Toxic proteins leads to sporadic type of Alzheimer's, Israeli study finds

Unlike the rare type of dementia called familial Alzheimer’s, which is caused by genetic mutations and runs in families, the most common type is sporadic, whose underlying mechanism has not been well understood. 

It was named after the German psychiatrist and neuropathologist in 1906 Dr. Alois Alzheimer, who first described it in a 51-year-old woman named Auguste Deter in a psychiatric hospital in Frankfurt and saw amyloid tangles in her brain after her death. 

The disease is characterized by the degeneration and death of nerve cells, processes that lead to a progressive impairment of cognitive abilities. It occurs typically in adults over the age of 65, but a small share of all Alzheimer’s patients are hereditary cases that affect younger patients.

Dr. Inbal Maniv and Prof. Michael Glickman of the Technion-Israel Institute of Technology in Haifa and their team have just published a study in the prestigious journal Nature Communications entitled “Altered ubiquitin signaling induces Alzheimer’s disease-like hallmarks in a three-dimensional human neural cell.” They identified the mechanism leading to the accumulation of proteins that are involved in the development of the sporadic form.

The Technion researchers believe that beyond the findings they presented in the article, the platform they developed could be used to screen drugs for the treatment and prevention of sporadic Alzheimer's disease. They add that this platform will help reduce animal experiments in the development of new Alzheimer’s treatments.

The team included Mahasen Sarji, Anwar Bdraneh, Dr. Yaron Fuchs, and other researchers at the Technion in collaboration with researchers from Tel Aviv University, Maastricht University in the Netherlands, and the University of Glasgow in Scotland.

What accumulates in the brain of an Alzheimer's patient?

Toxic proteins pile up in the brains of Alzheimer’s patients. The mechanism of accumulation in familial patients is clear because there is an obvious link between the known mutations and the proteins that accumulate. But in sporadic Alzheimer's disease, on the other hand, the trigger for protein accumulation has been unknown.

As protein experts, Glickman’s research group proposed that the accumulation of toxic proteins in the brain is due to a disruption in the protein clearance mechanism known as the ubiquitin-proteasome system. 

Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms whose cells have a membrane-bound nucleus. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. The basic functions of ubiquitin and the components of the ubiquitylation pathway were made clear three decades ago a the Technion by Prof. Aaron Ciechanover, Prof. Avram Hershko, and the late American biologist Irwin Rose for which they received the Nobel Prize in Chemistry in 2004. 

To test their hypothesis, the group set up a model system of human neurons that made it possible for them to examine the involvement of the ubiquitin system in the development of the disease. They found that damage to the ubiquitin system leads to the accumulation of toxic proteins even in healthy tissue, mimicking the typical Alzheimer’s pathology.

To assess the importance of their findings, they went on to engineer an RNA molecule that specifically silences one of the components of the ubiquitin system. Treatment with this molecule reduced the pathology in their experimental model. The team proposed that this RNA molecule could serve as a prototype for the development of effective treatments. 

The past few years have seen major advancements in the packaging and delivery of bio-active RNA molecules as therapies. With proper modifications and packaging, the interference RNA targeting the component that the team has identified could yield promising results in a clinical setting, they said. “This discovery highlights the importance of the ubiquitin system in clearing defective proteins to maintain the cells’ health. Disruption in this system could lead to the development of the disease.”