Friday, 2 March 2012

Restricting Enzyme Reverses Alzheimer's Symptoms In Mice

A study conducted by Li-Huei Tsai, a researcher at MIT, has found that an enzyme (HDAC2) overproduced in the brains of individuals with Alzheimer's, blocks genes needed to develop new memories. With this finding, the team were able to restrict this enzyme in mice and reverse symptoms of Alzheimer's. Results from the study are published in the February 29 online edition of Nature. 

Alzheimer's currently affects 5.4 million people in the United States. Findings from the study indicate that medications targeting HDAC2 could be a new techniques to treating Alzheimer's. Globally, the incidence of people with Alzheimer's is expected to increase two fold every two decades. Recently, President Barack Obama set a goal date of 2025 to find an effective treatment. 

According to Tsai, this goal could be achieved with the help of HDAC2 inhibitors, although it would probably take a minimum of at least a decade in order to develop and test such medications. Lead author of the report is Johannes Gräff, a postdoc at the Picower Institute. 

Tsai, director of the Picower Institute for Learning and Memory at MIT, explained: 

"I would really strongly advocate for an active program to develop agents that can contain HDAC2 activity. The disease is so devastating and affects so many people, so I would encourage more people to think about this."


Histone deacetylases (HDACs) are a class of 11 enzymes that control gene regulation by altering histones, which consist of highly alkaline proteins and are the chief protein components of chromatin. Histones act as spools around which DNA winds and play a role in gene regulation. HDACs transform a histone via a method called deacetylation. During this process, chromatin is packaged more tightly, making gens in that area less likely to be expressed. 

This effect can be reversed using HDAC inhibitors. These inhibitors open up the DNA and allow it to be transcribed. 

In prior investigations, Tsai has demonstrated the HDAC2 is an important regulator of memory and learning. In this study, the team found that restricting HDAC2 can reverse symptoms of Alzheimer's in rodents. 

The team discovered that HDAC2, yet no other HDACs, is overproduced in the hippocampus of mice with Alzheimer's symptoms. The hippocampus is a region in the brain where new memories are created. 

HDAC2 was most frequently found attached to genes involved in synaptic plasticity. Synaptic plasticity is the brains ability change the connection strength between two neurons, in response to new information, which is vital to making memories. 

In addition, the researchers found that those genes had significantly lower levels of acetylation and expression in the affected mice. 

Tsai explains: 

"It's not just one or two genes, it's a group of genes that work in concert to control different phases of memory formation. Which such a blockade, the brain really loses the ability to quickly respond to stimulation. You can imagine that this creates a huge problem in terms of learning and memory functions, and perhaps other cognitive functions."


Using short hairpin RNA, a molecule which can develope to attach to a carrier RNA, the team blocked HDAC2 in the hippocampi of mice with Alzheimer's symptoms. RNA is a molecule that delivers genetic instructions from DNA to the rest of the cell. 

The researchers found that reduced HDAC2 activity restarted histone acetylation, allowing genes needed for synaptic plasticity and other memory and learning processes to be expressed. They discovered that synaptic density increased considerably in treated mice, and that the rodents regained normal cognitive function. 

Tsai, said: 

"This result really advocates for the notion that if there is any agent that can selectively down-regulate HDAC2, it's going to be very beneficial."


In addition, the team evaluated postmortem brains of Alzheimer's patients and discovered increased levels of HDAC2 in the hippocampus and entorhinal cortex, which play vital roles in memory storage. 

According to Tsai, results from the study may explain why medications that remove beta-amyloid proteins from the brains of Alzheimer's patients have only provided modest, if any, improvements in human trials. 

In the brains of Alzheimer's patients, beta-amyloid proteins are known to clump. This clumping interferes with a type of cell receptor required for synaptic plasticity. Results from the study demonstrate that beta-amyloid also activates the generation of HDAC2, possibly initiating the restriction of memory and learning genes. 

Tsai explains: 

"We think that once this epigenetic blockage of gene expression is in place, clearing beta amyloid may not be sufficient to restore the active configuration of the chromatin." 

According to Tsai, HDAC2 inhibitors are appealing, as they could possibly reverse Alzheimer's symptoms even after the blockage is well-established, although significantly more medication development needs to be conducted before using such drugs in human trials. 

Tsai says: 

"It's really hard to predict. Clinical trials would probably be five years down the line. And if everything goes well, to become an approved drug would probably take at least 10 years." 

Although some researchers have tested some general HDAC inhibitors, not specific to HDAC2, in human trials as cancer medications, a more selective approach is required to treat Alzheimer's. Tsai explains: 

"You want something as selective as possible, and as safe as possible." 

Grace Rattue. (2012, February 29). "Restricting Enzyme Reverses Alzheimer's Symptoms In Mice." Medical News Today.

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