This Discovery Could Halt the Progression of Diseases Like Alzheimer's

[DIGEST: IFLS, blog.alzheimers.org.uk, academic.oup.com, BBC (a, b), Science]

A study published in April 2017 shows two drugs—one already on the market and one being tested for cancer treatment—may be able to stop the progression of certain neurodegenerative diseases, and perhaps even improve disease-related symptoms. The drugs work by preventing a natural, but potentially destructive, self-defense on the cellular level. This protective response by the body, if not kept in check by the drugs, leads to the neurological symptoms, and eventually death.


Fighting the Body’s Own Self-Defense

Many neurodegenerative diseases develop similarly to viruses that attack a cell’s own natural proteins. For example, a cell attacked by a virus halts all protein production to protect itself, while a virus generates its viral proteins. Likewise, in many neurodegenerative diseases, damaged or “unfolded” proteins begin to overtake the cell, and the cell continues to fight back by not creating any new proteins—but for a much more extended period of time, causing the cells to die. When neurons follow this same process and die off, symptoms of impaired movement, memory loss or even death can occur.

Professor Giovanna Mallucci, of University of Cambridge and head of the studies leading to this discovery, refers to this defense mechanism—through which the cell reacts to the growth of unfolded proteins by largely stopping further production of additional proteins—as “the unfolded protein response.” She told the Alzheimer’s Society: “The response suspends much protein-making activity in the cell while it fixes the problem. If it can’t be fixed, the cell will die.”

Mallucci’s team first sought to block the unfolded protein response in mice, and prevent brain degeneration. She said, “If we can find a way to block this response with drugs, then we might be able to develop a treatment that works for people with all these different conditions.”

First Compound to Prevent Neurodegeneration

In a breakthrough study in 2013, mice with prion disease—a group of neurodegenerative conditions that cause dementia, changes in behavior, and coordination—were given an oral compound to halt the auto-defense mechanism to the unfolded proteins. According to the

results, the compound is effective both before and after symptoms emerge. However, it causes damage to the pancreas. Thus, further study was required to find a drug without damaging side effects.

Mallucci told BBC: "What's really exciting is a compound has completely prevented neurodegeneration and that's a first.” According to Mallucci, despite the detrimental side effects, it still offered a "new pathway” that may lead to protective drugs.

Two Promising Drugs Emerge

Since 2013, while testing more than 1000 drugs on nematode worms, mice, and human cells in a petri dish, Mallucci’s team discovered the positive effects of trazodone – an antidepressant – and DBM, found in small amounts in licorice; DBM is currently being tested for its ability to treat cancer.

The two drugs were tested on both prion-related conditions and a specific protein, known as tau. Tau is linked to multiple forms of dementia, including Alzheimer’s, where it forms toxic clumps. Results of the new study show positive results for both prion conditions and tau proteins.

Mallucci told BBC: "Both [drugs] were very highly protective and prevented memory deficits, paralysis and dysfunction of brain cells." Moreover, the mice’s disease-related behavior showed improvement after receiving the drugs.

Dr. Doug Brown from the Alzheimer's Society said: "We're excited by the potential of these findings, from this well-conducted and robust study.”

Because trazodone and DBM either have already been or are in the process of being approved for human use, researchers should be able to gain approval for their use in human trials for neurodegenerative research more quickly.

“A clinical trial is now possible, to test whether the protective effects of the drug we see on brain cells in mice with neurodegeneration also applies to people in the early stages of Alzheimer’s disease or other dementias,” Mallucci said. “We could know in 2-3 years whether this approach can slow down disease progression, which would be a very exciting first step in treating these disorders.”

Mallucci explained, "We're very unlikely to cure [neurodegenerative diseases] completely, but if you arrest the progression you change Alzheimer's disease into something completely different so it becomes liveable with."

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