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Alzheimer's, Dementia & Mental Health
Long-Term Memory Restored in Mice by Toys or Nerve
Cell Growth Drug
Promising avenues for treatment for humans with
Alzheimer's or other neurodegenerative diseases
 April 30, 2007 A new study indicates that
memories are not really erased in such disorders as Alzheimer's, but
that they are rendered inaccessible but can be recovered. Toys and other
sensory stimuli, or a drug that encourages nerve cell (neuronal) growth,
both helped mice regain long-term memories and the ability to learn,
after their brains had lost a large number of nerve cells due to
neurodegeneration. The most common risk for this loss of nerve cells is
aging.
This new studies comes from researchers at the
Howard Hughes Medical Institute and suggest two promising avenues for
treatment that might alleviate learning deficits and memory loss in
humans with Alzheimer's or other neurodegenerative diseases.
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The results of the experiments suggest that the
term "memory loss" may be an inaccurate description of the kinds of
mental deficits associated with neurodegenerative diseases.
"The memories are still there, but they are
rendered inaccessible by neural degeneration," said the senior author
Li-Huei Tsai, a Howard Hughes Medical Institute researcher at the
Massachusetts Institute of Technology.
Tsai led the research group that published its
findings on April 29, 2007, in an advance online publication in the
journal Nature.
"I believe that these findings could have
particular significance for treatment of people who already have
advanced neurodegenerative disease," said Tsai.
"Most current treatments seem to be aimed at
affecting the early stages of the disease. But our mouse model shows
that even when there has been a significant loss of neurons, it is still
possible to improve learning and memory."
Over the last five plus years, Tsai's research team
has developed and refined a mouse model of Alzheimer's disease. In
earlier studies, Tsai's group had shown that a protein called p25
contributes to neurodegeneration.
Over time they developed a genetically engineered
mouse in which they are able to turn on p25 gene expression at specific
stages in development. In these animals, evidence of neuronal loss is
first detected six weeks after the induction of p25.
At this age, animals exhibit a profound impairment
in learning and memory that is accompanied by synaptic loss and impaired
long-term potentiation (LTP), a process involved in the storage of
memories.
The researchers engineered mice so that they could
switch the p25 transgene on at will. Activation of p25 has been
implicated in a variety of neurodegenerative diseases. Once activated in
the mice, the p25 transgene produces neural pathology very similar to
that of patients with Alzheimer's disease, said Tsai. The animals show
brain atrophy and loss of neurons due to the same kind of cellular
abnormalities seen in people who have Alzheimer's disease, she said.
Researchers have long known that an environment
rich in sensory stimuli can improve learning in mice. So, Tsai and her
colleagues decided to explore whether such an environment could improve
learning and memory in their mice after a large number of neurons were
already lost.
In their experiments, they switched on p25 in older
mice. The genetic change induced brain atrophy and neuronal loss.
They then used two tests to assess learning and
memory in these older mice. In the "fear-conditioning" test, the animals
were required to learn to associate a specific chamber with a mild
electric shock. The second test required the animals to learn to find a
submerged platform in a tank of murky water.
The researchers placed some of the animals in a
large chamber with a variety of stimuli: an exercise treadmill, colorful
toys with various shapes and textures that were changed daily, and other
mice.
Their experiments showed that animals with
neurodegeneration due to p25 activation had significant gains in
learning and memory when they were exposed to this enriched environment.
Those animals fared better on memory tests than the animals that
remained in standard cages.
The researchers also tested the effects of an
enriched environment on the animals' long-term memory. They knew that
the fear-conditioning test established a lasting long-term memory in the
mice.
So, they tested whether environmental enrichment
improved the p25-induced animals' ability to remember that conditioning
weeks after training. They found that the enriched animals showed marked
recovery of the long-term memory when compared to mice that did not live
in a stimuli-rich environment.
"This recovery of long-term memory was really the
most remarkable finding," said Tsai. "It suggests that memories are not
really erased in such disorders as Alzheimer's, but that they are
rendered inaccessible and can be recovered."
When the researchers studied the brains of the
animals that had been exposed to the extra stimuli, they found no
evidence of increased growth or formation of new neurons when compared
to brains of mice that had not experienced the enriched environment.
However, they did find anatomical and biochemical evidence for growth of
connections among neurons.
Tsai and her colleagues also sought to understand
the biological mechanism by which environmental enrichment enhanced
learning and memory in the mice.
"Even though the learning-enhancement effects of
environmental enrichment have been known for half a century, nobody
really knows the mechanism behind it," said Tsai.
"However, there has also been a growing body of
evidence that chromatin remodeling has a beneficial effect on learning
and memory," she said.
Chromatin is found in the nuclei of cells. It is
composed of DNA spooled around bundles of histone proteins. The addition
of small chemical tags to known as acetyl of methyl groups to the
histones can alter the way chromatin is organized, which in turn
determines which genes are turned on.
Indeed, when Tsai and her colleagues analyzed the
histones of enriched mice versus non-enriched animals, they found that
environmental enrichment induced histone modification in the enriched
mice.
Tsai and her colleagues tested whether a class of
drugs that preserves histone acetylation, called histone deacetylases
inhibitors, could affect learning and memory in the p25-induced mice.
"In those studies, we found that using drugs to
increase histone acetylation artificially produced an effect very
similar to that observed in environmental enrichment," said Tsai.
"This leads us to believe that further studies of
ways to target chromatin remodeling could offer a treatment for
Alzheimer's and other forms of dementia," she said. Tsai's group is now
investigating the molecular mechanism by which such drugs work and which
specific drug targets might be most effective at enhancing learning and
memory.
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