Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New TAU Research Links Alzheimer's Disease to Brain Hyperactivity

01.07.2014

Study identifies molecular mechanism that triggers hyperactivity of brain circuits in early stages of the disease

Patients with Alzheimer's disease run a high risk of seizures. While the amyloid-beta protein involved in the development and progression of Alzheimer's seems the most likely cause for this neuronal hyperactivity, how and why this elevated activity takes place hasn't yet been explained — until now.

A new study by Tel Aviv University researchers, published in Cell Reports, pinpoints the precise molecular mechanism that may trigger an enhancement of neuronal activity in Alzheimer's patients, which subsequently damages memory and learning functions.

The research team, led by Dr. Inna Slutsky of TAU's Sackler Faculty of Medicine and Sagol School of Neuroscience, discovered that the amyloid precursor protein (APP), in addition to its well-known role in producing amyloid-beta, also constitutes the receptor for amyloid-beta. According to the study, the binding of amyloid-beta to pairs of APP molecules triggers a signalling cascade, which causes elevated neuronal activity.

Elevated activity in the hippocampus — the area of the brain that controls learning and memory — has been observed in patients with mild cognitive impairment and early stages of Alzheimer's disease. Hyperactive hippocampal neurons, which precede amyloid plaque formation, have also been observed in mouse models with early onset Alzheimer's disease. "These are truly exciting results," said Dr. Slutsky. "Our work suggests that APP molecules, like many other known cell surface receptors, may modulate the transfer of information between neurons."

With the understanding of this mechanism, the potential for restoring memory and protecting the brain is greatly increased.

Building on earlier research

The research project was launched five years ago, following the researchers' discovery of the physiological role played by amyloid-beta, previously known as an exclusively toxic molecule. The team found that amyloid-beta is essential for the normal day-to-day transfer of information through the nerve cell networks. If the level of amyloid-beta is even slightly increased, it causes neuronal hyperactivity and greatly impairs the effective transfer of information between neurons.

In the search for the underlying cause of neuronal hyperactivity, TAU doctoral student Hilla Fogel and postdoctoral fellow Samuel Frere found that while unaffected "normal" neurons became hyperactive following a rise in amyloid-beta concentration, neurons lacking APP did not respond to amyloid-beta. "This finding was the starting point of a long journey toward decoding the mechanism of APP-mediated hyperactivity," said Dr. Slutsky.

The researchers, collaborating with Prof. Joel Hirsch of TAU's Faculty of Life Sciences, Prof. Dominic Walsh of Harvard University, and Prof. Ehud Isacoff of University of California Berkeley, harnessed a combination of cutting-edge high-resolution optical imaging, biophysical methods and molecular biology to examine APP-dependent signalling in neural cultures, brain slices, and mouse models. Using highly sensitive biophysical techniques based on fluorescence resonance energy transfer (FRET) between fluorescent proteins in close proximity, they discovered that APP exists as a dimer at presynaptic contacts, and that the binding of amyloid-beta triggers a change in the APP-APP interactions, leading to an increase in calcium flux and higher glutamate release — in other words, brain hyperactivity.

A new approach to protecting the brain

"We have now identified the molecular players in hyperactivity," said Dr. Slutsky. "TAU postdoctoral fellow Oshik Segev is now working to identify the exact spot where the amyloid-beta binds to APP and how it modifies the structure of the APP molecule. If we can change the APP structure and engineer molecules that interfere with the binding of amyloid-beta to APP, then we can break up the process leading to hippocampal hyperactivity. This may help to restore memory and protect the brain."

Previous studies by Prof. Lennart Mucke's laboratory strongly suggest that a reduction in the expression level of "tau" (microtubule-associated protein), another key player in Alzheimer's pathogenesis, rescues synaptic deficits and decreases abnormal brain activity in animal models. "It will be crucial to understand the missing link between APP and 'tau'-mediated signalling pathways leading to hyperactivity of hippocampal circuits. If we can find a way to disrupt the positive signalling loop between amyloid-beta and neuronal activity, it may rescue cognitive decline and the conversion to Alzheimer's disease," said Dr. Slutsky.

The study was supported by European Research Council, Israel Science Foundation, and Alzheimer's Association grants.

George Hunka | Eurek Alert!
Further information:
http://www.aftau.org/newsroom?5f7e87de-afbe-463c-9aa4-ac1596360ac1

Further reports about: APP Brain Building Disease Faculty Medicine activity cognitive engineer protein signalling

More articles from Life Sciences:

nachricht Protein Shake-Up
27.03.2015 | Oak Ridge National Laboratory

nachricht How did the chicken cross the sea?
27.03.2015 | Michigan State University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Experiment Provides the Best Look Yet at 'Warm Dense Matter' at Cores of Giant Planets

In an experiment at the Department of Energy's SLAC National Accelerator Laboratory, scientists precisely measured the temperature and structure of aluminum as...

Im Focus: Energy-autonomous and wireless monitoring protects marine gearboxes

The IPH presents a solution at HANNOVER MESSE 2015 to make ship traffic more reliable while decreasing the maintenance costs at the same time. In cooperation with project partners, the research institute from Hannover, Germany, has developed a sensor system which continuously monitors the condition of the marine gearbox, thus preventing breakdowns. Special feature: the monitoring system works wirelessly and energy-autonomously. The required electrical power is generated where it is needed – directly at the sensor.

As well as cars need to be certified regularly (in Germany by the TÜV – Technical Inspection Association), ships need to be inspected – if the powertrain stops...

Im Focus: 3-D satellite, GPS earthquake maps isolate impacts in real time

Method produced by UI researcher could improve reaction time to deadly, expensive quakes

When an earthquake hits, the faster first responders can get to an impacted area, the more likely infrastructure--and lives--can be saved.

Im Focus: Atlantic Ocean overturning found to slow down already today

The Atlantic overturning is one of Earth’s most important heat transport systems, pumping warm water northwards and cold water southwards. Also known as the Gulf Stream system, it is responsible for the mild climate in northwestern Europe. 

Scientists now found evidence for a slowdown of the overturning – multiple lines of observation suggest that in recent decades, the current system has been...

Im Focus: Robot inspects concrete garage floors and bridge roadways for damage

Because they are regularly subjected to heavy vehicle traffic, emissions, moisture and salt, above- and underground parking garages, as well as bridges, frequently experience large areas of corrosion. Most inspection systems to date have only been capable of inspecting smaller surface areas.

From April 13 to April 17 at the Hannover Messe (hall 2, exhibit booth C16), engineers from the Fraunhofer Institute for Nondestructive Testing IZFP will be...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

World Conference On Regenerative Medicine 2015: Registration And Abstract Submission Now Open

25.03.2015 | Event News

University presidents from all over the world meet in Hamburg

19.03.2015 | Event News

10. CeBiTec Symposium zum Big Data-Problem

17.03.2015 | Event News

 
Latest News

Two Most Destructive Termite Species Forming Superswarms in South Florida

27.03.2015 | Agricultural and Forestry Science

ORNL-Led Team Demonstrates Desalination with Nanoporous Graphene Membrane

27.03.2015 | Materials Sciences

Coorong Fish Hedge Their Bets for Survival

27.03.2015 | Ecology, The Environment and Conservation

VideoLinks
B2B-VideoLinks
More VideoLinks >>>