Our brain runs on sugar, and new research links the lack of glucose with cognitive impairment typical of Alzheimer’s disease and dementia. Additionally, researchers may have identified a new drug target for treating the neurodegenerative disease.
Using a mouse model, researchers have uncovered the mechanism by which glucose deprivation in the brain leads to cognitive impairment.
More than 5 million people in the United States live with Alzheimer’s disease. Before they develop the full-blown illness, many of these patients start experiencing a mild form of cognitive impairment.
This can include problems with their reasoning, judgment, or memory that are greater than normal, yet do not interfere with daily functioning.
As recent studies have suggested, even before the first signs of cognitive impairment, the levels of glucose in the brain begin to decline.
Glucose is crucial for good cognitive functioning. In fact, our brains rely heavily on this source of energy, using half of all the sugar in our body to fuel reasoning, memory, and learning.
New research – led by Dr. Domenico Praticò, a professor at the Center for Translational Medicine at the Lewis Katz School of Medicine at Temple University in Philadelphia, PA – investigates more deeply the impact that glucose deprivation has on the brain.
The findings were published in the Nature journal Translational Psychiatry.
Dr. Praticò has shown in a previous study that, to make up for glucose deprivation, the brain builds up the protein called phosphorylated tau.
The tau protein then creates so-called tangles – “gridlocks” of twisted fibers of tau that block the transportation of nutrients through to the neurons. Eventually, these tangles cause the brain cells to die. A larger number of tau tangles is usually associated with an increased severity of Alzheimer’s and dementia.
The previous study by Dr. Praticò investigated this mechanism in vitro and showed that tau buildup occurs using the P38 kinase pathway.
In this new research, the team has examined the mechanism of tau phosphorylation as a response to glucose deprivation in vivo, using a mouse model.
Dr. Praticò and colleagues used mice that have been genetically modified in a way that replicates memory problems and tau pathology typical of Alzheimer’s disease.
When the mice were 4 or 5 months old, some of them were administered 2-deoxyglucose (DG) – a chemical compound that prevents glucose from entering the cell and being processed into energy.
The mice were injected with the substance over several months, and at the end they were tested for cognitive function using maze tests to evaluate memory and learning.
The glucose-deprived mice performed much worse in the cognition tests than those that had not received DG.
Additionally, a microscopic evaluation of the mice’s brains revealed that neurons in the glucose-deprived mice had abnormal synaptic functioning. Memory encoding and storage were impaired because the interneural synapses were unable to communicate properly with each other.
Furthermore, the researchers also found high levels of phosphorylated tau and high numbers of dead cells in the brains of DG-treated mice.
Following up on Dr. Praticò’s previous research, the team examined P38 activation and found it to be directly associated with memory deficits.
“The findings are very exciting,” says Dr. Praticò. “There is now a lot of evidence to suggest that P38 is involved in the development of Alzheimer’s disease.”
According to him, the findings support the fact that even small episodes of chronic glucose deprivation can damage the brain. “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. Insulin resistance in type 2 diabetes is a known risk factor for dementia,” Dr. Praticò explains.
The authors conclude by noting that this is the first time that a study has offered “in vivo experimental evidence” that glucose deprivation in the brain – by activation of the P38 kinase pathway – triggers memory and cognitive impairment, synaptic miscommunication between neurons, and neuronal death.
They also comment on the possibilities for treatment, as this is the first time that P38 has been identified as a potential new drug target for Alzheimer’s disease:
“Drugs targeting this kinase in the brain may represent a suitable therapeutic approach for the treatment of both AD [Alzheimer’s disease] and related tauopathies for which impaired glucose utilization is an established risk factor.”
“It is an exciting avenue of research,” Dr. Praticò adds. “A drug targeting this protein could bring big benefits for patients.”
Written by Ana Sandoiu
Published: Tuesday 31 January 2017