Gene therapy prevents memory problems in mice with Alzheimer's disease

November 28, 2010

Scientists at the Gladstone Institute of Neurological Disease (GIND) in San Francisco have discovered a new strategy to prevent memory deficits in a mouse model of Alzheimer's disease (AD). Humans with AD and mice genetically engineered to simulate the disease have abnormally low levels of an enzyme called EphB2 in memory centers of the brain. Improving EphB2 levels in such mice by gene therapy completely fixed their memory problems. The findings will be published in the November 28 issue of the journal Nature.

In both humans and mice, learning and memory requires effective communication between called neurons. This communication involves the release of chemicals from neurons that stimulate cell surface receptors on other neurons. This important process, called neurotransmission, is impaired by amyloid proteins, which build up to abnormally high levels in brains of AD patients and are widely thought to cause the disease. But how exactly these poisonous proteins disrupt neurotransmission is unknown.

"EphB2 is a really cool molecule that acts as both a receptor and an enzyme," said Moustapha Cisse, PhD, lead author of the study. "We thought it might be involved in of AD because it is a master regulator of neurotransmission and its brain levels are decreased in the disease."

To determine if low EphB2 levels actually contribute to the development of memory problems, the investigators used to experimentally alter EphB2 levels in memory centers of mice.
Reducing EphB2 levels in normal healthy mice disrupted neurotransmission and gave them memory problems similar to those seen in AD. This finding suggests that the reduced EphB2 levels in AD brains contribute to the memory problems that characterize this condition.

"What we were most curious about, of course, was whether normalizing EphB2 levels could fix memory problems caused by amyloid proteins," said Lennart Mucke, MD, director of the GIND and senior author of the study. "We were absolutely thrilled to discover that it did."

Increasing EphB2 levels in neurons of mice engineered to produce high levels of human amyloid proteins in the brain prevented their neurotransmission deficits, memory problems and behavioral abnormalities. The scientists also discovered that amyloid proteins directly bind to EphB2 and cause its degradation, which helps explain why EphB2 levels are reduced in AD and related mouse models.

"Based on our results, we think that blocking amyloid proteins from binding to EphB2 and enhancing EphB2 levels or functions with drugs might be of benefit in AD." said Mucke. "We are excited about these possibilities and look forward to pursuing them in future studies."

Related Stories

Recommended for you

The 16 genetic markers that can cut a life story short

July 27, 2017
The answer to how long each of us will live is partly encoded in our genome. Researchers have identified 16 genetic markers associated with a decreased lifespan, including 14 new to science. This is the largest set of markers ...

A rogue gene is causing seizures in babies—here's how scientists wants to stop it

July 26, 2017
Two rare diseases caused by a malfunctioning gene that triggers seizures or involuntary movements in children as early as a few days old have left scientists searching for answers and better treatment options.

Scientists provide insight into genetic basis of neuropsychiatric disorders

July 21, 2017
A study by scientists at the Children's Medical Center Research Institute at UT Southwestern (CRI) is providing insight into the genetic basis of neuropsychiatric disorders. In this research, the first mouse model of a mutation ...

Scientists identify new way cells turn off genes

July 19, 2017
Cells have more than one trick up their sleeve for controlling certain genes that regulate fetal growth and development.

South Asian genomes could be boon for disease research, scientists say

July 18, 2017
The Indian subcontinent's massive population is nearing 1.5 billion according to recent accounts. But that population is far from monolithic; it's made up of nearly 5,000 well-defined sub-groups, making the region one of ...

Mutant yeast reveals details of the aberrant genomic machinery of children's high-grade gliomas

July 18, 2017
St. Jude Children's Research Hospital biologists have used engineered yeast cells to discover how a mutation that is frequently found in pediatric brain tumor high-grade glioma triggers a cascade of genomic malfunctions.

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.