An international research team says they have provided the first evidence that the lack of a naturally occurring protein is linked to early signs of dementia. They report that the absence of the MK2/3 protein promotes structural and physiological changes to cells in the nervous system.
These changes were shown to have a significant correlation with early signs of dementia, including restricted learning and memory formation capabilities, according to the scientists, who published their findings (“The MK2/3 cascade regulates AMPAR trafficking and cognitive flexibility”) in Nature Communications.
An absence of MK2/3, in spite of the neurons having significant structural abnormalities, did not prevent memories being formed, but did prevent these memories from being altered. The results have led the researchers to call for greater attention to be paid to studying MK2/3.
“Understanding how the brain functions from the subcellular to systems level is vital if we are to be able to develop ways to counteract changes that occur with aging,” said Sonia Correa, Ph.D., from the University of Warwick in the U.K. “By demonstrating for the first time that the MK2/3 protein, which is essential for neuron communication, is required to fine-tune memory formation this study provides new insight into how molecular mechanisms regulate cognition.” Dr. Correa’s University of Warwick group is working with researchers at the University of Bradford in the U.K. and Hannover Medical University.
Neurons can adapt memories and make them more relevant to current situations by changing the way they communicate with other cells. Information in the brain is transferred between neurons at synapses using neurotransmitters released from one presynaptic neuron, which then act on receptors in the next postsynaptic neuron in the chain.
MK2/3 regulates the shape of spines in properly functioning postsynaptic neurons. Postsynaptic neurons with MK2/3 feature wider, shorter spines than those without.
The researchers found that change, caused by MK2/3’s absence, in the spine’s shape restricts the ability of neurons to communicate with each other, leading to alterations in the ability to acquire new memories.
“We provide evidence that MAPK-activated protein kinases 2 and 3 (MK2/3) regulate neuronal spine morphology, synaptic transmission and plasticity. Furthermore, mGluR-LTD is impaired in the hippocampus of MK2/3 double knockout (DKO) mice, an observation that is mirrored by deficits in endocytosis of GluA1 subunits,” wrote the investigators. "Consistent with compromised mGluR-LTD, MK2/3 DKO mice have distinctive deficits in hippocampal-dependent spatial reversal learning. These novel findings demonstrate that the MK2/3 cascade plays a strategic role in controlling synaptic plasticity and cognition.”
“Deterioration of brain function commonly occurs as we get older but, as result of dementia or other neurodegenerative diseases, it can occur earlier in people’s lives,” noted Dr. Correa. “For those who develop the early signs of dementia it becomes more difficult for them to adapt to changes in their life, including performing routine tasks. For example, washing the dishes; if you have washed them by hand your whole life and then buy a dishwasher it can be difficult for those people who are older or have dementia to acquire the new memories necessary to learn how to use the machine and mentally replace the old method of washing dishes with the new. The change in shape of the postsynaptic neuron due to absence of MK2/3 is strongly correlated with this inability to acquire the new memories.”
Given their vital role in memory formation, MK2/3 pathways are important potential pharmaceutical targets for the treatment of cognitive deficits associated with aging and dementia, according to Dr. Correa.