Mitochondria power-supply failure may cause age-related cognitive impairment

Newswise —

The brain can be likened to a complex puzzle, comprised of numerous interwoven and interdependent pieces that work together for optimal functioning. It is divided into different areas, each housing millions of neurons that are interconnected through thousands of synapses. These synapses, which facilitate communication between neurons, rely on even smaller components such as message-sending boutons (bulb-like structures at the tips of neuron branches), message-receiving dendrites (branch-like structures that receive messages from boutons), and energy-producing mitochondria. To ensure a coherent and efficient brain function, all of these intricate pieces must be taken into consideration.

However, in the aging brain, these pieces can get lost or altered and no longer fit in the greater brain puzzle.

Previous studies had established that synapse loss occurs in the aging brain, a pattern that was also observed in the animal model used in the researchers' study. However, upon further investigation of the remaining synapses, the team discovered a breakdown in the coordination between the size of boutons and the mitochondria they contained. This breakdown contradicts the fundamental neuroscientific principle known as the ultrastructural size principle, which states that changes in size of one part of the synaptic complex should be proportional to changes in size of all other parts. In other words, the synapse, mitochondria, and boutons should scale in harmony with each other. The Salk team's study, published in Frontiers in Aging Neuroscience on April 12, 2023, sheds light on the possibility that this principle may be violated in the context of age or disease, a previously unexplored area of research.

To investigate this phenomenon, the research team employed electron microscopy, as explained by Casey Vanderlip, a former research assistant in Professor Reynolds' lab and co-first author of the study. This cutting-edge imaging technique allowed them to visualize the components of synapses across a large number of samples. The findings revealed that synaptic loss was observed both in healthy and impaired aging brains. However, the crucial difference was observed in the breakdown of correlation between the sizes of boutons and their mitochondria, indicating a disruption in the normal scaling relationship between these synaptic components in the aging brain with cognitive impairment.

As stated by Glavis-Bloom, the impact of these minute synaptic structural changes goes beyond what may be comprehended, as they have a ripple effect on networks of neurons, brain function, and ultimately, behavior. Delving into these microscopic dysfunctions represents a novel frontier in research, with the potential to revolutionize our understanding of the aging process and its profound impact on cognition. By unraveling the intricacies of these synaptic alterations, we may gain valuable insights into the underlying mechanisms of age-related cognitive decline, paving the way for new approaches to mitigate or prevent cognitive impairment in the elderly population.

“It is a ripple effect, with unfathomably small synaptic structures altering networks of neurons, brain function, and behavior,” says 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 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 study also involved contributions from other esteemed authors, including Sammy Weiser Novak and Uri Manor from the Salk Institute, as well as Masaaki Kuwajima, Lyndsey Kirk, and Kristen M. Harris from the University of Texas at Austin. Their collective expertise and collaboration enriched the research findings and added valuable insights to the study's conclusions. The collaborative efforts of these researchers from multiple institutions highlight the interdisciplinary nature of scientific inquiry and the importance of collaboration in advancing our understanding of complex scientific phenomena, such as age-related cognitive decline.

Other authors include Sammy Weiser Novak and Uri Manor of the Salk Institute; and Masaaki Kuwajima, Lyndsey Kirk, and Kristen M. Harris of the University of Texas at Austin.

The work was supported by an Allen Initiative in Brain Health and Cognitive Impairment award made jointly through the American Heart Association and the Paul G. Allen Frontiers Group (19PABH134610000AHA), the National Institutes of Health (1R21AG068967-01, P30014195), the National Science Foundation (2014862), the Kavli Institute for Brain and Mind at UC San Diego (Innovative Research Grant 2021), the Waitt Foundation, the Larry L. Hillblom Foundation, the Don and Lorraine Freeberg Foundation, and the Conrad Prebys Foundation.

About the Salk Institute for Biological Studies:

Unlocking the secrets of life itself is the driving force behind the Salk Institute. Our team of world-class, award-winning scientists pushes the boundaries of knowledge in areas such as neuroscience, cancer research, aging, immunobiology, plant biology, computational biology, and more. Founded by Jonas Salk, developer of the first safe and effective polio vaccine, the Institute is an independent, nonprofit research organization and architectural landmark: small by choice, intimate by nature, and fearless in the face of any challenge. Learn more at www.salk.edu.