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Jul 23, 2014

In Aging Brain, Extracellular Scaffolding Loses Flexibility, Memory Deficits Worsen

  • Even during healthy aging, we slowly lose our ability to learn and remember new things. Often, cognitive decline is associate with loss of synaptic plasticity—the ability to alter the connections between brain cells. But what causes synaptic connections to become less, well, plastic?

    To answer that question, scientists from the University of Luxembourg and the VU University of Amsterdam investigated the molecular basis of memory loss. In particular, they looked at the molecular composition of brain connections in healthy mice of 20 to 100 weeks of age—an age span roughly equivalent to the period between puberty and retirement in humans.

    The scientists, led by Luxembourg’s Antonio del Sol Mesa, Ph.D., and Amsterdam’s Ronald van Kesteren, Ph.D., described their work in an article that appeared July 20 in Molecular and Cellular Proteomics, in an article entitled, “Hippocampal extracellular matrix levels and stochasticity in synaptic protein expression increase with age and are associated with age-dependent cognitive decline.”

    The scientists investigated the temporal profile of the mouse hippocampal synaptic proteome. “Extracellular matrix proteins were the only group of proteins that showed a robust and progressive upregulation over time,” the authors wrote. “This was confirmed by immunoblotting and histochemical analysis, indicating that the increased levels of hippocampal extracellular matrix may limit synaptic plasticity as a potential cause of age-related cognitive decline.”

    “Amazingly, there was only one group of four proteins of the extracellular matrix that increased strongly with age. The rest stayed more or less the same,” said Prof. Dr. del Sol Mesa. “The extracellular matrix is a mesh right at the connections between brain cells. A healthy amount of these proteins ensures a balance between stability and flexibility of synapses and is vital for learning and memory.”

    “An increase of these proteins with age makes the connections between brain cells more rigid, which lowers their ability to adapt to new situations,” Dr. van Kesteren added. “Learning gets difficult, memory slows down.”

    In addition, the scientists not only looked at the individual molecules but also analyzed the whole picture using a systems biology approach. Here they described the interplay between molecules as networks that together tightly control the amount of individual molecules and their interactions.

    “We observed that stochasticity in synaptic protein expression increased with age, in particular for proteins that were previously linked with various neurodegenerative diseases," the scientists continued. "[Yet] low variance in expression was observed for proteins that play a basal role in neuronal function and synaptic neurotransmission.”

    “A healthy network keeps all molecules in the right level for proper functioning. In older mice we found, however, that the overall molecular composition is more variable compared to younger animals. This shows that the network is losing its control and can be more easily disturbed when we age,” Prof. Dr. del Sol Mesa explained. According to the researchers, increasing variability in network composition makes the brain more susceptible to diseases.

    Hence, this insight into the normal aging process could also help in the future to better understand complex neurodegenerative diseases such as Alzheimer's and Parkinson's disease. Chemical compounds that modulate the extracellular matrix might be promising new treatments for learning disorders and memory loss.


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