Researchers led by the University of California San Diego created a new technique to test medications for the treatment of Alzheimer’s disease by examining disease pathways in human neurons. Their research reveals the reasons why Alzheimer’s medications have so far failed to reverse or cure the disease and provides fresh targets for treatment development.
The findings, reported in a paper published Jan. 27 in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association, could help pave the way for radically new therapeutic approaches to treating Alzheimer’s.
One method to reduce or manage memory loss, issues with thinking and reasoning, and daily functioning may be Alzheimer’s medication. Drugs for Alzheimer’s can enhance quality of life and assist maintain independence even though they cannot treat the illness.
The idea that amyloid plaques, which are created when amyloid-beta proteins accumulate in the brain and damage neurons, are what cause Alzheimer’s disease has long been the basis for the creation of anti-medications. Alzheimer’s As a result, numerous research projects have concentrated on developing medications that remove these plaques.
“But this approach has not led to a cure or improved dementia in patients. Sometimes it 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 colleagues created a drug screening method that examines how the endotypes of disease mechanisms, or endotypes, change in patients’ neurons as a result of treatment, in order to comprehend why. Amyloid plaque development is the endotype of Alzheimer’s that has been studied the most.
Now we have a prescription for what endotypes to target during drug screening. What we are seeing is 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. Once neurons de-differentiate into non-neurons, they lose their synaptic connections, which leads to loss of memory and cognition and as a consequence, dementia.
Professor Shankar Subramaniam
However, there are other endotypes that Subramaniam and colleagues initially described in a prior study and that also deserve consideration. These include the loss of synaptic connections, the de-differentiation of neurons to an earlier “non-neuron” cell state, and the silencing of neuronal genes.
“This is a new test for measuring whether an Alzheimer’s drug works,” said Subramaniam. “The key here is that 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 in the process?”
What’s also special about this method is 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 procedure involves generating neurons from human induced pluripotent stem cells taken from people with familial Alzheimer’s disease, a hereditary form of Alzheimer’s.
The endotypes of these neurons are drug-treated by the researchers, who then analyze the endotype changes using next-generation sequencing methods. As a control experiment, the researchers also run this chemical screen on neurons taken from healthy people.
In this study, the researchers screened two experimental Alzheimer’s drugs that were designed to reduce or prevent growth of amyloid plaques. One was a drug candidate developed by Eli Lilly, called semagacestat, which had failed late-stage clinical trials.
The other was a medication candidate created by Steven Wagner, a professor of neurosciences at the UC San Diego School of Medicine and Subramaniam’s collaborator and research co-author.
The creation of amyloid plaques, for example, is one one endotype that the medications can correct, according to the researchers. The medications also cause “non-neuron” cells to revert to neurons, partially reversing the de-differentiation endotype.
Subramaniam pointed out that this change is not complete because the neurons still lack synaptic connections and are unable to communicate with one another.
“Now we have a prescription for what endotypes to target during drug screening,” said Subramaniam. “What we are seeing is 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. Once neurons de-differentiate into non-neurons, they lose their synaptic connections, which leads to loss of memory and cognition and as a consequence, dementia.”
“I am very excited to use these novel screening strategies for the Alzheimer’s drugs that are being developed in my laboratory,” added Wagner. “In my experience in industry and now academia, this is the first effort to use multiple endotypes for overcoming the failures of drugs targeted only at amyloid plaques.”
Next, the researchers will evaluate their drug screening method on brain organoids. “We want to take this a step further to screen drugs on more realistic tissues, not just neurons in a dish,” said Subramaniam.
The group will also concentrate on creating fresh medication candidates for Alzheimer’s and testing them using their technique.
Paper: “Endotype reversal as a novel strategy for screening drugs targeting familial Alzheimer’s disease.”
