That result was described in the study “Impairment of Glycolysis-Derived L-Serine Production in Astrocytes Contributes to Cognitive Deficits in Alzheimer’s Disease,” published in the journal Cell Metabolism.
The brain uses large amounts of energy produced from the breakdown, or metabolism, of a type of sugar called glucose. Previous studies have shown that in the early phases of Alzheimer’s disease there is a reduction in the use of glucose by astrocyte cells, found in brain and spinal cord. Astrocytes are non-neuronal cells that surround neurons, providing support and protection.
Scientists at the Université Paris-Saclay and the Université de Bordeaux, France, used a mouse model of Alzheimer’s disease to understand how these metabolic alterations may be connected to impaired cognition.
The team found that less glucose use by astrocytes in the context of Alzheimer’s also lowered the levels of the amino acid L-serine, which is produced from the breakdown of glucose and is used in the biosynthesis of proteins.
L-serine is used to produce D-serine in the brain, a compound that stimulates N-methyl-D-aspartate (NMDA) receptors present in neuronal cells. These receptors are essential for brain function and for establishing memories.
The team found that with less L-serine available, the activity of NMDA receptors was reduced. This altered neuronal synaptic plasticity and the capacity of brain nerve cells to store memories. Of note, synapses are the junctions between two nerve cells that allow them to communicate; synaptic plasticity refers to the ability of synapses to strengthen or weaken over time.
Mice with low levels of L-serine and D-serine had impaired spatial memory, which is the type of memory that allows us to remember where things are located, both on a short-term and long-term basis, as well as spatial relations between objects.
Mice with Alzheimer’s, as well as healthy controls, were given a 10% L-serine-enriched diet for two months. Total L-serine content in the whole hippocampus — a brain region involved in the formation of new memories — was significantly higher in these two groups of animals when compared to animals who did not receive that diet.
This diet also increased the activity of NMDA receptors and improved mice’s spatial memory.
“These results show that the availability of L-serine synthesized (…) in astrocytes is a key determinant for normal NMDAR function and support our hypothesis that its dysregulation could contribute to memory deficits in AD,” the researchers wrote.
In addition, researchers found low levels of the enzyme 3-phosphoglycerate dehydrogenase (PHGDH), involved in the production of L-serine, in brain samples from Alzheimer’s patients. Importantly, PHGDH levels were found to decrease further as the disease progressed from intermediate to advanced.
“These results indicate that a progressive alteration of the astrocytic serine synthetic pathway occurs in the brain of AD patients,” the researchers wrote.
“Altogether, these data support the contribution of defective production and release of L-serine in astrocytes to the pathogenesis [disease manifestations] of AD and point to L-serine supplementation as a potential therapy,” they concluded.
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