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The human brain may be the crown of creation, but it tarnishes with time. Some cognitive capacities diminish even in healthy aging, and risk of the most common neurodegenerative disorders, Alzheimer’s disease and Parkinson’s disease, increases with advancing years.
For the most part, attempts to understand brain aging and the diseases it brings have focused on neurons, whose connections and communications underlie thought, feeling, and behavior. But they are not the whole story.
“Neurons are the workhorses of the brain, but they have to be very delicately maintained in an optimal environment to do their job properly,” says Donna Wilcock of the Sanders-Brown Center on Aging at the University of Kentucky. When neurons misfire or die, “it’s like the canary in the mine,” Wilcock suggests. “The real problem isn’t that the canary’s dead, but that it didn’t have the right air to breathe. The glia are responsible for that.”
Glia, the “other” brain cells, maintain and support neurons. There are three main types—microglia, astrocytes and oligodendrocytes—whose complex and complementary functions include immune surveillance, tissue repair, electrolyte regulation, and synapse formation and maintenance.
“I think in the Alzheimer’s field and in other neurodegenerative disorders as well, our appreciation for non-neuronal cells and the role they may be playing has certainly increased in the last 5-10 years,” Wilcock says.
What Changes with Age
A 2017 paper in in Cell Reports extends that appreciation to healthy aging. When researchers at UCL (University College London) and the Francis Crick Institute explored diverse cell types in brains at different ages, “we found that glia changed more than neurons,” says Jernej Ule, professor of molecular neuroscience at the university and senior author of the paper.
The team examined post-mortem tissue of people who had died, apparently free of neurodegenerative disease, between the ages of 16 and 101. Looking at gene expression in multiple regions of the brain, they found that, as previous research had suggested, overall activity increased in microglia, which regulate the inflammatory response, and declined in oligodendrocytes, which produce and maintain the myelin sheath that insulates axons.
“But what was most interesting to us was that regional patterns of glial expression are diminished in aging, while neuronal patterns are preserved,” Ule says. In younger brains, the expression profiles of genes specific for astrocytes and oligodendrocytes vary from region to region, indicating that these cells function somewhat differently in each area. With age, such regional differences become less marked.
The consequences of this loss of distinctive regional identity are “an open question raised by our study that remains to be explored,” Ule says. “Neurons and glia are tightly linked. The diminution of regional expression is telling us that somehow this communication may become less specific during the process of brain aging.”
One thing that the findings strongly suggest, he says, is that “each brain region ages in a different way; the process isn’t generic, but very dependent on the types of interactions of neurons and glia within the region.”
The biggest shift in region-specific glial expression, he points out, were in the hippocampus and substantia nigra—areas implicated in Alzheimer’s and Parkinson’s disease, respectively.
Taken together, changes in glial gene expression predicted age more accurately than changes in neurons. The association was strongest in nine genes that changed in all the brain regions that were examined.
Although the details of an age-disease connection remain unclear, “there’s more and more evidence that the changes of aging can inform us about the preclinical mechanisms of neurodegeneration,” he says. “Our assumption is that if you can delay the aging process, slow it down, neurodegeneration may never get to the [clinical] threshold.”
His team’s findings suggest the possibility of new targets for intervention, Ule says. “While neurons for the most part can’t be replaced, glial cells are able to proliferate. If there’s a defect in glia, there should be a way to tease them back to a healthy system that can regenerate, and that might prevent neurons from degenerating.”
“This is a great paper,” says Donna Wilcock. “I think regional differences could be very important in understanding different disease processes. We know that certain brain regions are more susceptible to some of these pathologies than others, but until now, never realized why that is. I think this may actually point to some of those mechanisms.”
The findings in this paper “will lead to many novel hypotheses of disease,” she says. “We’re all going to change a little bit of what we’re thinking about; I have some new ideas based on this.
“The fact that astrocytes and oligodendrocytes shift their profile so dramatically in the substantia nigra—does that mean we have to pay more attention to glia in Parkinson’s disease? That’s the kind of queries that this paper opens up.”
Clinical applications that emerge indirectly, from testing such hypotheses, “may be significant in the long run,” she says.
The Dancers and the Dance
Other recent studies have focused on the role of specific glial cells in aging and disease, with microglia the object of special scrutiny, Wilcock says. The recognition that inflammation plays a significant role in Alzheimer’s and other neurodegenerative disease has brought these, the brain’s principal immune cells, to the forefront. Microglia are also involved in the formation of synapses, “making sure neurons are connecting properly, and maintaining that connection,” she says.
A 2016 review paper suggested that changes in microglia underlie an age-related loss of resilience that makes the brain more vulnerable to injury or disease.
“After a blow to the head, for example, the young brain is able to recover and repair itself—amazingly so,” says Paula Bickford, professor of neuroscience at the Center of Excellence for Aging and Brain Repair at the University of South Florida, and lead author of the paper. “As we get older, some functions that help brain repair don’t work the same way. In fact, they make things worse.”
The dual nature of microglia makes them a likely suspect. Sensitively attuned to their environment, these glial cells are designed to respond immediately to chemical signals and to deal with whatever is not supposed to be there—dying cells, viruses, the wrong kind of protein. “They’re the first responders to injury,” says Bickford.
The microglial response takes two forms. Through “classical” activation they express cytokines that initiate inflammation, and highly reactive oxygen molecules that destroy invading organisms. “Alternative” activation generates anti-inflammatory cytokines and trophic factors, promoting healing processes that clean up damaged tissue and facilitate the growth of new blood vessels and neurons.
Microglia can be in both activation states concurrently. These are normally kept in balance, but with aging the pro-inflammatory classical response gets the upper hand.
“Some studies show that a consequence is the decreased ability to get rid of tau protein and beta amyloid, making the brain more susceptible to neurodegenerative disease,” says Bickford. “Improving resilience won’t eliminate the pathology–it won’t keep you from getting Alzheimer’s disease. But it could help modify progression, to lengthen the time you’re healthy.”
To be sure, microglia don’t age alone.
Other studies have shown that astrocytes, which also have a hand in neuron defense and regeneration, become less functional and less responsive with age. When time reduces the generation of oligodendrocytes from progenitor cells, myelin production falls, compromising communication among neurons.
The elements combine in an immensely complicated, interlocking system. “There’s a lot of signaling that we don’t understand,” says Wilcock. “Microglia communicate with oligodendrocytes. Astrocytes and microglia have intimate communication with each other through cytokines; there’s a tight relationship between these cells.” Astrocytes and neurons are closely linked through bidirectional signaling.
Through insight into “the complete consort dancing together,” (as the poet T.S. Eliot wrote in a meditation on time), findings like the regional changes identified in the Cell Reports paper may help us understand how the brain ages, how age-linked diseases develop, and how we might intervene to forestall or restore the damage.