Hibernation as a model to study Alzheimer’s disease

July 17, 2024

-written by Pablo Largo Barrientos, a postdoctoral researcher at the VIB-KU Leuven Center for Brain & Disease Research

How can studying hibernation in hamsters help us to fight against Alzheimer’s disease? The answer is in the brain!

Pablo Largo Barrientos presenting his research at the VIB Seminar

The brain is the most complex body organ, filled with highly specialized cells called neurons. Neurons form connections, or synapses, with other neurons. These synaptic connections enable communication between neurons, which is essential for the formation and storage of memories. The human brain contains more than one hundred billion neurons, each forming an average of 7000 synapses with other neurons. This means that, in total, a human brain has around 700 trillion synapses –more than stars in our galaxy, the Milky Way. However, this number does not stay constant throughout our lifetime.

Synapses form during development, peaking around birth. Afterward, a lot of excessive non-functional synapses are removed in a process called “synaptic pruning”. This is a tightly regulated process that, if it goes wrong, can result in neurological disorders such as autism or schizophrenia. Around adolescence, pruning is finished, and the number of synapses in the brain will remain more or less constant for decades. However, as we age, the risk of developing a neurodegenerative disorder increases, many of which are characterized by a drastic reduction synapse. Alzheimer’s disease is one such disorder.

Alzheimer's disease is characterized by a drastic reduction in synapses, the connections between brain cells.

The number of synapses in the human brain throughout time and during certain neurological disorders

Alzheimer’s disease is the most common form of dementia, affecting more than 50 million people worldwide. Despite extensive research conducted over the last decades, there is still no available treatment that can stop or delay the progression of the disease. In the brains of Alzheimer’s patients, synapses are lost, leading to memory loss. However, we do not fully understand how this happens or how to prevent or recover lost synapses. This is where hibernating animals come into play.

Hibernation is a survival response to adverse external conditions like cold or food scarcity, where animals reduce bodily functions to preserve energy. One of the strategies that hibernating animals, such as hamsters, use to preserve energy is to remove many synapses in their brain, since they are highly energy-demanding and not needed during hibernation. Remarkably, when hamsters “awake” from hibernation their synapses are recovered within hours. The fact that hibernators are very evolutionarily distant from each other (from frogs to bears) and that they have very close species that do not hibernate (hamsters hibernate, but other rodents such as mice or rats do not) suggests the existence of a common hibernator ancestor. As a matter of fact, there is even archaeological evidence that the hominins from Atapuerca, who lived only half a million years ago, also hibernated in winter. This means that there is likely a shared, evolutionary conserved, genetic basis for hibernation and that we might still conserve the mechanisms of synapse recovery in our genetic code.

When hamsters “awake” from hibernation their synapses are recovered within hours.

The number of synapses in the hamster brain during arousal ("wake") and torpor ("asleep") states of hibernation

Thus, we believe that investigating the mechanisms that hamsters use to lose and regrow synaptic connections during hibernation will unveil new and unexplored targets for developing potential treatments for Alzheimer’s disease. With this aim, we established our own colony of hamsters in the lab, and we can induce them to hibernate by progressively reducing the temperature and light hours. We then used a technology called “single-cell RNA sequencing” to look at the expression of all genes within each individual hamster brain cell. With that information, we built the first ever single-cell resolution atlas of a hibernating brain. In our experiment, we included hamsters at the different stages of the hibernation cycle (before, during, and after), allowing us to detect all the genes that change in each cell type during hibernation. Each of these genes represents a potential target for preventing synapse loss or promoting the recovery of lost synapses. Our future research will determine whether any of these hibernation-related genes could be used for the treatment of Alzheimer’s disease.

In our experiment, we included hamsters at the different stages of the hibernation cycle (before, during, and after), allowing us to detect all the genes that change in each cell type during hibernation.