Brain Metabolism of Hibernating Hamsters May Reveal Novel Therapeutic Targets for Alzheimer’s Disease

Upon hibernation, the brains of Syrian hamsters undergo metabolic changes that involve the phosphorylation of tau protein — a hallmark of Alzheimers’ disease. However, this process is rapidly reversed upon waking and understanding it could lead to the development of new therapies for Alzheimer’s, a study suggests.

The study, “Metabolomic Study of Hibernating Syrian Hamster Brains: In Search of Neuroprotective Agents,” was published in the Journal of Proteome Research.

Syrian hamsters, golden-haired rodents often kept as house pets, can undergo periods of hibernation of three to four days, interspersed with short periods of activity. During hibernation, these animals’ brains go through changes, at the structural and metabolic levels, to help neurons survive during low temperatures.

Specifically, during hibernation the protein tau undergoes a chemical modification, called phosphorylation, in which a phosphate group is added to the protein. Hyperphosphorylation of the tau protein results in the formation of intracellular tangles whose buildup in nerve cells is known to drive the progression of Alzheimer’s. In these hibernating animals, however, phosphorylated tau and its tangles are rapidly and totally reversed as soon as the animals wake up.

Researchers at the Centre for Metabolomics and Bioanalysis, Universidad CEU San Pablo, Spain, and colleagues set out to investigate the metabolic changes in the brain tissue of Syrian hamsters during hibernation. They hypothesized that understanding how the hamsters’ hibernating brains clear tau protein tangles may lead to the development of new therapies for Alzheimer’s disease.

Using a technique called mass spectrometry — which provides information about the structure of molecular compounds — the team investigated the metabolic changes that occur in the hamsters’ brains before, during, and after hibernation.

The analysis revealed 337 metabolites that showed statistically significant changes during hibernation. These included specific amino acids, endocannabinoids — chemical compounds that activate the same receptors as the active component in the cannabis plant — and brain cryoprotectants, such as polyols, a group of sugar alcohols that stabilize protein structure at low temperatures and prevent the formation of ice crystals, which would otherwise destroy cells.

A special group of fats (lipids), called long-chain ceramides, were also enriched in the brain of hibernating animals compared with those who had recently woken up. This specific lipid, along with other types of lipids, is known to regulate synapses — the junctions between two nerve cells that allows them to communicate.

Moreover, long-chain ceramides may help prevent damage to the brain due to oxidative stress, a condition caused by an imbalance between the body’s production of free radicals and its ability to contain them.

Phosphatidic acid, which is known to activate an enzyme that introduces a phosphate group into tau protein, was the metabolite that showed more pronounced changes — a 4.39 fold increase during hibernation.

These results suggest that “the Syrian hamster represents an excellent experimental model to study changes in brain metabolomics induced by hibernation that may provide insights into novel neuroprotective agents,” the researchers wrote.

“The mechanisms involved in these changes may be relevant for a better understanding of brain alterations that occur in neurodegenerative diseases such as AD (Alzheimer’s disease),” they concluded.