Behind the Headlines

Thursday May 7 2009

The study used genetically modified mice

Scientists have “successfully reversed the effects of Alzheimer's with experimental drugs”, according to BBC news. The news service highlights results from a study on genetically modified mice. The inhibitor drug tested is thought to reduce the effect of certain genes, and is on the market to treat some cancers.

This new research found that modifying the expression of a gene can boost mental skills in mice, including their ability to access forgotten information. It is hoped that this could lead humans who are given the drugs to recover lost memories. Much further research will be needed to clarify both whether the drugs will have the same effects in humans with Alzheimer’s and whether they are safe.

Professor Li-Huei Tsai, one author of the study, said to the BBC that: "This is exciting because more potent and safe drugs can be developed to treat Alzheimer's by targeting this HDAC. However, treatment for humans is still a decade or more away.”


Where did the story come from?

This research was conducted by Dr Ji-Song Guan, Professor Li-Huei Tsai and colleagues mostly from the Massachusetts Institute of Technology in the US. Funding was provided by a number of societies and foundations including the National Institute of Neurological Disorders and Stroke in the US. It was published in the peer-reviewed science journal Nature.


What kind of scientific study was this?

This was an animal study conducted in mice, looking at how histone deacetylase (HDAC) inhibitor drugs affected their brains, behaviour and learning. HDAC inhibitors are a class of compounds that interfere with histone deacetylase, an enzyme that is thought to play a role in regulating the expression of genes by changing how they form coils.

Drugs that inhibit HDACs are in experimental stages and the researchers say that, to date, HDAC inhibitors have not been used to treat Alzheimer's disease or dementia. They have been tested in early studies to treat Huntington's disease, and some HDAC inhibitors are already on the market to treat certain forms of cancer.

The researchers were interested in seeing the effect these drugs had on mice, so they genetically engineered two strains of “transgenic” mice that produced larger amounts of HDAC1 or HDAC2 proteins in their brains than normal mice.

The researchers then conducted learning and memory tasks using these transgenic mice. For example, they used a water maze to test if the mice could remember the correct swimming path to escape onto a platform. These tests were recorded by a video camera and analysed. They then injected the mice with HDAC inhibitors into the abdominal cavity and retested them.

The researchers then looked at a number of different aspects within the mouse brains including immunochemistry and gene expression. They were interested in synapse formation, memory formation and “synaptic plasticity”. Synaptic plasticity describes the strength of a connection, or synapse, between two neurons. Changes in strength can be due to changes in the levels of neurotransmitters released into the synapse or to changes in how effectively cells respond to those neurotransmitters.

Synaptic plasticity is important because memories are thought to be represented by the large interconnected networks of synapses in the brain, and, therefore, it is an important neurochemical foundation for learning and memory.


What were the results of the study?

The large quantities of HDAC1 and 2 the mice produced did not affect their brain anatomy, but HDAC2 did affect the memory, learning and behaviours of the mice. Synapses in the brains of HDAC2 mice were affected too, and these mice had impaired synaptic plasticity.

After taking HDAC inhibitors the mice regained their long-term memory and ability to learn new tasks. When mice were genetically engineered to produce no HDAC2 at all they exhibited enhanced memory formation.


What interpretations did the researchers draw from these results?

The researchers say that their research has shown that “inhibiting HDAC2 has the potential to boost synaptic plasticity, synapse formation and memory formation”. They say the next step is to “develop new HDAC2-selective inhibitors and test their function for human diseases".

The researchers say that the fact that long-term memories can be recovered supports the idea that apparent memory loss is really a reflection of memories becoming inaccessible. They say that their findings are in line with a phenomenon known as fluctuating memories, in which demented patients experience temporary periods of apparent clarity.


What does the NHS Knowledge Service make of this study?

This study will be of interest to those researching new treatments and approaches to Alzheimer’s disease. The fact that reduced neuronal levels of HDAC2 but not HDAC1 increase synaptic plasticity, memory formation and changes in the neurons that are associated with memory raises the possibility that drugs specifically targeted at HDAC2 might be of value in the treatment of human diseases associated with memory loss.

Further research will clarify how close we are to any potential use of these drugs in humans with Alzheimer’s. Professor Li-Huei Tsai, one author of the study, said to the BBC that: "This is exciting because more potent and safe drugs can be developed to treat Alzheimer's by targeting this HDAC. However, treatment for humans is still a decade or more away.”

Analysis by Bazian

Edited by NHS Choices

Links to the headlines

Trial drugs 'reverse' Alzheimer's. BBC news, May 07 2009

Drugs could aid memory. Daily Mirror, May 07 2009

Links to the science

Guan JS, Haggarty SJ, Giacometti E et al. HDAC2 negatively regulates memory formation and synaptic plasticity. Nature 459, 55-60 (7 May 2009)


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