New screening method answers why Alzheimer’s drugs don’t work

Drug development for Alzheimer’s disease has long been driven by the hypothesis that amyloid plaques are formed by the accumulation of amyloid-beta proteins in the brain. is what kills nerve cells and causes Alzheimer’s disease. Therefore, much research effort has been focused on the design of drugs that help remove these plaques.

“But this approach does not lead to a cure or improvement in dementia in patients,” said senior author Shankar Subramaniam, a professor of bioengineering at UC San Diego Jacobs College of Engineering. It makes the disease worse.”

To understand why, Subramaniam and his colleagues developed a drug-screening method that looks at disease mechanisms, or organ types, that change in patients’ neurons as a result of treatment. treat. The most widely studied cause of Alzheimer’s disease is the formation of amyloid plaques. But are there other prejudices?? was first reported by Subramaniam and colleagues in an earlier study ?? also need attention. These include the differentiation of neurons into an earlier “non-neuronal” cellular state; inhibition of neuronal genes; and loss of synaptic connection.

“This is a new trial to measure whether an Alzheimer’s drug is working,” Subramaniam said. “The key here is that we’re using the endotypes we’ve discovered to see how existing drugs fail. When drugs interact with human neurons, which endotype does that repair drugs and what endotypes do they not repair in the process?”

What’s special about this method is that it screens the drug on the actual cells of the patient. “The power of this is that you can do precision medicine and have a good model system for studying Alzheimer’s disease,” says Subramaniam.

The method involves taking induced human pluripotent stem cells derived from patients with familial Alzheimer’s disease, an inherited form of Alzheimer’s disease, and transforming them into neurons. The researchers treated these neurons with drugs and used next-generation sequencing techniques to assess what endotypes changed before and after the treatment. The researchers also performed this drug screen on nerve cells derived from healthy people as a control experiment.

In this study, researchers screened two experimental Alzheimer’s drugs designed to reduce or stop the growth of amyloid plaques. One is a drug candidate developed by Eli Lilly, called semagacestat, that has failed in late-stage clinical trials. The other is a drug candidate developed by Subramaniam’s collaborator and co-author on the study, Steven Wagner, a professor of neuroscience at UC San Diego School of Medicine.

The researchers found that the drugs only corrected certain forms of endotypes, such as the formation of amyloid plaques. The drug also partially corrects the dedifferentiated endotype, by activating “non-neuronal” cells to convert back into neurons. However, this transition is not complete, Subramaniam notes, because neurons still lack synaptic connections and therefore cannot communicate with each other.

“We now have a prescription for what endotypes to target during drug testing,” Subramaniam said. “What we’re seeing is that immobilizing amyloid plaque formation doesn’t reverse the disease in any way. It turns out that this endotype is going downstream so it’s too late. Once the neurons don’t, it’s too late. differentiate into non-neuronal neurons, they lose their synaptic connections, leading to memory and cognitive loss and consequent amnesia.”

Wagner added: “I am excited to use these novel screening strategies for Alzheimer’s drugs being developed in my lab. “In my experience in industry and now academia, this is the first attempt to use multiple prototypes to overcome the failure of drugs that target only the amyloid plaque.”

Next, the researchers will evaluate their drug screening method on organics in the brain. “We wanted to go one step further to screen for drugs on more realistic tissues, not just neurons in a dish,” says Subramaniam. The team will also work to develop new Alzheimer’s drug candidates and screen them with their methods.

Article: “Reverse prototyping as a novel strategy for screening drugs targeting familial Alzheimer’s disease.”

This study was supported by the Alzheimer’s Association New Investigator Research Award (NIRG-14-322164), National Institutes of Health (grant P50 AGO5131, U01 NS 074501-05, U01 AG048986, R01 LM012595, U01 CA198941, U01 DK097430, R01 DK109365, R01 HD084633 and R01 HL108735), National Science Foundation (grant STC CCF-0939370), Joan and Irwin Jacobs Endowment; The Alzheimer’s Fund (CAF), Veterans Affairs (RR&D 1I01RX002259), and the Chen Foundation.

Source: Eurekalert

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