Cognitive Decline in Old Age May Be Linked to Increased ‘Pruning’ of Brain Cell Connections
A study led by BU researcher Douglas Rosene sheds new light on the potential links between age-related cognitive decline and the mechanism that helps the brain target and eliminate weak synapses.
By Jim Cooney
As adults age they begin to exhibit impairments in learning, memory, and other cognitive functions. Age is the biggest risk factor for many common neurodegenerative diseases, including Alzheimer’s Disease, but cognitive impairment occurs even in the absence of such illnesses as a part of the normal aging process, and many scientists are determined to better understand why.
In a new study published in GeroScience, a team of researchers from Boston University’s Center for Systems Neuroscience and the Department of Anatomy & Neurobiology examined age-related cognitive decline in the context of “synapse remodeling,” the process by which the brain optimizes and maintains the vast network of connections (synapses) necessary for communication between brain cells (neurons).
One critical aspect of synapse remodeling is the targeted removal of weaker synapses—those synapses across which there is little or no neural activity—so that resources can be diverted toward creating stronger and more stable connections elsewhere. Microglia, which are the immune cells that patrol the brain responding to various threats, are guided by signal proteins that tell them which synapses to eliminate and which to leave alone. While this process of “synaptic pruning” is most active during the earliest years of development, the pruning mechanism remains in place throughout the life of the brain. Scientists have started to wonder whether this mechanism might play a role in age-related synapse loss and subsequent cognitive impairment.
Sarah DeVries, a PhD student and lead author of the new study, said the team examined two particular signal proteins in the brains of cognitively tested normal aging monkeys, which exhibit age-related cognitive impairment similar to humans. “There’s the C1q protein, which is the ‘eat me’ signal, and the CD47 protein, which is the ‘don’t eat me’ signal.” DeVries said previous studies had found that levels of the C1q “eat me” protein increase with age, and that higher levels seemed to correlate with higher, age-related cognitive impairment, but no one had ever looked at the other side of the signal protein coin, the protective CD47 protein. “What’s novel about our study is that we looked at both proteins, and we found that the levels of both change with age—the C1q increases, and the CD47 decreases, so much so that the balance between the two actually seems to flip in favor of synapse elimination.”
In other words, not only is there more C1q “eat me” protein targeting synapses, but there is also less CD47 “don’t eat me” protein protecting synapses from microglia as the brain gets older. This is summarized in the accompanying Figure.
Douglas Rosene, the study’s principal investigator, said interpreting the study’s results requires consideration of other age-related factors, such as an increased inflammation of the microglia, which affects how they respond to threats, and the increased degradation of the neuron’s insulating protein sheath (myelin) which can weaken the strength of the neuronal signal being transmitted. “One possible interpretation of our results is that as myelin degrades, neuronal activity and synaptic activity decreases, and so the signal proteins are just responding to their environment and guiding elimination of those synapses,” said Rosene. “Another interpretation could be that the age-related inflammation of the microglia causes an overproduction of C1q or an underproduction of CD47, leading to an aberrant excess of synapse elimination.”
According to Rosene, studies like this represent a major shift in the scientific understanding around cognitive impairment in normal aging. “For decades, the conventional wisdom was that cognitive impairment in normal aging was the result of neurons dying, as they do in Alzheimer’s Disease, only to a lesser extent.” In the 1970s, several papers were published that reported age-related neuron loss in aging brains even without Alzheimer’s Disease. Though highly influential, these studies suffered from methodical weaknesses, said Rosene, and it wasn’t until much later that more methodically sound studies emerged reporting that, in fact, there is no significant loss of neurons with age, which has motivated the search for alternative mechanisms. “Increasingly, the view of cognitive impairment in normal aging is not that the neurons are dying, but rather that they’re not able to talk to each other as effectively.”
This new focus on impaired connectivity between neurons has led to a host of new studies (many of which are conducted in Rosene’s lab) examining cognitive impairment in normal aging as it relates to processes that impact how well neurons communicate, such as the health and behavior of microglia, myelin degradation and repair, and of course, synapse loss and elimination. Gaining a more precise understanding of the mechanisms underlying age-related cognitive impairment, said Rosene, will open possibilities for therapeutic interventions that could slow this decline, an increasingly important aspiration as advances in living standards, public health and medicine allow humans to live longer and longer lives.