Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Reversing Alzheimer's gene 'blockade' can restore memory, other cognitive functions

01.03.2012
Neuroscientists show that HDAC2 enzyme could be a good target for new drugs

MIT neuroscientists have shown that an enzyme overproduced in the brains of Alzheimer's patients creates a blockade that shuts off genes necessary to form new memories. Furthermore, by inhibiting that enzyme in mice, the researchers were able to reverse Alzheimer's symptoms.

The finding suggests that drugs targeting the enzyme, known as HDAC2, could be a promising new approach to treating the disease, which affects 5.4 million Americans. The number of Alzheimer's victims worldwide is expected to double every 20 years, and President Barack Obama recently set a target date of 2025 to find an effective treatment.

Li-Huei Tsai, leader of the research team, says that HDAC2 inhibitors could help achieve that goal, though it would likely take at least 10 years to develop and test such drugs.

"I would really strongly advocate for an active program to develop agents that can contain HDAC2 activity," says Tsai, director of the Picower Institute for Learning and Memory at MIT. "The disease is so devastating and affects so many people, so I would encourage more people to think about this."

Tsai and her colleagues report the findings in the Feb. 29 online edition of Nature. Lead author of the paper is Johannes Gräff, a postdoc at the Picower Institute.

Genome modification

Histone deacetylases (HDACs) are a family of 11 enzymes that control gene regulation by modifying histones — proteins around which DNA is spooled, forming a structure called chromatin. When HDACs alter a histone through a process called deacetylation, chromatin becomes more tightly packaged, making genes in that region less likely to be expressed.

HDAC inhibitors can reverse this effect, opening up the DNA and allowing it to be transcribed.

In previous studies, Tsai had shown that HDAC2 is a key regulator of learning and memory. In the new study, her team discovered that inhibiting HDAC2 can reverse Alzheimer's symptoms in mice.

The researchers found that in mice with Alzheimer's symptoms, HDAC2 (but not other HDACs) is overly abundant in the hippocampus, where new memories are formed. HDAC2 was most commonly found clinging to genes involved in synaptic plasticity — the brain's ability to strengthen and weaken connections between neurons in response to new information, which is critical to forming memories. In the affected mice, those genes also had much lower levels of acetylation and expression.

"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," Tsai says. "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."

The researchers then shut off HDAC2 in the hippocampi of mice with Alzheimer's symptoms, using a molecule called short hairpin RNA, which can be designed to bind to messenger RNA — the molecule that carries genetic instructions from DNA to the rest of the cell.

With HDAC2 activity reduced, histone acetylation resumed, allowing genes required for synaptic plasticity and other learning and memory processes to be expressed. In treated mice, synaptic density was greatly increased and the mice regained normal cognitive function.

"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," Tsai says.

The researchers also analyzed postmortem brains of Alzheimer's patients and found elevated levels of HDAC2 in the hippocampus and entorhinal cortex, which play important roles in memory storage.

Reversing the blockade

The findings may explain why drugs that clear beta-amyloid proteins from the brains of Alzheimer's patients have offered only modest, if any, improvements in clinical trials, Tsai says.

Beta-amyloid proteins are known to clump in the brains of Alzheimer's patients, interfering with a type of cell receptor needed for synaptic plasticity. The new study shows that beta amyloid also stimulates production of HDAC2, possibly initiating the blockade of learning and memory genes.

"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," Tsai says.

The appeal of HDAC2 inhibitors, Tsai says, is that they could conceivably reverse symptoms even after the blockade is well-established. However, much more drug development has to take place before such a compound could enter clinical trials. "It's really hard to predict," Tsai says. "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."

Some general HDAC inhibitors, not specific to HDAC2, have been tested in clinical trials as cancer drugs. However, to treat Alzheimer's, a more selective approach is needed, Tsai says. "You want something as selective as possible, and as safe as possible," she says.

Written by Anne Trafton, MIT News Office

David Vaughn, Picower | EurekAlert!
Further information:
http://www.mit.edu

More articles from Life Sciences:

nachricht New risk factors for anxiety disorders
24.02.2017 | Julius-Maximilians-Universität Würzburg

nachricht Stingless bees have their nests protected by soldiers
24.02.2017 | Johannes Gutenberg-Universität Mainz

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Breakthrough with a chain of gold atoms

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

In the field of nanoscience, an international team of physicists with participants from Konstanz has achieved a breakthrough in understanding heat transport

Im Focus: DNA repair: a new letter in the cell alphabet

Results reveal how discoveries may be hidden in scientific “blind spots”

Cells need to repair damaged DNA in our genes to prevent the development of cancer and other diseases. Our cells therefore activate and send “repair-proteins”...

Im Focus: Dresdner scientists print tomorrow’s world

The Fraunhofer IWS Dresden and Technische Universität Dresden inaugurated their jointly operated Center for Additive Manufacturing Dresden (AMCD) with a festive ceremony on February 7, 2017. Scientists from various disciplines perform research on materials, additive manufacturing processes and innovative technologies, which build up components in a layer by layer process. This technology opens up new horizons for component design and combinations of functions. For example during fabrication, electrical conductors and sensors are already able to be additively manufactured into components. They provide information about stress conditions of a product during operation.

The 3D-printing technology, or additive manufacturing as it is often called, has long made the step out of scientific research laboratories into industrial...

Im Focus: Mimicking nature's cellular architectures via 3-D printing

Research offers new level of control over the structure of 3-D printed materials

Nature does amazing things with limited design materials. Grass, for example, can support its own weight, resist strong wind loads, and recover after being...

Im Focus: Three Magnetic States for Each Hole

Nanometer-scale magnetic perforated grids could create new possibilities for computing. Together with international colleagues, scientists from the Helmholtz Zentrum Dresden-Rossendorf (HZDR) have shown how a cobalt grid can be reliably programmed at room temperature. In addition they discovered that for every hole ("antidot") three magnetic states can be configured. The results have been published in the journal "Scientific Reports".

Physicist Dr. Rantej Bali from the HZDR, together with scientists from Singapore and Australia, designed a special grid structure in a thin layer of cobalt in...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Booth and panel discussion – The Lindau Nobel Laureate Meetings at the AAAS 2017 Annual Meeting

13.02.2017 | Event News

Complex Loading versus Hidden Reserves

10.02.2017 | Event News

International Conference on Crystal Growth in Freiburg

09.02.2017 | Event News

 
Latest News

Stingless bees have their nests protected by soldiers

24.02.2017 | Life Sciences

New risk factors for anxiety disorders

24.02.2017 | Life Sciences

MWC 2017: 5G Capital Berlin

24.02.2017 | Trade Fair News

VideoLinks
B2B-VideoLinks
More VideoLinks >>>