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Inhibiting Alzheimer Enzyme Could Reverse Memory Loss

Research to reverse or stop memory loss in Alzheimer's

Scientists have found a way to reverse memory loss and other Alzheimer’s symptoms in mice. The approach involves inhibiting the activity of an enzyme called HDAC2, which is overproduced in the brains of people who have Alzheimer’s disease.

The race to stop or cure Alzheimer’s disease

Over the years, researchers have been engaged in a long, slow race to stop or cure Alzheimer’s disease, as the number of cases continues to rise. As of 2010, there were an estimated 35.6 million people with dementia around the world, and that figure is projected to rise to more than 115 million by 2050, according to Alzheimer’s Disease International.

Scientists at Massachusetts Institute of Technology (MIT), under the leadership of Li-Huei Tsai, director of the Picower Institute for Learning and Memory at MIT, recently reported that HDAC2 blocks the genes required to form new memories, but when they inhibited this enzyme’s actions in mice, they were able to reverse symptoms of Alzheimer’s, including memory loss.

Histone deacetylases (HDACs) are enzymes that alter proteins called histones through a process called deacetylation. This activity results in the formation of a structure that makes it less likely for genes in the area to be expressed.

HDAC2 is just one of 11 such enzymes, but it is the only one found in excessive levels in the hippocampus of mice with Alzheimer’s symptoms. This is significant because HDAC2 has been shown in previous studies to have a key role in regulating memory and learning. High levels of HDAC2 in the hippocampus have also been found in the postmortem brains of people with Alzheimer’s disease.

Tsai and her team found that HDAC2 was most often attached to genes involved in the brain’s ability to form memories. They then discovered that when they inhibited HDAC2 in the hippocampi of mice with Alzheimer’s symptoms, they reduced HDAC2 activity, which in turn allowed the genes to be expressed. The treated mice then regained normal cognitive function.

The Alzheimer enzyme and beta-amyloid
For years, one of the hallmarks of Alzheimer’s disease has been the accumulation in the brain of protein fragments called beta-amyloid (or amyloid plaque). Although these fragments are eliminated in a healthy brain, they accumulate and form hard plaques between the nerve cells in people who have Alzheimer’s disease.

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In this latest study, the researchers discovered that beta-amyloid stimulates production of HDAC2. It is possible this activity triggers the blockage of gene expression.

Given the results of this latest research, Tsai noted “I would really strongly advocate for an active program to develop agents that can contain HDAC2 activity.” She pointed out that HDAC2 inhibitors could reverse symptoms of Alzheimer’s disease, but that more drug development is necessary before such inhibitors could be the subject of clinical trials.

And that translates into time, meaning years. According to Tsai, “Clinical trials would probably be five years down the line,” and the wait for an approved drug could take at least a decade.

In the meantime, the search for effective preventive and treatment options for Alzheimer’s disease continues. Scientists recently discovered some interesting traits of a peptide called amyloid-beta peptide 43, for example, that is more toxic to nerve cells and more abundant than other amyloids studied in Alzheimer’s research. Could this peptide hold a key to solving the Alzheimer’s puzzle?

How about an Alzheimer’s vaccine? In 2011, the AD02 Alzheimer’s vaccine candidate met the main endpoints of a Phase I clinical trial and entered Phase II trials. In Phase I, the vaccine helped stabilize cognitive function in most of the patients given the drug. Other vaccines are also under consideration.

And now the door has opened for a possible agent that will inhibit an Alzheimer enzyme that could reverse memory loss and other symptoms of Alzheimer’s disease. That door, like others, opens slowly, and for those waiting for an effective agent or cure for Alzheimer’s disease, the pace can seem agonizingly slow.

Alzheimer’s Disease International
Graff J, Rei D, Guan J-S et al. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature 2012; doi:10.1038/nature10849

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