August 30, 2007
What was the name of your first-grade teacher? What is the name of your beloved child? Many of us may not be able to recall the answer to that first question. Sadly, for someone with Alzheimer's disease, even the second may be difficult to answer.
An intriguing new study from the Massachusetts Institute of Technology gives new insights into the way the brain and memories work, and raises the possibility that it may one day be possible to develop a drug to recover lost memories. The findings could lead to new treatments for Alzheimer's, a disease that saps the memory of more than five million Americans.
The MIT researchers, led by Dr. Andre Fischer, conducted an innovative experiment using mice that had been genetically bred to develop a disease that results in the loss of brain cells and memory. The mice produced a protein called p25 that, in high amounts, kills off cells in the hippocampus, an area of the brain that is critical for memory. The result of high p25 levels is memory loss and other symptoms typical of Alzheimer's disease.
In the experiments, the mice were taught to navigate a water maze, then find a platform under the water's surface where they could rest from their aquatic exertions. Over time, normal mice remembered where the resting platform was, and could promptly recall its location when placed in the maze.
The investigators induced toxic levels of the protein p25 in the mice, killing off nearly half the brain cells in the rodents' hippocampus. As expected, the mice could no longer learn how to navigate the water maze and find the resting platform.
The mice were then divided into two groups. Some spent the next four weeks living in a standard laboratory cage. After that time, the mice were still unable to successfully navigate the water maze.
But other mice lived in an environmentally enriched cage, full of spinning wheels and novel toys that stimulated their senses and prompted them to explore and interact. The researchers found that the mice that had spent a month in these stimulating surroundings were able to learn to navigate the maze and find the resting platform.
These findings are consistent with previous research in people suggesting that men and women who engage in mentally stimulating activities show less cognitive decline as they age. Reading a novel, engaging in travel, doing a crossword puzzle, or learning to play a new musical instrument all seem to help boost learning and keep memory sharp.
Similar findings have been demonstrated in earlier animal studies as well. Old and young animals living in enriched environments show improved learning and memory. Environmental stimulation likewise leads to increased growth of brain cells in the hippocampus. Increased levels of brain growth factors may be linked to the boost in memory and learning, some studies suggest.
In other experiments, the researchers found that mice that had forgotten a learned experience (due to induction of the p25 protein) had the "lost" memory revived after environmental enrichment.
Boosting Brain Connections
In the current experiment, the researchers found that the stimulating environment did not lead the mice to grow new brain cells in the hippocampus. It did, however, stimulate the growth of new connections, or synapses, between the brain cells that remained. This rich network of brain cell connections may have restored their ability to learn new things and also revived lost memories in the mice.
The investigators also discovered that environmental enrichment is associated with the prevention of a chemical alteration that occurs in a protein called histone, which is associated with our DNA. This chemical alteration occurs during the aging process, and the enzyme responsible for it is called HDAC, for histone deacetylase.
When the researchers blocked HDAC with a drug-like compound, the chemical change in histone was prevented and the mice were able to learn and remember. Remarkably, this occurred even without environmental enrichment. In other words, the compound blocked the enzyme HDAC, and this mimicked the effects of environmental enrichment. So the researchers may have identified the mechanism by which environmental enrichment rescues learning and memory.
The hope is that, with more testing, brain cell connections might be rejuvenated in men and women with memory problems. This could lead to a new treatment that boosts connections between remaining brain cells, and revives memory, in those afflicted with Alzheimer's disease.
This study is a provocative example of how basic laboratory research is expanding our understanding of how the brain works.
The Fisher Center for Alzheimer's Research Foundation funds critical laboratory research into the underlying causes of memory loss. Such research is essential for finding a cure for Alzheimer's disease. To learn more or to make a donation, visit www.ALZinfo.org.
Marilyn S. Albert, Ph.D.: "Changing the Trajectory of Cognitive Decline?" Clinical Implications of Basic Research. The New England Journal of Medicine, August 2, 2007, pages 502-503
A. Fischer et al: "Recovery of Learning and Memory Is Associated with Chromatin Remodeling." Nature 447: 2007, pages 178-182