California US January 28, ANI A team of researchers has developed a new method to screen drugs for treating Alzheimer's disease and find out why Alzheimer's drugs so far have been ineffective at curing or reversed the disease.
The findings could pave the way for new therapeutic approaches to treating Alzheimer's disease.
Drug development for Alzheimer's has been driven by the hypothesis that amyloid plaques - formed by the buildup of amyloid-beta proteins in the brain -- are what kill neurons and cause Alzheimer's. Many research efforts have focused on designing drugs that clear out plaques.
This approach has not led to a cure or improved dementia in patients. The disease has made the disease worse, said senior author Shankar Subramaniam, a professor of bioengineering at the UC San Diego Jacobs School of Engineering.
Subramaniam and his collaborators developed a drug screening method that looks at what disease mechanisms, or endotypes, change in patients' neurons as a result of treatment. The most widely studied Alzheimer's endotype is amyloid plaque formation.
There are also other endotypes that warrant attention, reported by Subramaniam and colleagues in a previous study. These included de-differentiation of neurons to an earlier non-neuron cell state, suppression of neuronal genes and loss of synaptic connections.
We are using the endotypes that we discovered to see how current drugs fail. When drugs interact with human neurons, what endotypes do the drugs fix and what endotypes do they not fix? He added.
This method is unique in that it screens drugs on actual patient cells.
The power of this is that you can do precision medicine and have a good model system to study Alzheimer's, said Subramaniam.
The method involved taking human induced pluripotent stem cells derived from patients with familial Alzheimer's disease, which is a hereditary form of Alzheimer's, and transforming them into neurons. The researchers used next-generation sequencing techniques to evaluate what endotypes changed before and after treatment and how they treated these neurons with drugs. The researchers also performed a drug screen on neurons derived from healthy individuals as a control experiment.
In this study, the researchers screened two experimental Alzheimer's drugs that were designed to reduce or prevent the growth of amyloid plaques. One of the drug candidates developed by Eli Lilly, called semagacestat, had failed clinical trials late in life. Steven Wagner, a professor of neurosciences at the UC San Diego School of MedicineSan Diego School of Medicine, was the other drug candidate developed by Subramaniam's collaborator and co-author on the study.
The researchers found that the drugs did not fix some endotypes, such as the formation of amyloid plaques. The drugs also fix the de-differentiation endotype by triggering non-neuron cells to transform back into neurons.
Subramaniam noted that the transformation is not complete because the neurons don't have synaptic connections and cannot communicate with each other.
Subramaniam said they had a prescription for what endotypes to target during drug screening.
We have seen that fixing amyloid plaque formation does not reverse the disease in any way. It turns out that this endotype is way downstream, so it's too late. He added that when neurons de-differentiate into non-neurons, they lose synaptic connections, which leads to loss of memory and cognition and as a result of dementia.
Wagner said that they are very excited to use these novel screening strategies for Alzheimer's drugs that are being developed in my laboratory.
This is the first effort to use multiple endotypes for overcoming the failures of drugs targeted only at amyloid plaques, according to my experience in the industry and now academia.
The drug screening method will be evaluated by the researchers on brain organoids.
Subramaniam said we want to take this step further to screen drugs on more realistic tissues, not just neurons in a dish.