of valine in the brain tissue of the participants with a risk of AD, which is in opposite as their association in the periphery out of blood-brain barrier 10,32,33,[14][15][16]34 . This may be explained by the impaired astrocytes in the early stage of AD, or less inefficient astrocytes in the APOE4 carriers 27 , resulting in a decreased BCAA metabolism in the brain 40 . Thus, besides ketone bodies, more valine in the periphery should be transported to the brain to support the energy metabolism of brain.…”