Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Findings show how toxic proteins rob Alzheimer’s patients of memory

02.12.2004


Researchers at Northwestern University have discovered a molecular mechanism -- a tiny protein attacking nerve cells -- that could explain why the brain damage in early Alzheimer’s disease results in memory loss and not other symptoms such as loss of balance or tremors.



The research team, led by William L. Klein, professor of neurobiology and physiology, found that toxic proteins, called "amyloid ß-derived diffusible ligands" (ADDLs, pronounced "addles"), from the brain tissue of individuals with Alzheimer’s disease specifically attack and disrupt synapses, the nerve cell sites responsible for information processing and memory formation.

These results, which show that only particular neurons and synapses are targeted by the neurotoxins, were published Nov. 10 in the Journal of Neuroscience. An understanding of how ADDLs disrupt synapses without killing neurons could lead to the development of new therapeutic drugs capable of reversing memory loss in patients who are treated early, in addition to preventing or delaying the disease. "Memory starts at synapses, so it was probable that Alzheimer’s disease would be a synapse failure," said Klein. "Our work, which shows that ADDLs bind with great specificity to synapses, is the first demonstration of that.


"Why is the damage so specific to memory? First, ADDLs bind to some synapses and not others -- a very specific attack. Second, at the vulnerable synapses there is a gene linked to memory that is normally expressed. When ADDLs attack those synapses they disrupt the normal expression of that gene, resulting in memory loss." Over-expression of that gene, called Arc, has been linked to dysfunctional learning in earlier studies of memory.

Last year Klein and his colleagues were the first to discover and report the presence of ADDLs in humans. They found up to 70 times more of the toxic proteins in the brain tissue of individuals with Alzheimer’s disease compared to that of normal individuals.

In the current study, the research team used both ADDLs obtained from human brain tissue and ADDLs synthesized in the laboratory. Experiments showed that all the ADDLs, regardless of origin, showed the same pattern of binding to synapses on specific neurons. What is striking about ADDLs, said Klein, is that they disrupt the neurons’ ability to communicate with each other without killing the neurons.

"Human and animal studies have pointed to synaptic damage and loss as the key determinant of the severity of memory loss, correlating better than either neuronal loss or the presence of plaques," said Pascale N. Lacor, lead author on the paper and a research assistant professor of neurobiology and physiology.

"ADDLs selectively target a synaptic population," said Lacor, "and at these sites they modify the expression of essential memory-related molecules. We saw subtle changes happening to the gene Arc after only five minutes of exposure to ADDLs, and those changes were sustained for an unexpected long time. Our next step is to understand why ADDLed synapses have trouble staying connected and storing memories."

ADDLS are small, soluble aggregated proteins. The clinical data strongly support a recent theory in which ADDLs accumulate at the beginning of Alzheimer’s disease and block memory function by a process predicted to be reversible.

Although both are a form of amyloid beta, ADDLs and their properties differ significantly from the amyloid fibrils (known as plaques) that are a diagnostic hallmark of Alzheimer’s. ADDLs found in human brains, mostly 12 or 24 amyloid beta proteins clumped together, are tiny and undetectable in conventional neuropathology; fibrils are much, much larger. While fibrils are immobile toxic waste dumps, ADDLs are soluble and diffuse between brain cells until they find vulnerable synapses. (Single pieces of amyloid beta protein in the brain is normal.)

Klein, Grant A. Krafft, formerly at Northwestern University’s Feinberg School of Medicine and now chief scientific officer at Acumen Pharmaceuticals, Inc., and Caleb E. Finch, professor of biological sciences and gerontology at the University of Southern California, reported the discovery of ADDLs in 1998. Krafft and Finch are co-authors on the Journal of Neuroscience paper. Northwestern and USC hold joint patents on the composition and use of ADDLs in neurodisorders.

The patent rights have been licensed to Acumen Pharmaceuticals, based in Glenview, Ill., for the development of drugs that treat Alzheimer’s disease and other memory-related disorders.

