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Alzheimer's, Dementia & Mental Health
Cold Sore Virus Suspected of a Role in Causing
Alzheimer's Disease
ApoE-4 gene, leading risk factor of Alzheimer's in
senior citizens, linked with herpes
January 3, 2007 - A gene known to be a major risk
factor for Alzheimer's disease puts out the welcome mat for the virus
that causes cold sores, allowing the virus to be more active in the
brain compared to other forms of the gene. The new findings, published
online in the journal Neurobiology of Aging, add some scientific heft to
the idea, long suspected by some scientists, that herpes somehow plays a
role in bringing about Alzheimer's disease.
The study links a form of the ApoE gene known as
ApoE-4, which after advanced age is the leading known risk factor for
getting Alzheimer's disease, with the form of herpes herpes simplex 1
or HSV that infects more than 80 percent of Americans and causes cold
sores around the mouth.
The findings from a group at the University of
Rochester Medical Center show that the particular form of the gene that
puts people at risk also creates a fertile environment for herpes in the
brain, allowing the virus to be more active than allowed by other forms
of the ApoE gene.
Scientists have known for more than 15 years that
the ApoE-4 gene is a player in Alzheimer's disease, but the idea that it
works in concert with the herpes virus is new. (Herpes is a viral
infection causing small painful blisters and inflammation, most commonly
at the junction of skin and mucous membrane in the mouth or nose, or in
the genitals.)
"This work raises the question whether herpes in
concert with ApoE-4 increases the risk of Alzheimer's disease. The data
suggests that ApoE-4 may support the ability of HSV to be a more
virulent pathogen," said Howard Federoff, M.D., Ph.D., the leader of the
team and professor of Neurology, Medicine, and Microbiology &
Immunology. He worked closely with post-doctoral research associate
Renee Miller, Ph.D., on the project.
The findings, which are based on measurements of
the activity levels of the herpes virus in the brains of mice with
different forms of the human ApoE gene, bring together several lines of
research that have pointed toward a possible role for herpes in
Alzheimer's disease.
Ruth Itzhaki of the University of Manchester has
led the way with several studies showing a correlation between herpes
and Alzheimer's. She has shown that Alzheimer's patients who have the
ApoE-4 form of the gene have more herpes DNA in the brain regions that
are affected by Alzheimer's, compared to Alzheimer's patients who also
have herpes but who have a different form of the ApoE gene.
And she has shown that people with the ApoE-4
version of the gene who are infected with herpes are more likely to get
Alzheimer's disease than people infected with herpes who have a
different form of the ApoE gene, or than people who have the ApoE-4 gene
but who don't have herpes.
Other scientists have found that a herpes infection
is active more often causing the tell-tale cold sores around the mouth
in the 25 percent of people who have a copy of the ApoE-4 gene. In
other words, people who are frequently troubled by cold sores are more
likely to have the gene that makes them more vulnerable to Alzheimer's
disease.
Cold sores that come and go are the outward sign of
the two different phases of the virus's life cycle. Herpes simplex is a
chronic infection that lives in a person for a lifetime, periodically
flaring up in a "lytic" phase where it causes cell damage, then
retreating and seeking safe harbor within the body's nerves in a
"latent" phase.
The virus spends most of its time in the latent
phase, sequestered in cells, not active and not replicating. But
occasionally, when triggered by factors like stress, fatigue, certain
foods, or even sunlight, the virus becomes active, traveling from its
hiding places in the nervous system to cells around the mouth, damaging
cells and causing cold sores.
It was this cycle of activity and latency that
Miller and Federoff focused on while looking at the brain cells of mice
with different forms of the ApoE gene. They looked at four groups of
mice: Some had ApoE-3, which is what the majority of people carry; some
had ApoE-4, which in people makes them more likely to get Alzheimer's;
some had ApoE-2, which makes people less likely to get the disease; and
some had no ApoE gene at all.
The team found that the virus infiltrates brain
cells about the same no matter which gene is involved. But they found
that the subsequent activity level of the virus generally mirrored the
disease-causing potential of the gene. They found that in animals with
the ApoE-4 gene, the virus is less likely to be in the quiet, latent
stage of its life cycle, suggesting it has more of an opportunity to
replicate. In animals with the ApoE-2 gene, the virus was less active.
The work suggests that ApoE-4 may alter the balance
between the HSV life cycle forms. It's possible that the ApoE gene works
as a sort of bodyguard that tries to keep cells safe from herpes,
perhaps by facilitating latency. Somehow the ApoE-2 version is extremely
effective at keeping the virus at bay, while in this study, the ApoE-4
version wasn't any more effective than not having an ApoE gene at all.
The ApoE gene is well known to Alzheimer's
researchers. The gene, which normally plays a role in ferrying
cholesterol around the body, is associated with both the cellular
tangles and amyloid plaques that are found in the brains of patients
with the disease.
Researchers have found several ways in which the
gene might make a person vulnerable to getting a disease like
Alzheimer's. In people with the ApoE-4 gene, brain cells don't seem to
recover as well from injury, and the cells don't form new connections as
well as cells equipped with either ApoE-2 or ApoE-3.
Other scientists have shown that the gene plays a
role in clearing toxic amyloid beta from the brain.
"Just how ApoE-4 makes people vulnerable to
Alzheimer's disease isn't resolved at all," said Federoff, who is
director of the University's Center for Aging and Developmental Biology.
"It may be that it works in multiple ways."
The team is exploring different ways that herpes
might affect the development of Alzheimer's disease. In one study the
team looking at the role of Nectin-1, a cell adhesion molecule that
herpes uses as one route to infect a cell. Nectin-1 plays a crucial role
in forming synapses, the structures between brain cells that move
information and signals from one cell to the next. The team is studying
whether herpes somehow disturbs the receptor, possibly altering the
structure and function of the synapse. Damage to synapses is one of the
earliest signs of Alzheimer's disease.
Another possibility is that the body's immune
response against herpes somehow damages the brain, and that such damage
is worse in people with the ApoE-4 copy of the gene.
Earlier this year Federoff's team published a study
that showed inflammation is the earliest change that could be detected
in a brain affected by Alzheimer's disease, before any of the hallmark
plaques or tangles and certainly long before any behavioral changes are
seen. Such inflammation often is a byproduct when the immune system
fights an infection.
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