Low glucose levels in the brain are known to lead memory problems and cognitive decline, and new research suggests they do so by triggering a series of molecular reactions that ultimately kill neurons.
These findings provide fresh insight into changes that set the stage for Alzheimer’s disease. The research also identified a protein that appears to be involved in Alzheimer’s development and could be a target for its treatment.
The study, “Glucose Deficit Triggers Tau Pathology And Synaptic Dysfunction In A Tauopathy Mouse Model,” was published in the journal Translational Psychiatry.
Declining brain levels of glucose is a known warning sign of Alzheimer’s onset, and the drop begins before profound symptoms of memory loss are evident. What’s not clear, however, is exactly how low brain glucose is linked to cognitive loss, and whether it is a cause or a consequence of neurological impairment.
Researchers treated mice with 2-deoxyglucose (DG), a molecule that prevents neurons from using glucose to obtain energy, for several months to study the mechanisms leading to cognitive decline. They then checked the animals’ cognitive and memory abilities using a series of tests, and compared their responses to a control group of untreated mice.
DG-treated mice indeed performed worse on the memory tests than control animals, showing signs of memory loss. Further experiments revealed that DG-treated mice had signs of abnormal neuronal communication and, consequently, anomalies in the processes that ensure memory formation and its retention or storage.
Researchers also found that when glucose levels decrease in the brain, neurons activate a protein called p38, possibly as a defense mechanism against the loss of this preferential fuel. But in the long term, p38 activation raises the levels of phosphorylated tau, which form aggregates in the brain that block neuronal activity and cause neurons to die. The more phosphorylated tau accumulates in the brain, the more severe is the person’s dementia.
“The findings are very exciting,” Domenico Praticò, MD, and the study’s senior author , said in a news release. “There is now a lot of evidence to suggest that p38 is involved in the development of Alzheimer’s disease.”
Even small, chronic episodes of glucose shortage in the brain damages neurons, the findings show.
“There is a high likelihood that those types of episodes are related to diabetes, which is a condition in which glucose cannot enter the cell,” Praticò said. “Insulin resistance in type 2 diabetes is a known risk factor for dementia.”
Further studies are needed to investigate whether inhibiting p38 would prevent memory impairment, even in the presence of lower glucose levels in the brain.
“It is an exciting avenue of research. A drug targeting this protein could bring big benefits for patients,” Praticò added.