Neuroprotective Function of High Glycolytic Activity in Astrocytes: Common Roles in Stroke and Neurodegenerative Diseases

Abstract

Astrocytes (also, astroglia) consume huge amounts of glucose and produce lactate regardless of sufficient oxygen availability, indicating a high capacity for aerobic glycolysis. Glycolysis in astrocytes is activated in accordance with neuronal excitation and leads to increases in the release of lactate from astrocytes. Although the fate of this lactate remains somewhat controversial, it is believed to fuel neurons as an energy substrate. Besides providing lactate, astrocytic glycolysis plays an important role in neuroprotection. Among the minor pathways of glucose metabolism, glucose flux to the pentose-phosphate pathway (PPP), a major shunt pathway of glycolysis, is attracting research interest. In fact, PPP activity in astrocytes is five to seven times higher than that in neurons. The astrocytic PPP plays a key role in protecting neurons against oxidative stress by providing neurons with a reduced form of glutathione, which is necessary to eliminate reactive oxygen species. Therefore, enhancing astrocytic glycolysis might promote neuronal protection during acute ischemic stroke. Contrariwise, the dysfunction of astrocytic glycolysis and the PPP have been implicated in the pathogenesis of various neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, since mitochondrial dysfunction and oxidative stress trigger and accelerate disease progression.

Oxidative Stress and Beta Amyloid in Alzheimer’s Disease. Which Comes First: The Chicken or the Egg?

“…This phenomenon, termed the astrocyte-to-neuron lactate shuttle (ANLS), was first described by Pellerin and Magistretti in the 1990s [ 155 ] and is supported by accumulating evidence [ 156 , 157 ]. Notably, increased lactate is associated with tau and Aβ deposition, see review [ 158 ]. A human in vivo PET study revealed a spatial correlation between glycolysis and Aβ deposition, suggesting a possible link between region-specific glycolysis in young brains and the subsequent development of AD pathology [ 159 ].…”

Activation and Role of Astrocytes in Ischemic Stroke

“…The Keap1/Nrf2 complex is continuously degraded by ubiquitination, so the transcriptional activity of Nrf2 is inhibited. When ischemia occurs, the stimulation of ROS allows dissociation of the Keap1/Nrf2 complex, Nrf2 is released and translocates to the nucleus, where it binds to the ARE to regulate the transcriptional activity of antioxidant enzymes ( Takahashi, 2021 ). The sulforaphane (classical Nrf2 activator) significantly increased GSH in astrocytes cultured in vitro ( Takahashi et al, 2012 ).…”

Senescence in Primary Rat Astrocytes Induces Loss of the Mitochondrial Membrane Potential and Alters Mitochondrial Dynamics in Cortical Neurons

“…It is known that astrocytes are mainly glycolytic and synthesize lactate from pyruvate, which is released and taken up by neurons, then it is reoxidized to pyruvate to continue with oxidation in the tricarboxylic acid cycle, where energy is obtained through oxidative phosphorylation ( Dienel, 2017 ; Takahashi, 2021 ). It has been observed that astrocytes have an age-related metabolic change from glycolytic metabolism to oxidative metabolism, carried out by the mitochondria ( Jiang and Cadenas, 2014 ).…”