Memory Restoration for Sufferers of Alzheimer’s

July 4, 2012 § Leave a comment

Alzheimer’s affects 5.4 million Americans. This number is expected to double every 20 years. Neuroscientists at MIT have discovered the culprit of memory impairment associated with Alzheimer’s disease. The findings were published in the February online edition of Nature, lead by author Johannes Gräff, postdoctoral at the Picower Institute.

The overproduction of a blockading enzyme in the brain of Alzheimer’s patients thwarts the formation of new memories. The enzyme is known as HDAC2. MIT researchers observed that by inhibiting the enzyme in mice, a reversal of the symptoms of Alzheimer’s occurs. The findings suggest that therapeutic drugs aimed at this enzyme could better treat the disease.

The leader of the research team is Li-Huei Tsai, director of the Picower Institute for Learning and Memory at MIT. Tsai says that the enzyme inhibitors could achieve this goal, but that it could take up to 10 years to develop and test the drugs. However, she strongly advocates a program to develop the agents. She says, “The disease is so devastating and affects so many people, so I would encourage more people to think about this.”

HDACs are a group of 11 enzymes that regulate genes by modifying histones. Histones are proteins that DNA reels around, forming chromatin. Through a process called deacetylation, HDACs alter histones, causing the chromatin to tighten its DNA and histone spool, making it less likely for the genes in this region to be expressed. The HDAC inhibitors loosen the spools, allowing for DNA expression. Tsai explains, “With 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.”

During the study, researchers discovered that mice with Alzheimer’s symptoms had an overabundance of HDAC2 in the hippocampus. This is the site of new memory formation. This enzyme was clinging to the genes implicated in synaptic plasticity – the brain’s capacity for strengthening and weakening connections between neurons, which is critical for memory formation. Afflicted mice had less expression in these genes, due to tightening effect of the high concentration of the HDAC2 enzymes.

Using a molecule called short hairpin RNA – the molecule that carried genetic instructions from DNA to the cell – researchers shut off the HDAC2 in the afflicted mice. Histone acetylation recommenced and genes responsible for synaptic plasticity and learning memory processes were able to express. Normal cognitive function was redeemed in the treated mice.

Beta-amyloid protein clearing drugs are the treatment option most commonly used. The results are modest at best. These proteins cluster in the brains of Alzheimer’s patients and this causes an interference with the cell receptors required for synaptic plasticity. This new study revealed that beta amyloid stimulates the production of the HDAC2 enzyme.

Tsai explains, “We think that once this epigenetic blockade of gene expression is in place, clearing beta amyloid may not be sufficient to restore the active configuration of the chromatin.” He says that the HDAC2 inhibitors could reverse the symptoms of Alzheimer’s even after the blockade is created.

Before the drug can be entered into clinical trials, many more tests and development steps must be taken. Tsai believes clinical trials could be as many as 5 years away and approval will take as many as 10 years. To treat Alzheimer’s, the process of testing inhibitors must be extremely selective and precise.

Works Cited

“Reversing Alzheimer’s Gene Blockade Can Restore Memory, Other Cognitive Functions”. (February 29, 2012). Neuroscience News. March 3, 2012.


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