The brain relies heavily on mitochondria to produce energy and is made up of mitotic and postmitotic cells that need to closely coordinate their metabolism to maintain essential bodily functions. During aging, damaged mitochondria that produce less ATP and more reactive oxygen species (ROS) accumulate. Now, Salk scientists report that mitochondria at dysfunctional synapses fail to meet energetic demand, supplying either too much or too little power and potentially cause age-related cognitive impairment.

The findings are published in Frontiers in Aging Neuroscience in an article titled, “Violation of the ultrastructural size principle in the dorsolateral prefrontal cortex underlies working memory impairment in the aged common marmoset (Callithrix jacchus).”

“Fifty percent of people experience loss of working memory with old age, meaning their ability to hold and manipulate information in the short-term decreases,” explained co-first author Courtney Glavis-Bloom, PhD, a senior staff scientist in the lab of John Reynolds, PhD, Salk Institute. “We set out to understand why some individuals maintain healthy working memory as they age, while others do not. In the process, we discovered a novel mechanism for the synaptic basis of cognitive impairment.”

Previous studies have found that brains lose synapses as they age, and the researchers saw this pattern in their non-human primate model, too. But when they looked at the synapses that remained, they found evidence of a breakdown in coordination between the size of boutons and the mitochondria they contained.

“To examine this, we turned to electron microscopy,” said co-first author Casey Vanderlip, a former research assistant in Reynolds’ lab. “This enabled us to visualize these components across many synapses. We found that synaptic loss occurred with healthy and impaired aging, but what differed was the breakdown in the correlation between the sizes of boutons and their mitochondria.”

“It is a ripple effect, with unfathomably small synaptic structures altering networks of neurons, brain function, and behavior,” said Glavis-Bloom. “Investigating these microscopic dysfunctions is uncharted territory that could revolutionize our understanding of aging and its impact on cognition.”

The team found that adherence to the ultrastructural size principle was essential for avoiding working memory impairment with age. By viewing the violation of the ultrastructural size principle and mitochondria-related failures as the key to age-related cognitive impairment, the study ushers in a new era for aging research.

“The images we have captured of synapses are snapshots of a dynamic process,” said Reynolds, holder of the Fiona and Sanjay Jha chair in neuroscience. “With these snapshots in hand, we can begin to think first about the mechanisms that coordinate the expansion and contraction of the various parts of the synaptic complex, then ask how disruption of these mechanisms can explain age-related cognitive decline. This opens an entirely new way of thinking about cognitive decline that could lead to new targets for future therapeutics.”

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