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Alzheimer's Memory Loss May One Day Be Reversible

Article Date: 30 Apr 2007

A new US study suggests it may one day be possible to reverse the memory loss associated with Alzheimer's and similar degenerative brain diseases.

The study is published in Nature.

Scientists at MIT's Picower Institute for Learning and Memory in Cambridge, Massachusetts, put mice with induced brain atrophy in an enriched environment; a "playground" where they had the company of other mice, were given new colourful toys to play with every day, and were able to exercise on wheels.

The enriched environment mice recovered long term memories while mice kept in a bare cage on their own did not.

Li-Huei Tsai, Picower Professor of Neuroscience in the Department of Brain and Cognitive Sciences and her colleagues got the same results when they gave the brain atrophied mice a new type of experimental drug called histone deacetylase (HDAC) inhibitors.

Neurodegenerative diseases of the central nervous system are frequently accompanied by impaired learning and memory, and eventually dementia.

Scientists have been trying to find ways to reverse the process and re-establish the ability to learn and remember.

In this study, Prof Tsai, who as a child in Taipei witnessed her grandmother's descent into dementia, showed it was possible to "re-established access to long-term memories after significant brain atrophy and neuronal loss had already occurred".

The stimulated mice's brain cells had sprouted new dendrites and produced new synapses -- in effect reversing the degeneration.

Prof Tsai, who is also a Howard Hughes Medical Institute investigator, said:

"This is exciting because our results show that learning ability can be improved and 'lost' long-term memories can be recovered even after a significant number of neurons have already been lost in the brain."

"This hints at the possibility that cognitive function can be improved even in advanced stages of dementia," she added.

Prof Tsai and her team used genetically engineered mice in which expression of p25, a protein linked to degenerative brain diseases, could be switched on and off with a change in their diet.

They trained the mice to avoid electric shocks and find their way around mazes to reach food and then induced the brain degeneration via the p25 protein switch.

After 6 weeks, the mice couldn't remember what they had learned.

Some of the mice were put in the enriched environment with other mice and some were put in cages on their own.

The mice in the enriched environment remembered the maze and shock test much better than the isolated mice and they were also much better at learning new things.

Giving the mice histone deacetylase (HDAC) inhibitors, produced the same effect as living in an enriched environment.

HDACs help genes that have been too tightly packed in the nucleus of cells to express themselves and make proteins. The mechanism is all to do with the way DNA is packed in the nucleus of cells.

Histone is a protein that makes chromatin. Chromatin does several things but in essence it helps to package the DNA so it will fit into the cell nucleus and it is also involved in controlling gene expression.

Acetylation modifies histone which modifies chromatin. Deacetylation stops this. So inhibiting deacetylation reverses the process and lets histone and chromatin start working again.

HDACs have been increasingly used by researchers in other fields, for instance in clinical trials with Huntington's disease patients. Some HDACs are already available to help chemotherapy drugs target DNA by opening up the chromatin structure.

However, as Prof Tsai said:

"To our knowledge, HDACs have not been used to treat Alzheimer's disease or dementia. Future research should address whether HDAC inhibitors will be effective for treating neurodegenerative diseases."

Speculating on their findings, Prof Tsai and her colleagues suggested that perhaps degenerative brain diseases like Alzheimer's do not wipe out memories, but make them inaccessible in some way.

Many treatments for Alzheimer's and other brain degenerative diseases target the early stages, while this study suggests memory and learning may be restorable even when the brain is already quite damaged.

A new report from the Alzheimer's Association says there are now more than 5 million Americans living with the disease.

This includes 4.9 million people over the age of 65 and between 200,000 and 500,000 under 65 with early onset Alzheimer's disease and other dementias.

The biggest known risk factor is age. At present one American develops Alzheimer's every 72 seconds. This is estimated to become every 33 seconds by 2050 as 78 million baby boomers began turning 60 last year.

"Recovery of learning and memory is associated with chromatin remodelling."
Andre Fischer, Farahnaz Sananbenesi, Xinyu Wang, Matthew Dobbin and Li-Huei Tsai.
Nature advance online publication 29 April 2007
doi:10.1038/nature05772

Written by: Catharine Paddock
Writer: Medical News Today


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