Alzheimer’s
disease: protective gene uncovered in human cell model – bringing promise for
new drug discoveries
By
Dean Nizetic, Queen Mary University
of London
The Conversation, July 10, 2020
-- Every three seconds, someone in the world develops dementia.
The most
common form of dementia is Alzheimer’s disease. While researchers have
identified a number of risk factors that are linked to dementia – including
genetics, smoking, and high blood pressure – there is currently still no cure.
Part
of the reason for this is because of how complicated it is to test potential
Alzheimer’s drugs. In order to conduct clinical trials participants need to
have symptoms. But by the time symptoms appear, it’s usually too late for
treatments to have a large effect as many of their brain cells have already
died.
But our
latest research developed a new human cell model that is able to rapidly
simulate the development of Alzheimer’s disease in the lab. This allowed us to
identify a gene, called BACE2, that is naturally able to suppress the signs of
Alzheimer’s disease in human brain cells. Our research is the result of around
five years’ work, and was the collaborative effort of teams based in London,
Singapore, Sweden and Croatia.
Researchers
already know a lot about which genes cause Alzheimer’s disease or make someone
more likely to develop it. These genes contribute to certain toxic proteins
accumulating in the human brain. So our team thought that the opposite must
also be true: our brain cells must also have proteins that can naturally slow
down the development of Alzheimer’s.
One
gene that can definitely cause Alzheimer’s disease is a gene found on the 21st
pair of human chromosomes that is responsible for making the amyloid
precursor protein (APP). Research shows that 100% of people born with just
one extra copy of the APP gene (called “DupAPP”) will develop dementia by age
60.
People
with Down’s syndrome are born with three copies of APP because they have a
third 21st chromosome. But by age 60, only 60% of them will develop
clinical dementia. We wanted to know why some people with Down’s syndrome have
delayed development of – or never develop – Alzheimer’s dementia compared to
those who have one extra DupAPP gene.
The
simple answer for this is because they have an extra dose of all other genes
located in chromosome 21. We believed that there could be some dose-sensitive
genes on chromosome 21 that, when triplicated, protect against Alzheimer’s
disease by counteracting the effects of the third APP gene.
These
genes must then appear to delay the onset of clinical dementia in some people
with Down’s syndrome by approximately 20 years. Studies have even shown
that any future drug able to delay dementia onset by just five years would
reduce the prevalence of Alzheimer’s in the general population by half.
To
study the potential of the extra genes, we took hair follicle cells from people
with Down’s syndrome and re-programmed the cells to become like stem cells.
This allowed us to turn them into brain cells in a Petri dish.
We
then grew them into 3D balls of cells that imitated the tissue of the grey
matter (cortex) of the human brain. The 3D nature of the culturing allowed
misfolded and toxic proteins to accumulate, which are crucial changes that lead
to Alzheimer’s disease in the brain.
We
found all three major signs of Alzheimer’s disease (plaque build-up in the
brain, misfolded “tau” proteins and dying brain neurons) in cell cultures from
71% of people with Down’s syndrome who donated samples. This proportion was
similar to the percentage of clinical dementia among adults with Down’s
syndrome.
We
were also able to use CRISPR – a technology that allows researchers
to alter DNA sequences and modify a gene’s function – to reduce the number of
BACE2 genes from three copies to two copies on chromosome 21. This was only
done in cases where there were no indications of Alzheimer’s disease in our
cellular model. Surprisingly, reducing the number of BACE2 genes on chromosome
21 provoked signs of the disease. This strongly suggest that having extra
copies of a normal BACE2 gene could prevent Alzheimer’s.
The
protective action of BACE2 reduces the levels of toxic amyloid proteins. This
was verified in our cellular models, as well as in cerebrospinal fluid and
post-mortem brain tissue from people with Down’s syndrome.
Our
study provides proof that natural Alzheimer’s-preventing genes exist, and now
we have a system to detect new potential protective genes. Importantly, recent
research showed the protective action of BACE2 might also be relevant to
people who don’t have Down’s syndrome.
Our
results also show that all three signs of Alzheimer’s disease can be
potentially detected in cells from live donors. Though this requires a lot more
research, it means we may be able to develop tests that identify which people
are at higher risk of Alzheimer’s disease by looking at their cells.
This
would allow us to detect the disease before it starts developing in a person’s
brain, and could make it possible to design personalised preventative
treatments. However, we are still a long way from reaching this goal.
Most
importantly, our work shows that all three signs of Alzheimer’s disease
detected using our model could be prevented by drugs known to inhibit the
production of the toxic amyloid protein – and this can be detected in as little
as six weeks in the lab. We hope our discovery could lead to the development of
new drugs aimed at delaying or preventing Alzheimer’s disease, before it causes
brain cell death.
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