US researchers administered a
therapy to Alzheimer’s patient-derived neurons in the lab, eliminating
deteriorating cells, leading to positive consequences for the remaining healthy
cells.
Scientists
from the Salk Institute, US, have found that neurons from people with
Alzheimer’s disease show deterioration and undergo a late-life stress process
called senescence. These neurons have a loss of functional activity, impaired
metabolism, and increased brain inflammation.
The
researchers’ discovery, published in Cell Stem Cell, found that targeting the
deteriorating neurons with therapeutics could be an effective strategy for
preventing or treating Alzheimer’s disease.
“Our
study clearly demonstrates that these non-replicating cells are going through
the deterioration process of senescence and that it is directly related to
neuroinflammation and Alzheimer’s disease,” said Professor Rusty Gage,
president of the Salk Institute and Chair for Research on Age-Related
Neurodegenerative Disease.
As cells
age, they can undergo cellular senescence, which contributes to tissue
dysfunction and age-related disorders. Senescence is also thought to play a
role in cellular stress, molecular damage, and cancer initiation. However,
scientists previously believed that senescence primarily occurred in dividing
cells, not in neurons. Little was known about the senescence-like state of
ageing human neurons.
In this study, the team took skin samples from
people with Alzheimer’s disease and converted those cells directly into neurons
in the lab. They tested these neurons to see if they undergo senescence and
examined the mechanisms involved in the process.
They also
explored senescence markers and gene expression of post-mortem brains from 20
people with Alzheimer’s disease and matched healthy controls. This allowed the
team to confirm that their results from the lab held true in actual human brain
tissue.
They
found that senescent neurons are a source of the late-life brain inflammation
observed in Alzheimer’s disease. As the neurons deteriorate, they release
inflammatory factors that trigger a cascade of brain inflammation and cause
other brain cells to run haywire. Additionally, the gene: KRAS, which is
commonly involved in cancer, could activate the senescent response.
The
authors note that the consequences of even a small number of senescent neurons
in the aging brain could have a significant impact on brain function. This is
because a single neuron can make more than 1,000 connections with other
neurons, affecting the brain’s communication system.
In
addition to these findings, the researchers also administered a therapeutic
cocktail of Dasatinib and Quercetin to the patient neurons, in a dish. Both
drugs are used to remove senescent cells in the body in conditions such as
osteoarthritis, so the authors wanted to see if they were effective in
senescent cells in the central nervous system as well.
They
found that the drug cocktail reduced the number of senescent neurons to normal
levels. Targeting senescent cells could thus be a useful approach for slowing
neuroinflammation and neurodegeneration in Alzheimer’s disease.
Yet, the therapeutic cocktail in this study cannot normally enter the brain. However, there are known medications that can cross the blood-brain barrier that likely act in a similar manner and could, possibly, be used as a treatment option in the future.
In the
future, the authors plan to test some of the drugs that can enter the brain to
see how they affect senescent neurons. They will also explore the driving
mechanisms of senescence and see if certain brain regions are more prone to
this deterioration than others.
European Journal of Case Reports and Clinical Images is an international open-access journal publi
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