RBM3 Mediates Protective Effects of Cooling on Neurodegeneration

The human brain displays the amazing capacity for synaptic plasticity by which brain synapses are continually strengthened or weakened in response to environmental, behavioral, emotional, and injury-related stimuli. Reduced synaptic numbers is an early hallmark of neurodegenerative diseases, such as Alzheimer’s disease. Although synaptic loss is a well-studied phenomenon in neurodegenerative disorders, how synaptic regeneration is affected is poorly understood. An exciting report in Nature (Peretti et al. 2015) demonstrates that the cold-shock protein RBM3 is a key mediator of synaptic regeneration and is protective against overall synapse loss in two neurodegeneration mouse models.

Cooling and rewarming model synaptic plasticity

When hibernating mammals enter torpor, brain synapses are lost as the body cools. Upon rewarming, synapses are reformed. When cooled to 16-18°C for 45 minutes wild-type laboratory mice show significant synaptic loss, which is reversed upon rewarming. Peretti et al. further examined synaptic regeneration following cooling and rewarming in two mouse models of neurodegeneration: the B6SJL-Tg(APPSwFlLon,PSEN1*M146L*L286V)6799Vas/Mmjax (5XFAD) mouse model of Alzheimer’s disease, which display synaptic loss by 4 months of age followed by cognitive defects, and the tg37 mouse model of prion disease, which, when infected with Rocky Mountain Laboratory prions, lose synapses by 7 weeks post-inoculation (wpi), followed by memory loss and finally death at around 12 wpi. Both models showed the capacity to regenerate synapses following cooling and rewarming early during disease development (at 2 months of age for the 5XFAD mice and at 4 wpi for the prion disease mice), but their capacity to regenerate synapses upon rewarming was lost by 3 months of age and 6 wpi, respectively, just prior to the onset of synaptic loss in the two models (Figure 1).

RBM3 expression linked to synapse reassembly

Overall, gene expression and cellular metabolism are repressed during periods of cooling, but a small set of proteins known as cold-shock proteins are expressed during these periods. RNA-binding motif protein 3 (RBM3) and cold-inducible RNA binding protein (CIRP) are two cold-shock proteins that are highly expressed in the brain. RBM3 expression is dramatically increased by cooling in wild-type mice, 2 month-old 5XFAD, and 4 wpi prion disease mice. This up-regulation of RBM3 is lost by 3 months of age in 5XFAD mice and by 6 wpi for the prion disease mice, which correlates to the time when the mice lose their ability to regenerate synapses. CIRP was not upregulated by cooling in either model.

Induction of RBM3 expression restores synaptic plasticity

Early cooling of the prion disease mice, at 3 wpi and 4 wpi, caused an increase in RBM3 expression in the brain for up to 6 weeks. Compared to control mice (infected with prions but not cooled), treatment of prion-infected mice with early cooling:

  • Delayed synaptic loss until 9 wpi
  • Prevented loss of synaptic transmission
  • Limited behavioral deficits
  • Significantly increased survival

Overexpression of RBM3 via injection of transgenic lentiviruses into the hippocampi of the prion-infected mice produced very similar results, indicating that RBM3 expression is neuroprotective in the absence of cooling. The 5XFAD model does not allow for similar exploration of RBM3 overexpression because the development of behavioral deficits and neuronal loss play out over many months. Knocking down RBM3 expression in 5XFAD mice using RNA interference, however, led to earlier onset of synaptic loss (3 months in treated mice versus 4 months in untreated controls), which indicates that RBM3 plays a protective role in synaptic plasticity in this model, too. Combined, these data demonstrate that RBM3 plays a critical role in synapse regeneration, and increased focus on synapse regeneration and cold-shock proteins offers new therapeutic targets for treating Alzheimer’s and other neurodegenerative diseases.