Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New therapeutic target discovered for Alzheimer's disease

18.03.2014

Drug candidate blocks production of disease-causing neurotoxins in mouse models

A team of scientists from the University of California, San Diego School of Medicine, the Medical University of South Carolina and San Diego-based American Life Science Pharmaceuticals, Inc., report that cathepsin B gene knockout or its reduction by an enzyme inhibitor blocks creation of key neurotoxic pGlu-Aβ peptides linked to Alzheimer's disease (AD). Moreover, the candidate inhibitor drug has been shown to be safe in humans.

The findings, based on AD mouse models and published online in the Journal of Alzheimer's Disease, support continued development of cysteine protease inhibitors as a new drug target class for AD. "No other therapeutic program is investigating cysteine protease inhibitors for treating AD," said collaborator Vivian Hook, PhD, professor in the UC San Diego Skaggs School of Pharmacy and Pharmaceutical Sciences and in the UC San Diego School of Medicine.

Current AD drugs treat some symptoms of the devastating neurological disorder, but none actually slow its progress, prevent or cure it. No new AD drug has been approved in more than a decade.

The researchers focused on cathepsin B production of N-truncated pGlu-Aβ, a peptide or short chain of amino acids, and the blockade of cathepsin B by E64d, a compound shown to inhibit cysteine proteases, a type of enzyme. AD is characterized by accumulation of a variety of Aβ peptides as oligomers and amyloid plaques in the brain, factors involved in neuronal loss and memory deficits over time. These neurotoxic Aβ peptides are created when enzymes cleave a large protein called amyloid precursor protein (APP) into smaller Aβ peptides of varying toxicity. N-truncated pGlu-Aβ has been shown to be among the most neurotoxic of multiple forms of Aβ peptides.

Much AD research has focused on the APP-cutting enzyme BACE1 β-secretase, but its role in producing pGlu-Aβ was unknown. Cathepsin B is an alternative β-secretase which cleaves the wild-type β-secretase site of APP, which is expressed in the major sporadic and many familial forms of AD. Hook and colleagues looked at what happened after gene knockout of BACE1 or cathepsin B. They found that cathepsin B, but not BACE1, produced the highly toxic pGlu-Aβ.

Perhaps most interestingly, the scientists found that E64d, an enzyme inhibitor of cathepsin B, reduced production of pGlu-Aβ and other AD-associated Aβ peptides. Key was the finding that E64d and cathepsin B gene knock out resulted in improved memory deficits in a mouse model of AD.

"This is an exciting finding," said Hook. "It addresses a new target – cathepsin B – and an effective, safe small molecule, E64d, to reduce the pGlu-Aβ that initiates development of the disease's neurotoxicity. No other work in the field has addressed protease inhibition for reducing pGlu-Aβ of AD."

Hook noted that E64d has already been shown to be safe in clinical trials of patients with muscular dystrophy and would, therefore, likely prove safe for treating AD as well. She hopes to launch Phase 1 human clinical trials in the near future with a modified version of the drug candidate.

###

Co-authors include Gregory Hook, American Life Science Pharmaceuticals, Inc.; Jin Yu and Mark Kindy, Medical University of South Carolina; and Thomas Toneff, UCSD Skaggs School of Pharmacy and Pharmaceutical Sciences.

Funding for this research came, in part, from the National Institutes of Health (grants R44AG032784, R01ES016774-02 and R21AG0428), a Veteran's Affairs Merit Review grant, and an Alzheimer's Association award.

Disclosure: Vivian Hook is chair of American Life Science Pharmaceuticals' scientific advisory board and holds equity in the company.

Scott LaFee | EurekAlert!

More articles from Health and Medicine:

nachricht One gene closer to regenerative therapy for muscular disorders
01.06.2017 | Cincinnati Children's Hospital Medical Center

nachricht The gut microbiota plays a key role in treatment with classic diabetes medication
01.06.2017 | University of Gothenburg

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: Can we see monkeys from space? Emerging technologies to map biodiversity

An international team of scientists has proposed a new multi-disciplinary approach in which an array of new technologies will allow us to map biodiversity and the risks that wildlife is facing at the scale of whole landscapes. The findings are published in Nature Ecology and Evolution. This international research is led by the Kunming Institute of Zoology from China, University of East Anglia, University of Leicester and the Leibniz Institute for Zoo and Wildlife Research.

Using a combination of satellite and ground data, the team proposes that it is now possible to map biodiversity with an accuracy that has not been previously...

Im Focus: Climate satellite: Tracking methane with robust laser technology

Heatwaves in the Arctic, longer periods of vegetation in Europe, severe floods in West Africa – starting in 2021, scientists want to explore the emissions of the greenhouse gas methane with the German-French satellite MERLIN. This is made possible by a new robust laser system of the Fraunhofer Institute for Laser Technology ILT in Aachen, which achieves unprecedented measurement accuracy.

Methane is primarily the result of the decomposition of organic matter. The gas has a 25 times greater warming potential than carbon dioxide, but is not as...

Im Focus: How protons move through a fuel cell

Hydrogen is regarded as the energy source of the future: It is produced with solar power and can be used to generate heat and electricity in fuel cells. Empa researchers have now succeeded in decoding the movement of hydrogen ions in crystals – a key step towards more efficient energy conversion in the hydrogen industry of tomorrow.

As charge carriers, electrons and ions play the leading role in electrochemical energy storage devices and converters such as batteries and fuel cells. Proton...

Im Focus: A unique data centre for cosmological simulations

Scientists from the Excellence Cluster Universe at the Ludwig-Maximilians-Universität Munich have establised "Cosmowebportal", a unique data centre for cosmological simulations located at the Leibniz Supercomputing Centre (LRZ) of the Bavarian Academy of Sciences. The complete results of a series of large hydrodynamical cosmological simulations are available, with data volumes typically exceeding several hundred terabytes. Scientists worldwide can interactively explore these complex simulations via a web interface and directly access the results.

With current telescopes, scientists can observe our Universe’s galaxies and galaxy clusters and their distribution along an invisible cosmic web. From the...

Im Focus: Scientists develop molecular thermometer for contactless measurement using infrared light

Temperature measurements possible even on the smallest scale / Molecular ruby for use in material sciences, biology, and medicine

Chemists at Johannes Gutenberg University Mainz (JGU) in cooperation with researchers of the German Federal Institute for Materials Research and Testing (BAM)...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Plants are networkers

19.06.2017 | Event News

Digital Survival Training for Executives

13.06.2017 | Event News

Global Learning Council Summit 2017

13.06.2017 | Event News

 
Latest News

Quantum thermometer or optical refrigerator?

23.06.2017 | Physics and Astronomy

A 100-year-old physics problem has been solved at EPFL

23.06.2017 | Physics and Astronomy

Equipping form with function

23.06.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>