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).
"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.
Scott LaFee | EurekAlert!
Zebrafish's near 360 degree UV-vision knocks stripes off Google Street View
22.06.2018 | University of Sussex
New cellular pathway helps explain how inflammation leads to artery disease
22.06.2018 | Cedars-Sinai Medical Center
In a recent publication in the renowned journal Optica, scientists of Leibniz-Institute of Photonic Technology (Leibniz IPHT) in Jena showed that they can accurately control the optical properties of liquid-core fiber lasers and therefore their spectral band width by temperature and pressure tuning.
Already last year, the researchers provided experimental proof of a new dynamic of hybrid solitons– temporally and spectrally stationary light waves resulting...
Scientists from the University of Freiburg and the University of Basel identified a master regulator for bone regeneration. Prasad Shastri, Professor of...
Moving into its fourth decade, AchemAsia is setting out for new horizons: The International Expo and Innovation Forum for Sustainable Chemical Production will take place from 21-23 May 2019 in Shanghai, China. With an updated event profile, the eleventh edition focusses on topics that are especially relevant for the Chinese process industry, putting a strong emphasis on sustainability and innovation.
Founded in 1989 as a spin-off of ACHEMA to cater to the needs of China’s then developing industry, AchemAsia has since grown into a platform where the latest...
The BMBF-funded OWICELLS project was successfully completed with a final presentation at the BMW plant in Munich. The presentation demonstrated a Li-Fi communication with a mobile robot, while the robot carried out usual production processes (welding, moving and testing parts) in a 5x5m² production cell. The robust, optical wireless transmission is based on spatial diversity; in other words, data is sent and received simultaneously by several LEDs and several photodiodes. The system can transmit data at more than 100 Mbit/s and five milliseconds latency.
Modern production technologies in the automobile industry must become more flexible in order to fulfil individual customer requirements.
An international team of scientists has discovered a new way to transfer image information through multimodal fibers with almost no distortion - even if the fiber is bent. The results of the study, to which scientist from the Leibniz-Institute of Photonic Technology Jena (Leibniz IPHT) contributed, were published on 6thJune in the highly-cited journal Physical Review Letters.
Endoscopes allow doctors to see into a patient’s body like through a keyhole. Typically, the images are transmitted via a bundle of several hundreds of optical...
13.06.2018 | Event News
08.06.2018 | Event News
05.06.2018 | Event News
22.06.2018 | Materials Sciences
22.06.2018 | Earth Sciences
22.06.2018 | Life Sciences