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

Abstract

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 [13C]‐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.

Astrocytes: The Stars in Neurodegeneration?

“…Persistent glutamate exposure is believed to cause excessive neuronal firing and abnormal neuronal calcium influx, which ultimately results in severe neuronal excitotoxicity [ 131 , 134 , 136 , 137 ]. Lack of EAAT1/2 receptors and consequent glutamate excitotoxicity is a common phenomenon in AD [ 138 , 139 , 140 , 141 , 142 ], PD [ 143 , 144 ], ALS [ 48 , 83 , 145 , 146 ] and HD [ 27 , 28 , 105 ]. Additionally, downregulation of astrocytic glutamate receptors drives abnormal microglial pruning and phagocytosis of hippocampal glutamatergic synapses in AD [ 147 ].…”

“…Astrocyte metabolic proteomics is increasingly enriched during the commencement and disease progression of AD, with markers expressing both neuroprotective and neurotoxic phenotypes [ 24 ]. More specifically, AD astrocytes display augmented glycolytic flux and reduced glycogen storage [ 142 ]. In PD, astrocytes have altered polyamine and phospholipid levels [ 29 ], and in ALS, astrocytic metabolic dysfunction with compromised adenosine, fructose and glycogen metabolism is observed [ 171 , 172 ].…”

Implications of microbe-derived ɣ-aminobutyric acid (GABA) in gut and brain barrier integrity and GABAergic signaling in Alzheimer’s disease

“…Glutamate can be produced in the brain via astrocytes and is also a component of human diets. 69–71 The gut and associated microbes have a high capacity for dietary glutamate; it is converted into several important molecules in the gut including proline, arginine, glutamine, and GABA. 71 , 72 The enzyme, glutamate decarboxylase (GAD), catalyzes the transformation of glutamate into GABA.…”