A pinboard by
Emil Jakobsen

Postgraduate, University of Copenhagen


Despite only taking up 2% of the body weight, the human brain consumes 20% of the total energy consumption at rest. Glia cells is believed to be responsible for at least 50% of the human brain, astrocytes is the most common glia cell. Astrocytes is important in several brain functions including memory formation. Glycogen breakdown (glycogenolysis) in astrocytes has been associated with memory formation, while a reduced glucose consumption (glycolysis) in astrocytes has been linked to reduced uptake of amyloid-beta, which is believed to play a role in development of Alzheimer’s disease. Both glycogenolysis and glycolysis are regulated by the second messengers cAMP and Ca2+. An increased understanding of the intracellular signaling pathways in astrocytes will enhance the knowledge of potential targets to alter astrocytic metabolism. Such alterations in metabolism can, potentially, be used to prevent, delay or treat diseases related to decreased metabolism e.g. Alzheimer’s disease. Our work, which is primarily done in cultured astrocytes, focus on understanding the regulation of cAMP and Ca2+ signaling in astrocytes and how to manipulate this signaling to change the metabolism.


Astrocyte glycogenolysis is triggered by store-operated calcium entry and provides metabolic energy for cellular calcium homeostasis.

Abstract: Astrocytic glycogen, the only storage form of glucose in the brain, has been shown to play a fundamental role in supporting learning and memory, an effect achieved by providing metabolic support for neurons. We have examined the interplay between glycogenolysis and the bioenergetics of astrocytic Ca(2+) homeostasis, by analyzing interdependency of glycogen and store-operated Ca(2+) entry (SOCE), a mechanism in cellular signaling that maintains high endoplasmatic reticulum (ER) Ca(2+) concentration and thus provides the basis for store-dependent Ca(2+) signaling. We stimulated SOCE in primary cultures of murine cerebellar and cortical astrocytes, and determined glycogen content to investigate the effects of SOCE on glycogen metabolism. By blocking glycogenolysis, we tested energetic dependency of SOCE-related Ca(2+) dynamics on glycogenolytic ATP. Our results show that SOCE triggers astrocytic glycogenolysis. Upon inhibition of adenylate cyclase with 2',5'-dideoxyadenosine, glycogen content was no longer significantly different from that in unstimulated control cells, indicating that SOCE triggers astrocytic glycogenolysis in a cAMP-dependent manner. When glycogenolysis was inhibited in cortical astrocytes by 1,4-dideoxy-1,4-imino-D-arabinitol, the amount of Ca(2+) loaded into ER via sarco/endoplasmic reticulum Ca(2)-ATPase (SERCA) was reduced, which suggests that SERCA pumps preferentially metabolize glycogenolytic ATP. Our study demonstrates SOCE as a novel pathway in stimulating astrocytic glycogenolysis. We also provide first evidence for a new functional role of brain glycogen, in providing local ATP to SERCA, thus establishing the bioenergetic basis for astrocytic Ca(2+) signaling. This mechanism could offer a novel explanation for the impact of glycogen on learning and memory.

Pub.: 28 Jan '14, Pinned: 22 Jun '17

Glycogen Shunt Activity and Glycolytic Supercompensation in Astrocytes May Be Distinctly Mediated via the Muscle Form of Glycogen Phosphorylase.

Abstract: Glycogen is the main storage form of glucose in the brain. In contrast with previous beliefs, brain glycogen has recently been shown to play important roles in several brain functions. A fraction of metabolized glucose molecules are being shunted through glycogen before reentering the glycolytic pathway, a phenomenon known as the glycogen shunt. The significance of glycogen in astrocyte energetics is underlined by high activity of the glycogen shunt and the finding that inhibition of glycogen degradation, under some conditions leads to a disproportional increase in glycolytic activity, so-called glycolytic supercompensation. Glycogen phosphorylase, the key enzyme in glycogen degradation, is expressed in two different isoforms in brain, the muscle and the brain isoform. Recent studies have illustrated how these are differently regulated. In the present study, we investigate the role of the two isoforms in glycolytic supercompensation in cultured astrocytes with the expression of either one of the isoforms silenced by siRNA knockdown. When reintroducing glucose to glucose-starved astrocytes, glycolytic activity increased dramatically. Interestingly, the increase was 30% higher in astrocytes not expressing the muscle isoform of glycogen phosphorylase. Based on these results and previously published data we couple the muscle isoform of glycogen phosphorylase to glycolytic supercompensation and glycogen shunt activity, giving insights to the underlying mechanistic of these phenomena.

Pub.: 13 May '17, Pinned: 22 Jun '17