Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:


Effectiveness of mouse breeds that mimic Alzheimer's disease symptoms questioned

Scientists have shown that recently developed mouse breeds that mimic the symptoms of Alzheimer's disease (AD) may not be as effective as previously assumed.

Sascha Weggen, Professor of Molecular Neuropathology at Heinrich-Heine-University, Duesseldorf, Germany; lead author Eva Czirr, Ph.D. student at the University of Mainz, Germany; and colleagues show in the August 24 issue of the Journal of Biological Chemistry that in some mouse breeds, drugs that had been shown to reduce levels of a toxic protein called amyloid beta had only minor or no effect on these mice.

“Testing drugs against AD on animals is not easy because animals don’t develop the disease,” Weggen says. “When using mice, scientists need to artificially induce one or several mutations in the mice and check whether they develop symptoms of the disease that are similar to the human ones. We showed that some of the mice currently bred to develop the disease don’t get better when they receive previously tested drugs.”

The new study was selected as a “Paper of the Week” by the journal’s editors, meaning that it belongs to the top one percent of papers reviewed in significance and overall importance.

Although no cure is yet available for AD – a neurodegenerative disorder affecting around 18 million patients worldwide – scientists are testing various compounds that could become drugs. Most compounds try to prevent brain proteins called amyloid beta peptides from aggregating and forming plaques, which is a hallmark of the disease.

Amyloid beta peptides result from the breakdown of a protein called amyloid precursor protein (APP) by enzymes called beta-secretase and gamma-secretase. In AD patients, the breakdown of APP molecules is increased, leading to an excess of amyloid beta peptides. To reduce the amount of amyloid beta, chemical compounds are tested for their ability to block gamma-secretase or reduce its activity.

Before being administered in humans, the compounds are tested on mice that carry mutations in the gene that produces APP proteins, leading to an excess of APP, which, when cleaved, generate too many amyloid beta peptides. New mouse breeds have recently been created to also carry mutant genes for a protein called presenilin, which is part of gamma-secretase. These mutations cause gamma-secretase to cut APP in a slightly different way than in normal mice, which also leads to an accumulation of amyloid beta peptides. Mouse breeds that carry both APP and presenilin mutations develop symptoms earlier and the disease has a more aggressive course.

Surprisingly, Weggen and colleagues noticed that chemical compounds that had been shown to reduce amyloid beta deposits did not affect some of these new mouse breeds. “Our study shows that these mouse breeds may not reflect what may really happen in the brains of Alzheimer’s patients if they were treated with such compounds in future clinical studies,” Weggen says. “These compounds may seem to be ineffective on these mice, while it’s actually the mouse breed that is to blame.”

The researchers suggest using mouse breeds that carry only APP mutations for further studies of compounds that block or reduce the activity of gamma-secretase. These breeds are probably more reliable than the ones that carry both APP and presenilin mutations, because they cause less aggressive symptoms, Weggen says.

The scientists also propose creating a mouse breed in which the presenilin mutation does not affect both members of the pair of chromosomes that carry the gene – as is the case in current transgenic mice – but only one of the two chromosomes. Such a breed, called a “knock-in” mouse, would reflect the genetic condition of about 5 percent of Alzheimer’s patients.

“Although most AD patients develop the disease after 65, about 5 percent of them are affected much earlier – some as early as their 20s and 30s,” Weggen says. “In these patients, the origin of the disease, called early-onset familiar AD, is mostly genetic, and mutations – including the presenilin one – are carried by only one chromosome in a pair. So far, scientists created only a few mouse breeds with a mutation on one chromosome; such breeds would probably better reflect what actually happens in the brains of AD patients.”

The researchers are now planning to investigate how presenilin mutations cause amyloid beta peptides to be overproduced and to understand how promising chemical compounds block gamma secretase or reduce its function.

“Until now, transgenic mice have been successfully used to understand how AD develops and how to treat it,” Weggen says. “Our study is a reminder that we need to work harder to create mice that reflect Alzheimer’s disease even more accurately, which could bring us closer to actual drugs against this devastating disease.”

Pat Pages | EurekAlert!
Further information:

Further reports about: APP Amyloid Chromosome Mutation Weggen beta compounds develop gamma-secretase peptides presenilin symptoms

More articles from Life Sciences:

nachricht Novel mechanisms of action discovered for the skin cancer medication Imiquimod
21.10.2016 | Technische Universität München

nachricht Second research flight into zero gravity
21.10.2016 | Universität Zürich

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: New 3-D wiring technique brings scalable quantum computers closer to reality

Researchers from the Institute for Quantum Computing (IQC) at the University of Waterloo led the development of a new extensible wiring technique capable of controlling superconducting quantum bits, representing a significant step towards to the realization of a scalable quantum computer.

"The quantum socket is a wiring method that uses three-dimensional wires based on spring-loaded pins to address individual qubits," said Jeremy Béjanin, a PhD...

Im Focus: Scientists develop a semiconductor nanocomposite material that moves in response to light

In a paper in Scientific Reports, a research team at Worcester Polytechnic Institute describes a novel light-activated phenomenon that could become the basis for applications as diverse as microscopic robotic grippers and more efficient solar cells.

A research team at Worcester Polytechnic Institute (WPI) has developed a revolutionary, light-activated semiconductor nanocomposite material that can be used...

Im Focus: Diamonds aren't forever: Sandia, Harvard team create first quantum computer bridge

By forcefully embedding two silicon atoms in a diamond matrix, Sandia researchers have demonstrated for the first time on a single chip all the components needed to create a quantum bridge to link quantum computers together.

"People have already built small quantum computers," says Sandia researcher Ryan Camacho. "Maybe the first useful one won't be a single giant quantum computer...

Im Focus: New Products - Highlights of COMPAMED 2016

COMPAMED has become the leading international marketplace for suppliers of medical manufacturing. The trade fair, which takes place every November and is co-located to MEDICA in Dusseldorf, has been steadily growing over the past years and shows that medical technology remains a rapidly growing market.

In 2016, the joint pavilion by the IVAM Microtechnology Network, the Product Market “High-tech for Medical Devices”, will be located in Hall 8a again and will...

Im Focus: Ultra-thin ferroelectric material for next-generation electronics

'Ferroelectric' materials can switch between different states of electrical polarization in response to an external electric field. This flexibility means they show promise for many applications, for example in electronic devices and computer memory. Current ferroelectric materials are highly valued for their thermal and chemical stability and rapid electro-mechanical responses, but creating a material that is scalable down to the tiny sizes needed for technologies like silicon-based semiconductors (Si-based CMOS) has proven challenging.

Now, Hiroshi Funakubo and co-workers at the Tokyo Institute of Technology, in collaboration with researchers across Japan, have conducted experiments to...

All Focus news of the innovation-report >>>



Event News

#IC2S2: When Social Science meets Computer Science - GESIS will host the IC2S2 conference 2017

14.10.2016 | Event News

Agricultural Trade Developments and Potentials in Central Asia and the South Caucasus

14.10.2016 | Event News

World Health Summit – Day Three: A Call to Action

12.10.2016 | Event News

Latest News

Resolving the mystery of preeclampsia

21.10.2016 | Health and Medicine

Stanford researchers create new special-purpose computer that may someday save us billions

21.10.2016 | Information Technology

From ancient fossils to future cars

21.10.2016 | Materials Sciences

More VideoLinks >>>