Alzheimer’s disease is devastating both for those who suffer from it and for those who love them.
It is also expensive. It’s estimated that the current worldwide cost of
coping with Alzheimer’s is £670
million ($818 billion). A cure for Alzheimer’s is not available and
current treatments for the disease focus on mitigating symptoms rather than
eliminating causes.
Recent research has
provided evidence that the memory loss associated with Alzheimer’s may be
preventable and reversible. Now, new
research published in the Proceedings
of the National Academy of Sciences reports on a gene therapy treatment
that stopped the development of Alzheimer’s disease dead in its tracks.
The destruction of
neurons that is the root cause of Alzheimer’s disease and other types of
dementia begins with the formation of plaque deposits in the brain that
are built from beta amlyoid peptides. Defective variants of
a type of protein called tau protein gather on the beta amyloid deposits.
The tau proteins cause inflammation in the brain and destroy surrounding
neurons.
Early-stage clinical
trials have shown that the antibody aducanumab is effective in destroying the beta amyloid deposits
that serve as the gathering place for the defective tau proteins. The
new research carried out by a team at Imperial College London describes a gene therapy treatment
that prevents the beta amyloid deposits from being formed.
The researchers
identified a gene called PGC-1α that interferes with the production of
beta amyloid peptides. They directly
tested the effect of PGC-1α on the development of Alzheimer’s disease
with transgenic mice that are genetically engineered to produce
elevated levels of amyloid beta peptides.
The
neural destruction associated with Alzheimer’s disease first appears in the
hippocampus (an area of the brain involved in memory) and the cortex (an area
involved in higher cognitive functions such as thinking and reasoning). The
researchers delivered the PGC-1α gene to the hippocampus and cortex of the
transgenic mice with a lentivirus which is a type of virus that can
inject genetic material into other cells.
The
hypothesis that was tested in the study was that the lentivirus
would deliver the PGC-1α gene into cells in the hippocampus and cortex
where it would interfere with the production of the beta amyloid peptides that
play a critical role in the development of Alzheimer’s disease.
The
researchers tested this hypothesis with four groups of mice. The strain of mice that are engineered to
produce elevated levels of amyloid beta peptides are known as APP23 mice. One group of APP23 mice, the PGC-1α
group, had a lentivirus with the PGC-1α gene surgically placed in in their
hippocampus and cortex. The
control APP23 mice received a lentivirus that did not
have the PGC-1α gene. The two
lentivirus treatments (with and without the PGC-1α gene) were
mirrored in two groups of mice that do not develop Alzheimer’s disease
because they do not produce elevated levels of amyloid beta peptides
(called wild-type mice). The four groups
of mice were tested four months after receiving the lentivirus treatments in
order to give the lentivirus time to work.
The
effects of the PGC-1α treatment on memory were examined with an
object location test and a novel object test. In an object location test a familiar object
in the mouse’s environment is moved to a different location.
If
the mouse remembers where the object had been before it was moved, it will
spend more time examining the object after it is moved. In a novel object test a new object is placed
in the mouse’s environment. If the mouse
remembers its environment, it will recognize that the new object was not there
before and will spend more time examining it.
Remember
that the APP23 mice produce elevated levels of the beta amyloid peptides that
lead to Alzheimer’s disease. If treatment with the PGC-1α gene
interferes with the formation of these peptides and thereby retards
the development of Alzheimer’s, the PGC-1α group of APP23 mice should
perform better on the memory tests than the control APP23 mice that did
not receive the PGC-1α treatment.
This
is exactly what was found. The
control APP23 mice displayed markedly impaired memory in both the object
location and novel object tests. In comparison, the PGC-1α APP23 mice
showed no memory impairments on either memory test and their performance on the
tests was the same as the two groups of wild-type mice who did not develop
Alzheimer’s disease.
The
memory tests indicate that treatment with the PGC-1α
gene prevented the development of Alzheimer’s disease by
interfering with the formation of beta amyloid peptides. The researchers delved more deeply into this
issue by examining the brain tissue of the mice that were in the study.
There
was a 19.1% reduction in beta amyloid peptides in the cortex and a 30%
reduction in the hippocampus of the PGC-1α APP23 mice in
comparison with the control APP23 mice. Beta amyloid plaque buildup was reduced by 43%
in the cortex and 51% in the hippocampus of the PGC-1α APP23 mice in
comparison with the controls. The PGC-1α
gene was successful in interfering with the production of beta amyloid
peptides.
In
addition, the inflammation surrounding beta amyloid plaques that
contributes to the destruction of neurons in Alzheimer’s disease was markedly
reduced in the PGC-1α APP23 mice in comparison with the control APP23
mice.
Looking
directly at the destruction of neurons, the researchers compared the APP23
mice that developed Alzheimer’s to the wild-type mice that did not. They found that the APP23 mice
with Alzheimer’s disease had 30% fewer neurons in an area
of hippocampus. There was no significant loss of neurons in the APP23
mice that were treated with the PGC-1α gene. In other words, mice that are genetically
engineered to develop Alzheimer’s disease but are treated with the PGC-1α
gene showed the same amount of neural destruction as mice that did not
develop Alzheimer’s.
The
results of this study provide very strong evidence that gene therapy treatment
with the PGC-1α gene has the potential to prevent the development of
Alzheimer’s disease. The key words here
are “has the potential.” This is a
proof-of-concept study that shows that the concept is sound. A great deal of further work is necessary to
determine whether the PGC-1α gene treatment works with humans and, if it
does, whether effective gene therapy treatments using the gene can be
developed.
In
a previous article written by Kevin Murnane, he discusses
that clinical trials showing that beta amyloid deposits can be destroyed
by an antibody is “a very important step toward the day when Alzheimer’s is no
longer feared because it can be controlled.” Viewed in a most optimistic and hopeful light,
the research carried out by the team at Imperial College
London is a very important step toward the day when Alzheimer’s is no
longer feared because it can be prevented.
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