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Switching glycolysis as a link between Alzheimer's disease and cancer ?


Detailed analysis of single cell gene expression in the brain has shown that Alzheimer's disease is associated with metabolic reprogramming to enhanced aerobic glycolysis. Increased levels of metabolic enzymes such as lactate dehydrogenase A and pyruvate kinase M (PKM) have been shown to be readily reproducible biomarkers in the cerebrospinal fluid of Alzheimer's patients. A study published last September in Cell Metabolism now suggests that a cancer-like metabolic change occurs in affected neurons, associated with reduced morphological complexity, number of synapses, and calcium influx.


This switch to aerobic glycolysis, resembling the so-called Warburg effect, is accompanied by an increase in PKM2 in the neuronal nucleus. Pyruvate kinase M is an important glycolytic enzyme that correlates with AD pathology and occurs in multiple isoforms. The switch from PKM1 to PKM2 is characteristic of the effect named after physiologist Otto Heinrich Warburg and is particularly evident in cancer cells, which obtain their energy mainly by glycolysis followed by excretion of lactate (lactic acid). Thus, they do not feed the end product of glycolysis to the citrate cycle in the mitochondria as normal cells do. Today we know that not only cancer cells, but also neurons in the context of neurodegenerative diseases show this very inefficient form of energy production, which is accompanied by increased glucose consumption, despite sufficient oxygen supply.


The current study used neuronally induced cells derived from fibroblasts of Alzheimer's disease patients and control subjects. These cells are generated by the proneuronal factors Ascl1 and neurogenin-2 and retain the aging signature of their donors. They represent a suitable model system to study age-related disease phenotypes in living human neurons. In this process, induced neurons from Alzheimer's disease patients lose their mature neuronal markers and transform into an immature state, which is similar to the malignant transformation of cancer cells. In this process, PKM2 specifically interacts in the nucleus with the transcription factors STAT3 and HIF1α and enhances their stress-related effects.


The results of the study suggest that the switch to aerobic glycolysis is independent of the ApoE genotype and is associated with functional mitochondria (similar to the Warburg effect in cancer cells). Metabolic regulators have therefore become the focus of "anti-Warburg" drug development. Because inhibition of PKM2 by shikonin slows glycolysis, the effect of toxic glycolytic metabolites and the propensity of cells to enter apoptosis is reduced.

Shikonin is a chemical compound used in traditional Chinese medicine. It is a naphthoquinone extracted from the roots of a plant (Lithospermum erythrorhizon) and may also be used to prevent neurodegeneration.


Further studies would still need to clarify the extent to which induced neurons in cell culture, which cannot interact with surrounding glial cells, actually reflect metabolic homeostasis in the brain. Powerful tools for reprogramming somatic cells into induced astrocytes and oligodendrocytes are currently lacking. They would allow co-culture experiments to study aging processes and neurodegeneration in human systems.


Reference:


Traxler L, Herdy JR, Stefanoni D, ..., Gage FH, D'Alessandro A, Mertens J (2022) Warburg-like metabolic transformation underlies neuronal degeneration in sporadic Alzheimer's disease. Cell Metabolism 34:1248-1263.e1246


Image credit: iStock/Dr_Microbe

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