Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gladstone study links Alzheimer’s with toxic protein fragments

16.12.2005


New research from the Gladstone Institute of Neurological Disease details exactly how a mutant form of the protein apolipoprotein E, also known as apoE, is a causative factor for Alzheimer’s disease.



It pinpoints mitochondria, the organelles within cells designed to turn glucose into energy, as a key site that specific fragments of a particular form of apoE attack, leading to the neuronal death characteristic of Alzheimer’s disease (AD).

The findings are published online by the Proceedings of the National Academy of Science, in advance of publication in the December 20, 2005, issue of PNAS.


According to Gladstone Assistant Investigator Yadong Huang, MD, PhD, who headed the study, it has been known for several years that a correlation exists between lowered glucose metabolism and the presence in the brain of a mutant form of a protein that transports cholesterol.

Scientists have been unable to determine if this mutant protein actually interferes with the ability of neurons to make use of glucose in the brain, but they have theorized that such an inability to access glucose might kill off crucial brain cells, causing AD symptoms.

The devastating effects of AD are well known: progressive and inexorable loss of cognitive function that erases memories, extinguishes personality, and robs people of their ability to think, reason and carry out the activities of everyday life. Despite intensive efforts to identify the underlying causes, and considerable progress in unraveling the web of contributing factors, the pathogenesis of AD remains tantalizingly elusive, and a cure is still out of reach, says Huang.

Seeking answers to a fundamental question in AD research on what actually causes brain cells to die in affected patients, Huang and his scientific team pursued a particularly promising avenue of research over the last few years. Their efforts focused on apoE, a protein comprised of 299 amino acids whose apoE4 isoform has been known for the last decade to be the most significant genetic risk factor for AD.

"Several years ago, we found that apoE is subject to cleavage that results in fragments that are toxic to neurons," says Huang, who also is assistant professor of pathology and neurology at UC San Francisco. "This study shows which parts of apoE are toxic and gives hints as to the site of its action."

The research team investigated the cellular and molecular mechanisms of the neurotoxicity caused by apoE4 fragments, performing a series of studies in cultured mouse neuronal cells. The cells expressed apoE fragments of various lengths and with mutations designed to enable the investigators to determine precisely which portions of the fragment--that is, which of apoE4’s 299 amino acids--are responsible for its detrimental effects.

Research findings showed that fragments containing both the lipid- and receptor-binding regions, but lacking the C-terminal 27 amino acids (273-299), were found to be neurotoxic. The toxic fragments appear in the mitochondria, where they impaired membrane integrity and mitochondrial function.

"Blocking interaction of apoE4 fragments with the mitochondria is a potential new strategy for inhibiting the detrimental effects of apoE4 in AD and other neurological diseases," Huang explains.

"Alzheimer’s disease is a complex condition," says co-author Robert W. Mahley, MD, PhD, president of the Gladstone Institutes and UCSF professor of pathology and medicine. "Many factors seem to be involved, and all need to be explored to help us find a way to combat this terrible disease. We are very excited about these particular results because they point to a new and potentially valuable therapeutic strategy."

John Watson | EurekAlert!
Further information:
http://www.gladstone.ucsf.edu
http://www.ucsf.edu

More articles from Studies and Analyses:

nachricht Do microplastics harbour additional risks by colonization with harmful bacteria?
05.04.2018 | Leibniz-Institut für Ostseeforschung Warnemünde

nachricht Rutgers-led innovation could spur faster, cheaper, nano-based manufacturing
14.02.2018 | Rutgers University

All articles from Studies and Analyses >>>

The most recent press releases about innovation >>>

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

Im Focus: Spider silk key to new bone-fixing composite

University of Connecticut researchers have created a biodegradable composite made of silk fibers that can be used to repair broken load-bearing bones without the complications sometimes presented by other materials.

Repairing major load-bearing bones such as those in the leg can be a long and uncomfortable process.

Im Focus: Writing and deleting magnets with lasers

Study published in the journal ACS Applied Materials & Interfaces is the outcome of an international effort that included teams from Dresden and Berlin in Germany, and the US.

Scientists at the Helmholtz-Zentrum Dresden-Rossendorf (HZDR) together with colleagues from the Helmholtz-Zentrum Berlin (HZB) and the University of Virginia...

Im Focus: Gamma-ray flashes from plasma filaments

Novel highly efficient and brilliant gamma-ray source: Based on model calculations, physicists of the Max PIanck Institute for Nuclear Physics in Heidelberg propose a novel method for an efficient high-brilliance gamma-ray source. A giant collimated gamma-ray pulse is generated from the interaction of a dense ultra-relativistic electron beam with a thin solid conductor. Energetic gamma-rays are copiously produced as the electron beam splits into filaments while propagating across the conductor. The resulting gamma-ray energy and flux enable novel experiments in nuclear and fundamental physics.

The typical wavelength of light interacting with an object of the microcosm scales with the size of this object. For atoms, this ranges from visible light to...

Im Focus: Basel researchers succeed in cultivating cartilage from stem cells

Stable joint cartilage can be produced from adult stem cells originating from bone marrow. This is made possible by inducing specific molecular processes occurring during embryonic cartilage formation, as researchers from the University and University Hospital of Basel report in the scientific journal PNAS.

Certain mesenchymal stem/stromal cells from the bone marrow of adults are considered extremely promising for skeletal tissue regeneration. These adult stem...

Im Focus: Like a wedge in a hinge

Researchers lay groundwork to tailor drugs for new targets in cancer therapy

In the fight against cancer, scientists are developing new drugs to hit tumor cells at so far unused weak points. Such a “sore spot” is the protein complex...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Invitation to the upcoming "Current Topics in Bioinformatics: Big Data in Genomics and Medicine"

13.04.2018 | Event News

Unique scope of UV LED technologies and applications presented in Berlin: ICULTA-2018

12.04.2018 | Event News

IWOLIA: A conference bringing together German Industrie 4.0 and French Industrie du Futur

09.04.2018 | Event News

 
Latest News

Magnetic nano-imaging on a table top

20.04.2018 | Physics and Astronomy

Start of work for the world's largest electric truck

20.04.2018 | Interdisciplinary Research

Atoms may hum a tune from grand cosmic symphony

20.04.2018 | Physics and Astronomy

VideoLinks
Science & Research
Overview of more VideoLinks >>>