New Clues to Age-Related Cognitive Decline

Mounting evidence suggests that age-related cognitive decline is caused not by nerve cell death, as it is in Alzheimer’s disease, but from a disruption in synapses, the structures that allow a nerve cell to transmit a signal to other nerve cells. Demonstrating these synaptic disruptions in the prefrontal cortex of the brain, and linking such disruptions to synaptic health, has been challenging for scientists—until now.

Researchers at the Icahn School of Medicine at Mount Sinai recently made new and significant advances to support this theory. With the use of high-powered electron microscopy, they were able to associate structures within nerve cells and synapses—mitochondria—with the disruption of these connections. Mitochondria are considered the cell’s energy source. In a second finding, they were able to restore healthy synapses and improve a type of short-term memory, known as “working memory,” with estrogen treatment. To function properly, working memory relies on a complex arrangement of synapses to activate nerve cells in the brain, a process that is extremely energy-demanding. The results were published in the January 7, 2014 Proceedings of the National Academy of Sciences.

“We are increasingly convinced that maintenance of synaptic health as we age is critically important in preventing age-related cognitive decline,” says John H. Morrison, PhD, Dean of Basic Sciences and the Graduate School of Biomedical Sciences, the senior author of the study. Dr. Morrison is also the W.T.C. Johnson Professor of Geriatrics and Palliative Medicine (Neurobiology of Aging), and Professor of Neuroscience.

Researchers studied the working memory of 29 young and aged rhesus monkeys, targeting mitochondria within key synapses that are vulnerable to aging and needed for optimal cognitive function. After the monkeys were trained to perform a working memory test, the research team used electron microscopy to reconstruct synapses in order to investigate the number and type of mitochondria in nerve terminals, which form synapses. Their conclusion: Poor working memory was associated with a higher incidence of malformed mitochondria in nerve terminals, which formed smaller and weaker synaptic contacts than those containing healthy mitochondria.

“We were excited to see that the occurrence of these malformed mitochondria could be reversed with estrogen, which has known antioxidant effects, suggesting that hormone replacement therapy may benefit cognitive aging,” says Yuko Hara, PhD, Assistant Professor, The Friedman Brain Institute and Fishberg Department of Neuroscience. Dr. Hara is the lead researcher of the study.

Their findings also have implications for neurodegenerative conditions, such as Alzheimer’s disease. “In many of these disorders, mitochondrial problems occur long before the onset of nerve cell death and clinical symptoms,” says Dr. Morrison. “Early interventions targeted at maintaining healthy mitochondrial structure and function may be keys in preventing cognitive decline.”

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