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

Here we uncover a pathological mechanism in Alzheimer's disease linking abnormal hypermetabolism of glucose in hiPSC-derived astrocytes and neurons to an abnormal and potentially toxic glutamate accumulation. Increased glucose metabolism was found in astrocytes and neurons carrying familial Alzheimer's disease mutations. Diseased astrocytes exhibit reduced expression of the excitatory amino acid transporter 2 but increased glutamate oxidative metabolism, which supports an increased synthesis of glutamine. Glutamine uptake is increased in diseased neurons, and glutamate release is enhanced completing a potentially toxic cycle. Our findings further identify metabolic and neurotransmitter imbalances that may operate at early phases of Alzheimer's disease pathophysiology. AbstractGlutamate 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 ...
Source: Journal of Neurochemistry - Category: Neuroscience Authors: Tags: ORIGINAL ARTICLE Source Type: research