Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Dysfunctional endosomes are early sign of neurodegeneration

12.04.2016

Enlarged cell structures precede hallmarks and symptoms of Alzheimer's Disease and Down Syndrome

Writing in the April 11 issue of the Journal of Clinical Investigation, researchers at University of California, San Diego School of Medicine say abnormalities in a protein that helps transport and sort materials inside cells are linked to axonal dysfunction and degeneration of neurons in Alzheimer's disease (AD) and Down syndrome (DS).


This is a false-colored scanning electron micrograph of a human neuron.

Image courtesy of Thomas Deerinck, NCMIR, UC San Diego

"Amyloid plaques and neurofibrillary tangles in the brain are hallmarks of AD patients and people with DS. However, these classical manifestations may only become detectable in late stages of the disease," said Chengbiao Wu, PhD, associate professor in the Department of Neurosciences at UC San Diego School of Medicine, and director for cellular and molecular biology at the UC San Diego Down Syndrome Center for Research and Treatment. "Effective treatments will have to target earlier changes that take place in the nerve cells, eventually leading to their demise. Our current study highlights the significance of abnormally active Rab5 protein as a key contributor to early development of the disease. We believe this will open new possibilities for understanding the disease and for developing novel and effective therapies."

The endosome/lysosome or endocytic pathway in cells moves molecules, such as signaling proteins, from the surface or distant regions of a cell into the cell's body (via compartments called endosomes) or to another type of cell organelle (lysosomes) where they can be recycled. A small molecule called Rab5 plays a key role in regulating these vital processes.

But in AD and DS, the endocytic system does not work properly, though the precise nature of the underlying dysfunction was not understood. In their new paper, Wu and colleagues suggest a major reason is abnormally enlarged versions of Rab5-endosomes, which occur early and precede the onset of dementia and emergence of the amyloid plaques and neurofibrillary tangles that characterize AD and DS.

Specifically, the scientists determined that increased accumulation of amyloid precursor protein (APP) and/or a small portion of APP (β-carboxyl terminal fragment) in neurons, boosts activation of Rab5, causing enlargement of early endosomes and disruption of retrograde axonal transport of nerve growth factors (NGF) signals. As a result, impacted neurons do not function normally.

The findings were based on tests with cultured cells and rodent models.

Interestingly, when researchers introduced a dominant-negative Rab5 mutant in a fruit fly model, APP-induced axonal blockage was reduced.

Wu said the research underscores the fundamental importance of endosomal function in regulating retrograde axonal trafficking, which conveys materials from axon to cell body, and signaling of NGF. He said further studies will be needed to determine whether reducing Rab5 activation prevents or reverses neurodegeneration in AD and DS.

###

Co-authors include Wei Xu, Fang Fang, Yiwen Wu, Xinyi Wang, Shendi Chren, and Jianqing Ding, Shanghai Jiao Tong University and UC San Diego; April M. Weissmiller, Xiaobei Zhao, Mariko Sawa, and William C. Mobley, UC San Diego; Matthew L. Pearn, UC San Diego and VA San Diego Healthcare System; Joseph A. White II, and Shermali Gunawardena, State University of New York, Buffalo.

Funding for this research came, in part, from the National Institutes of Health (PN2EY016525, NS084386, NS092024), LuMind Research Down Syndrome Foundation, Larry L. Hillblom Foundation, Alzheimer's Association, Thrasher Research Fund, Tau Consortium, Ministry of Science and Technology, People's Republic of China, National Natural Science Foundation of China, Science and Technology Commission of Shanghai Municipality and Shanghai Municipal Education Commission. 

Media Contact

Scott LaFee
slafee@ucsd.edu
619-543-6163

 @UCSanDiego

http://www.ucsd.edu 

Scott LaFee | EurekAlert!

More articles from Life Sciences:

nachricht Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery
20.01.2017 | GSI Helmholtzzentrum für Schwerionenforschung GmbH

nachricht Seeking structure with metagenome sequences
20.01.2017 | DOE/Joint Genome Institute

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Traffic jam in empty space

New success for Konstanz physicists in studying the quantum vacuum

An important step towards a completely new experimental access to quantum physics has been made at University of Konstanz. The team of scientists headed by...

Im Focus: How gut bacteria can make us ill

HZI researchers decipher infection mechanisms of Yersinia and immune responses of the host

Yersiniae cause severe intestinal infections. Studies using Yersinia pseudotuberculosis as a model organism aim to elucidate the infection mechanisms of these...

Im Focus: Interfacial Superconductivity: Magnetic and superconducting order revealed simultaneously

Researchers from the University of Hamburg in Germany, in collaboration with colleagues from the University of Aarhus in Denmark, have synthesized a new superconducting material by growing a few layers of an antiferromagnetic transition-metal chalcogenide on a bismuth-based topological insulator, both being non-superconducting materials.

While superconductivity and magnetism are generally believed to be mutually exclusive, surprisingly, in this new material, superconducting correlations...

Im Focus: Studying fundamental particles in materials

Laser-driving of semimetals allows creating novel quasiparticle states within condensed matter systems and switching between different states on ultrafast time scales

Studying properties of fundamental particles in condensed matter systems is a promising approach to quantum field theory. Quasiparticles offer the opportunity...

Im Focus: Designing Architecture with Solar Building Envelopes

Among the general public, solar thermal energy is currently associated with dark blue, rectangular collectors on building roofs. Technologies are needed for aesthetically high quality architecture which offer the architect more room for manoeuvre when it comes to low- and plus-energy buildings. With the “ArKol” project, researchers at Fraunhofer ISE together with partners are currently developing two façade collectors for solar thermal energy generation, which permit a high degree of design flexibility: a strip collector for opaque façade sections and a solar thermal blind for transparent sections. The current state of the two developments will be presented at the BAU 2017 trade fair.

As part of the “ArKol – development of architecturally highly integrated façade collectors with heat pipes” project, Fraunhofer ISE together with its partners...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Sustainable Water use in Agriculture in Eastern Europe and Central Asia

19.01.2017 | Event News

12V, 48V, high-voltage – trends in E/E automotive architecture

10.01.2017 | Event News

2nd Conference on Non-Textual Information on 10 and 11 May 2017 in Hannover

09.01.2017 | Event News

 
Latest News

Helmholtz International Fellow Award for Sarah Amalia Teichmann

20.01.2017 | Awards Funding

An innovative high-performance material: biofibers made from green lacewing silk

20.01.2017 | Materials Sciences

Ion treatments for cardiac arrhythmia — Non-invasive alternative to catheter-based surgery

20.01.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>