New drug screening method answers why Alzheimer's drugs fail, suggests
new targets

Date:
January 27, 2022
Source:
University of California - San Diego
Summary:
A new study sheds light on why Alzheimer's drugs so far have been
ineffective at curing or reversing the disease. The researchers
identify new targets for drug development and present a new method
to screen drugs for treating Alzheimer's disease.



FULL STORY ==========================================================================
By analyzing disease mechanisms in human neurons, researchers led by
the University of California San Diego developed a new method to screen
drugs for treating Alzheimer's disease. Their work 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.


==========================================================================
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.

Drug development for Alzheimer's has long 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. As a result,
many research efforts have focused on designing drugs that clear out
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.

To understand why, 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. But there
are other endotypes -- reported for the first time by Subramaniam and colleagues in a previous study -- that also warrant attention. These
include de-differentiation of neurons to an earlier "non-neuron" cell
state; suppression of neuronal genes; and loss of synaptic connections.

"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 method involves 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 treat these neurons with drugs and use next generation
sequencing techniques to evaluate what endotypes change before and after treatment. The researchers also perform this 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 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 drug candidate developed by Subramaniam's collaborator and co-author on the study,
Steven Wagner, who is a professor of neurosciences at UC San Diego School
of Medicine.

The researchers found that the drugs only fix some endotypes, such
as the formation of amyloid plaques. The drugs also partly fix the de-differentiation endotype, by triggering "non-neuron" cells to transform
back into neurons.

However, this transformation is not complete, noted Subramaniam,
because the neurons still lack synaptic connections and therefore cannot communicate with each other.

"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 team will also work
on developing new Alzheimer's drug candidates and screening them with
their method.

Paper: "Endotype reversal 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),
the National Institutes of Health (grants P50 AGO5131, U01 NS 074501-05,
U01 AG048986, R01 LM012595, U01 CA198941, U01 DK097430, R01 DK109365, R01 HD084633 and R01 HL108735), the National Science Foundation (grant STC CCF-0939370), the Joan and Irwin Jacobs Endowment; the Cure Alzheimer's
Fund (CAF), the Veterans Affairs (RR&D 1I01RX002259), and the Chen
Foundation.

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University_of_California_-_San_Diego. Original written by Liezel
Labios. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. Andrew B. Caldwell, Qing Liu, Can Zhang, Gary P. Schroth, Douglas R.

Galasko, Kevin D. Rynearson, Rudolph E. Tanzi, Shauna H. Yuan,
Steven L.

Wagner, Shankar Subramaniam. Endotype reversal as a novel
strategy for screening drugs targeting familial Alzheimer's
disease. Alzheimer's & Dementia, 2022; DOI: 10.1002/alz.12553 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/01/220127104219.htm

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