In the adult brain, communication between neurons is constantly remodeled by the elimination of old synapses and the formation of new ones; this turnover of synapses is called structural plasticity. Patients with neurodegenerative diseases such as Alzheimer’s disease have fewer synapses compared to normally aging adults, suggesting that their brains have decreased structural plasticity. While it is difficult to analyze this plasticity across aging in humans, research on hibernating animals provides an important model to study structural plasticity at a molecular level.
During hibernation, mammals such as bears and hedgehogs cool their bodies temporarily, and this cooling induces a temporary loss of synapses. Synapses are reformed when body temperature warms. To mimic hibernation in a laboratory setting, Peretti and colleagues developed a model based on artificial cooling and re-warming of lab mice. They analyzed changes in synapse number in this model to study structural plasticity. Their results showed that the same number of synapses that were lost upon cooling, reformed after warming the animals.
The researchers then analyzed whether differences in plasticity were present in two mouse models of human neurodegeneration: Alzheimer-type mice (called 5XFAD mice) or prion-infected mice. In both the prion-infected and Alzheimer-type mice, synapse number decreased after cooling, but these synapses did not reform after warming, indicating a loss of structural plasticity.
The investigators examined a protein that is expressed after cooling or hibernation, the cold-shock RNA-binding protein RBM3. They found that in healthy mice, RBM3 was expressed after cooling. However, in both prion-infected and Alzheimer-type mice, cooling failed to induce expression of RBM3. Enhancing RBM3 in both of the mouse models either by early cooling prior to disease onset, or by over-expressing RBM3 with virus prior to cooling, rescued the loss of structural plasticity. The effect was dramatic: not only were synapses reformed after cooling in prion-infected and Alzheimer-type mice, but also fewer neurons were lost. Additionally, these mice performed better on a memory task, and overall survival was increased compared to prion-infected or Alzheimer-type mice that did not receive these early interventions. Loss of RBM3 exacerbated symptoms and decreased survival in both models of neurodegeneration. The investigators then examined whether RBM3 alone, in the absence of cooling, was neuroprotective, and found that in both prion-infected mice and Alzheimer-type mice, early over-expression of RBM3 resulted in fewer synapses lost, decreased memory deficits, and better survival.
Understanding protective mechanisms of neurodegeneration may ultimately lead to the development of therapeutic targets or interventions for patients with early stage neurodegenerative disorders.
- Peretti D et al. (2015) RBM3 mediates structural plasticity and protective effects of cooling in neurodegeneration. Nature 518:236-239. doi: 10.1038/nature14142