In addition to Klein, Lacor, Krafft and Finch, other authors on the paper are Maria C. Buniel, Lei Chang, Sara J. Fernandez, Yuesong Gong, Kirsten L. Viola, Mary P. Lambert, Pauline T. Velasco and Eileen H. Bigio, from Northwestern University.

Megan Fellman | EurekAlert!
Further information:
http://www.northwestern.edu

More articles from Health and Medicine:

nachricht Study suggests possible new target for treating and preventing Alzheimer's
02.12.2016 | Oregon Health & Science University

nachricht The first analysis of Ewing's sarcoma methyloma opens doors to new treatments
01.12.2016 | IDIBELL-Bellvitge Biomedical Research Institute

All articles from Health and Medicine >>>

The most recent press releases about innovation >>>

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

Im Focus: Novel silicon etching technique crafts 3-D gradient refractive index micro-optics

A multi-institutional research collaboration has created a novel approach for fabricating three-dimensional micro-optics through the shape-defined formation of porous silicon (PSi), with broad impacts in integrated optoelectronics, imaging, and photovoltaics.

Working with colleagues at Stanford and The Dow Chemical Company, researchers at the University of Illinois at Urbana-Champaign fabricated 3-D birefringent...

Im Focus: Quantum Particles Form Droplets

In experiments with magnetic atoms conducted at extremely low temperatures, scientists have demonstrated a unique phase of matter: The atoms form a new type of quantum liquid or quantum droplet state. These so called quantum droplets may preserve their form in absence of external confinement because of quantum effects. The joint team of experimental physicists from Innsbruck and theoretical physicists from Hannover report on their findings in the journal Physical Review X.

“Our Quantum droplets are in the gas phase but they still drop like a rock,” explains experimental physicist Francesca Ferlaino when talking about the...

Im Focus: MADMAX: Max Planck Institute for Physics takes up axion research

The Max Planck Institute for Physics (MPP) is opening up a new research field. A workshop from November 21 - 22, 2016 will mark the start of activities for an innovative axion experiment. Axions are still only purely hypothetical particles. Their detection could solve two fundamental problems in particle physics: What dark matter consists of and why it has not yet been possible to directly observe a CP violation for the strong interaction.

The “MADMAX” project is the MPP’s commitment to axion research. Axions are so far only a theoretical prediction and are difficult to detect: on the one hand,...

Im Focus: Molecules change shape when wet

Broadband rotational spectroscopy unravels structural reshaping of isolated molecules in the gas phase to accommodate water

In two recent publications in the Journal of Chemical Physics and in the Journal of Physical Chemistry Letters, researchers around Melanie Schnell from the Max...

Im Focus: Fraunhofer ISE Develops Highly Compact, High Frequency DC/DC Converter for Aviation

The efficiency of power electronic systems is not solely dependent on electrical efficiency but also on weight, for example, in mobile systems. When the weight of relevant components and devices in airplanes, for instance, is reduced, fuel savings can be achieved and correspondingly greenhouse gas emissions decreased. New materials and components based on gallium nitride (GaN) can help to reduce weight and increase the efficiency. With these new materials, power electronic switches can be operated at higher switching frequency, resulting in higher power density and lower material costs.

Researchers at the Fraunhofer Institute for Solar Energy Systems ISE together with partners have investigated how these materials can be used to make power...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ICTM Conference 2017: Production technology for turbomachine manufacturing of the future

16.11.2016 | Event News

Innovation Day Laser Technology – Laser Additive Manufacturing

01.11.2016 | Event News

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

14.10.2016 | Event News

 
Latest News

UTSA study describes new minimally invasive device to treat cancer and other illnesses

02.12.2016 | Medical Engineering

Plasma-zapping process could yield trans fat-free soybean oil product

02.12.2016 | Agricultural and Forestry Science

What do Netflix, Google and planetary systems have in common?

02.12.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>