New Tactic Proposed To Find Drugs For Alzheimer’s Disease
By Deborah Borfitz
March 10, 2022 | A new method to screen drugs for treating Alzheimer’s disease could significantly improve the odds of therapeutic success by analyzing causal mechanisms in human neurons, according to Shankar Subramaniam, professor of bioengineering at the University of California (UC) San Diego. The plan now is to extend the work to organoids with microglia cells and vasculature, creating “realistic human brain avatars” for better understanding disease endotypes and their response to treatment.
The most widely studied Alzheimer’s endotype is amyloid plaque formation, which is believed to be what kills neurons, but other previously described endotypes (Science Advances, DOI: 10.1126/sciadv.aba5933) warrant more attention, he says. These include de-differentiation of neurons to an earlier, non-neuron cell state, suppression of neuronal genes, and loss of synaptic connections.
Late-onset Alzheimer’s disease is thought to arise from a complex series of brain changes, not a single protein or process, says Subramaniam. With early-onset Alzheimer’s, a genetic mutation could be involved.
With other conditions, such as diabetes and fatty liver disease, mice or primate models are available, he says. Organoids also faithfully recapitulate human biology, at least in some minimal respects. Things get much more complicated when the organ of interest is the brain because it is not easily accessible and relatively few tools exist for direct observation and intervention, Subramaniam continues. Organoid models are critical to develop since Alzheimer’s disease does not naturally occur in either mice or nonhuman primates.
Early-onset Alzheimer’s is typically diagnosed after patients present with cognitive decline and MRI imaging reveals the formation of tangled amyloid plaques, he says. “By the time that happens, it is already way too late… you are seeing the downstream effects.” To complicate matters further, Alzheimer’s disease isn’t known to manifest itself with markers in the blood, saliva, or urine.
The best first move toward a solution, Subramaniam and his colleagues decided, was a precision medicine approach whereby skin cells taken from people with familial Alzheimer’s disease get converted into pluripotent stem cells and then into neurons. “We just wanted to ask the question, ‘Are these neurons different from neurons in non-demented control patients… who have a healthy lifestyle and are cognitively stable?’ This was our whole guiding motivation.”
Results of their investigation recently published in Alzheimer’s & Dementia: The Journal of the Alzheimer’s Association (DOI: 10.1002/alz.12553). The article sheds light on why Alzheimer’s drugs so far have been ineffective at curing or reversing the disease and identifies new targets for drug development.
Properly treating Alzheimer’s disease means addressing all its effects, not just the plaque, Subramaniam says. An endotype-centric drug screening approach, using the human induced pluripotent stem cell (hiPSC)-derived neuron models, offers that versatility by going beyond pathological readouts and observable disease characteristics (endophenotypes).
Shared Endotypes
Nerve cells accurately represent Alzheimer’s disease in the human brain in that they point to the basic disease mechanisms. They don’t, however, represent the entire complexity of the brain’s anatomy, Subramaniam notes, referencing plans to put the neurons into organoids so they resemble mini-brain cells.
The approach is highly individualistic, he adds. “I can make my neurons or your neurons and build organoids from them, and it becomes a very personalized thing… at the level of brain.”
In the earlier paper in Science Advances, the research team used their hiPSC-derived neuron models to validate the mechanistic endotypes of early-onset Alzheimer’s disease and “it looks like these are common mechanisms that cross different mutations seen in the disease,” says Subramaniam.
More recently, they looked for endotypes of sporadic Alzheimer’s disease that generally strikes after age 65 and has no known genetic trigger. As it turns out, familial and sporadic Alzheimer’s disease share a common underlying set of endotypes, he says.
In the latest study, the researchers screened two experimental Alzheimer’s drugs that were designed to reduce or prevent growth of amyloid plaques: Eli Lilly’s inhibitor semagacestat, which failed late-stage clinical trials, and a drug candidate (modulator BPN-15606) developed by Subramaniam’s collaborator Steven Wagner, professor of neurosciences at UC San Diego School of Medicine.
Neither drug addressed all the endotypes seen in early-onset Alzheimer’s disease, Subramaniam says. They both fixed the formation of amyloid plaques and triggered non-neuron cells to transform back into neurons, but they lacked the synaptic connections to communicate with each other. “Now we have a prescription for what endotypes to target during drug screening.”
Extendable Approach
Subramaniam says next steps for he and Wagner are to start screening drugs on more realistic tissues rather than just neurons in a dish, in hopes of finding one with endotype-wide horsepower. The brain organoids they’ll be using will have microglia (immune cells of the central nervous system) and blood vessels, in addition to a lengthy, multi-month lifespan.
Johnson & Johnson, which has a strong interest in Alzheimer’s disease, has been closely watching developments on this front, says Subramaniam. Research efforts overall need to shift from designing drugs to clear out amyloid plaques because the strategy is not working and, in some cases, has made the disease worse.
Down the road, Subramaniam adds, his lab will be applying the same methodologies for identifying endotypes of other amyloid-type disorders. One of his grad students has already utilized data from the brains of people with Parkinson’s and Huntington’s diseases and, unsurprisingly, found the endotypes remarkably like those seen in Alzheimer’s disease.
The hallmarks of these endotypes are neurons de-differentiating into non-neurons, resulting in loss of synaptic connections and thus memory and cognition, impairing normal physiological functioning, he says. Most brain disorders likely share certain mechanistic features, and the same could hold true for diseases seen in other organs such as the liver.
