Featured Research

from universities, journals, and other organizations

Blockade of learning and memory genes may occur early in Alzheimer's disease: Treatable in mice

Date:
February 29, 2012
Source:
NIH/National Institute of Neurological Disorders and Stroke
Summary:
A repression of gene activity in the brain appears to be an early event affecting people with Alzheimer's disease, researchers have found. In mouse models of Alzheimer's disease, this epigenetic blockade and its effects on memory were treatable.

In a mouse model of Alzheimer's disease (right), HDAC2 levels in the hippocampus are higher than in the normal mouse hippocampus (left). Credit:
Credit: Dr. Li-Huei Tsai, MIT

A repression of gene activity in the brain appears to be an early event affecting people with Alzheimer's disease, researchers funded by the National Institutes of Health have found. In mouse models of Alzheimer's disease, this epigenetic blockade and its effects on memory were treatable.

"These findings provide a glimpse of the brain shutting down the ability to form new memories gene by gene in Alzheimer's disease, and offer hope that we may be able to counteract this process," said Roderick Corriveau, Ph.D., a program director at NIH's National Institute of Neurological Disorders and Stroke (NINDS), which helped fund the research.

The study was led by Li-Huei Tsai, Ph.D., who is director of The Picower Institute for Learning and Memory at the Massachusetts Institute of Technology and an investigator at the Howard Hughes Medical Institute. It was published online February 29 in Nature.

Dr. Tsai and her team found that a protein called histone deacetylase 2 (HDAC2) accumulates in the brain early in the course of Alzheimer's disease in mouse models and in people with the disease. HDAC2 is known to tighten up spools of DNA, effectively locking down the genes within and reducing their activity, or expression.

In the mice, the increase in HDAC2 appears to produce a blockade of genes involved in learning and memory. Preventing the build-up of HDAC2 protected the mice from memory loss.

Dr. Tsai and her team examined two mouse models of Alzheimer's around the time that the mice begin to show signs of brain cell degeneration. They found that the mice had higher levels of HDAC2, but not other related HDAC proteins, specifically in the parts of the brain involved in learning and memory. This increase in HDAC2 was associated with a decrease in the expression of neuronal genes that HDAC2 is known to regulate.

Use of a gene therapy approach to reduce the levels of HDAC2 prevented the blockade of gene expression. The treatment also prevented learning and memory impairments in the mice. It did not prevent neuronal death, but it did enhance neuroplasticity -- the ability of neurons to form new connections.

Dr. Tsai and her team also examined HDAC2 levels in autopsied brain tissue from 19 people with Alzheimer's at different stages of the disease, and from seven unaffected individuals. Even in its earliest stages, the disease was associated with higher HDAC2 levels in the learning and memory regions of the brain

"We think that the blockade of gene expression plays a very important role in the cognitive decline associated with Alzheimer's disease," said Dr. Tsai. "The good news is that the blockade is potentially reversible."

Alzheimer's disease is the most common cause of dementia in older adults, and affects as many as 5.1 million Americans. In the most common type of Alzheimer's disease, symptoms usually appear after age 65. A hallmark of the disease is the accumulation of a toxic protein fragment called beta-amyloid in brain cells, which is widely believed to be the initial trigger for neurodegeneration.

Dr. Tsai theorizes that HDAC2 is brought into play by beta-amyloid. Indeed, she and her team found that exposing mouse neurons to beta-amyloid caused them to produce more HDAC2.

"We think beta-amyloid triggers a cascade of damaging reactions. Once of these is to activate HDAC2, which in turn blocks the expression of genes needed for brain plasticity. Once this blockade is in place, it may have a more systemic, chronic effect on the brain," she said.

