New study in rats matches genetic influences and cognitive impairment

May 07, 2003

A study in rats matching the activity of 146 genes with brain aging and impaired learning and memory produces a new picture of brain aging and cognitive impairment. The research, by scientists at the University of Kentucky, uses powerful new gene microarray technology in a novel way to match gene activity with actual behavioral and cognitive performance over time, resulting in the identification of this wide range of aging- and cognition-related genes (ACRGs). Importantly, the changes in gene activity had mostly begun in the mid-life of the rats, suggesting that changes in gene activity in the brain in early adulthood might set off cellular or biological changes that could affect how the brain works later in life.

The report (embargoed for release until May 7, 2003, at 5 p.m. ET) appears in the May 2003 issue of The Journal of Neuroscience. It provides more information on genes already linked to aging, including some involved in inflammation and oxidative stress, and also describes additional areas in which gene activity might play a role in brain aging. These include declines in energy metabolism in cells and changes in the activity of neurons (nerve cells) in the brain and their ability to make new connections with each other. In addition, other areas in which genes appear to play an influential role involve increases in cellular calcium levels which could trigger cell death, cholesterol synthesis (also implicated in Alzheimer's disease in other research), iron metabolism and the breakdown of the insulating myelin sheaths that when intact facilitate efficient communication among neurons.

The study was conducted by a team led by Philip W. Landfield, Ph.D., and colleagues Eric M. Blalock, Kuey-Chu Chen, Keith Sharrow, Thomas C. Foster, and Nada M. Porter at the University of Kentucky, Lexington, and James P. Herman at the University of Cincinnati, Ohio. It was supported primarily by the National Institute on Aging (NIA). Additional support was provided by the National Institute of Mental Health (NIMH). Both are parts of the National Institutes of Health at the U.S. Department of Health and Human Services.

"Gene microarrays, which can measure activity of thousands of genes simultaneously, provide the most advanced genomics technology. This has allowed us to do what no other study has done before - use large numbers of microarrays to relate genes and behavior over the lifespan of the animals on a scale that can identify most of the important players," says Landfield. "The good news is that we have a new, more comprehensive model of brain aging at the genetic level; the downside is that this model shows just how very complex that process may be." "This study makes it very clear that it is not a single gene or even several genes that are responsible for brain aging. Here, we are presented a picture of age-related changes in multiple cellular pathways and systems which interact with one another to change the brain's structure and how it functions," notes Brad Wise, Ph.D., Program Director, Fundamental Neuroscience, NIA.

In the study, young, middle-aged, and aged rats were trained on two memory tasks, learning to navigate a water maze and remembering familiar objects in their cages. After training, the scientists examined the brain tissue of the rats, specifically the hippocampus, an area associated with memory and cognition. RNA (ribonucleic acid, which carries out the DNA's instructions for making proteins) was isolated from each rat and selectively bound to a separate chip containing over 8,700 fragments of genes to generate gene expression, or activity, profiles. One important step was further refining of the analyses to reduce false positives and false negatives while statistically assessing changes in gene activity. The researchers then homed in on genes that changed with aging and, finally, on genes involved in age-related changes in the performance of the rats on the two memory tests. Ultimately, they zeroed in on 146 ACRGs (aging- and cognition-related genes), which were then assigned to functional categories representing different cellular processes in the brain. A complete listing of the genes and what they do appears in the original journal article.

Offering one model of brain aging, the researchers suggest that loss of neuronal processes and the compromise of their insulating myelin sheaths may trigger brain inflammation, eventually leading to loss of the cells' function. The changes in gene expression for the most part were seen in mid-life, before cognition was impaired, suggesting that changes in gene activity in the brain in early adulthood might initiate cellular or biological changes that could lead to functional changes later in life.
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The NIA leads the Federal effort to support and conduct basic, clinical, and social and behavioral studies on aging and on age-related memory change and dementia. It supports the Alzheimer's Disease Education and Referral (ADEAR) Center, which provides information on research on age-related memory change and Alzheimer's disease. ADEAR's website can be viewed at www.alzheimers.org. ADEAR may also be contacted at 1-800-438-4380. Press releases, fact sheets, and other materials about aging and aging research can be viewed at the NIA's general information website www.nia.nih.gov.

NIH/National Institute on Aging

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