Vaccines and other therapies aimed at reducing beta-amyloid are in clinical trials. Efforts to reduce HDAC2 may provide a complementary approach to treating Alzheimer's, Dr. Tsai said. She has previously reported that HDAC inhibitor compounds can protect against signs of Alzheimer's disease in mice. A problem with such compounds is that they inhibit not only HDAC2 but related HDAC proteins, leading to broad and potentially toxic effects. The new study supports the possibility of developing drugs more specifically targeted to HDAC2 and the pathology of Alzheimer's disease, Dr. Tsai said. Her team is working to identify HDAC2-specific inhibitors that could be developed into drugs and moved into trials.

Dr. Tsai's study was supported by NINDS and the National Institute on Aging through the NIH Common Fund Epigenomics Program. Additional support was provided through the NIH Blueprint for Neuroscience Research and its Neuroplasticity initiative.


Story Source:

The above story is based on materials provided by NIH/National Institute of Neurological Disorders and Stroke. Note: Materials may be edited for content and length.


Journal Reference:

  1. Johannes Gräff, Damien Rei, Ji-Song Guan, Wen-Yuan Wang, Jinsoo Seo, Krista M. Hennig, Thomas J. F. Nieland, Daniel M. Fass, Patricia F. Kao, Martin Kahn, Susan C. Su, Alireza Samiei, Nadine Joseph, Stephen J. Haggarty, Ivana Delalle, Li-Huei Tsai. An epigenetic blockade of cognitive functions in the neurodegenerating brain. Nature, 2012; DOI: 10.1038/nature10849

Cite This Page:

NIH/National Institute of Neurological Disorders and Stroke. "Blockade of learning and memory genes may occur early in Alzheimer's disease: Treatable in mice." ScienceDaily. ScienceDaily, 29 February 2012. <www.sciencedaily.com/releases/2012/02/120229142132.htm>.
NIH/National Institute of Neurological Disorders and Stroke. (2012, February 29). Blockade of learning and memory genes may occur early in Alzheimer's disease: Treatable in mice. ScienceDaily. Retrieved August 29, 2014 from www.sciencedaily.com/releases/2012/02/120229142132.htm
NIH/National Institute of Neurological Disorders and Stroke. "Blockade of learning and memory genes may occur early in Alzheimer's disease: Treatable in mice." ScienceDaily. www.sciencedaily.com/releases/2012/02/120229142132.htm (accessed August 29, 2014).

Share This




More Mind & Brain News

Friday, August 29, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Treadmill 'trips' May Reduce Falls for Elderly

Treadmill 'trips' May Reduce Falls for Elderly

AP (Aug. 28, 2014) — Scientists are tripping the elderly on purpose in a Chicago lab in an effort to better prevent seniors from falling and injuring themselves in real life. (Aug.28) Video provided by AP
Powered by NewsLook.com
Alice in Wonderland Syndrome

Alice in Wonderland Syndrome

Ivanhoe (Aug. 27, 2014) — It’s an unusual condition with a colorful name. Kids with “Alice in Wonderland” syndrome see sudden distortions in objects they’re looking at or their own bodies appear to change size, a lot like the main character in the Lewis Carroll story. Video provided by Ivanhoe
Powered by NewsLook.com
Stopping Schizophrenia Before Birth

Stopping Schizophrenia Before Birth

Ivanhoe (Aug. 27, 2014) — Scientists have long called choline a “brain booster” essential for human development. Not only does it aid in memory and learning, researchers now believe choline could help prevent mental illness. Video provided by Ivanhoe
Powered by NewsLook.com
Personalized Brain Vaccine for Glioblastoma

Personalized Brain Vaccine for Glioblastoma

Ivanhoe (Aug. 27, 2014) — Glioblastoma is the most common and aggressive brain cancer in humans. Now a new treatment using the patient’s own tumor could help slow down its progression and help patients live longer. Video provided by Ivanhoe
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:

More Coverage


Reversing Alzheimer's Gene 'blockade' Can Restore Memory, Other Cognitive Functions

Feb. 29, 2012 — 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 ... read more
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:  

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile iPhone Android Web
Follow Facebook Twitter Google+
Subscribe RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins