The presence of ApoE4 increases the brain
damage caused by toxic tangles of a different Alzheimer's-associated protein
- ApoE4 variant increases brain damage that is caused
by toxic tangles of a different Alzheimer's-associated protein named tau.
- ApoE4 is a
variant of the ApoEgene that causes accumulation of amyloid B plaques
implicated in Alzheimer's disease.
- The tau
protein gets hyperphosphorylated in AD forming neurofibrillary tangles.
concluded a study led by researchers at Washington
University School of Medicine in St. Louis. Tau tangles do very little harm to
brain cells when ApoE is not present. The study is published in the journal Nature
Reason for Study
Mere accumulation of amyloid beta clumps does not
kill brain cells or produce the characteristic Alzheimer's symptoms such as
memory loss and confusion.
The findings suggest that targeting ApoE could help prevent
or treat the brain damage present in Alzheimer's disease, for which there are
currently no effective therapies.
‘The ApoE4 variant that is known to increase risk of Alzheimer’s disease, increases brain damage caused by toxic tangles of a different Alzheimer’s-associated protein named tau. This suggests it can become a possible therapeutic target.’
"Once tau accumulates, the brain degenerates,"
said senior author David Holtzman, MD, the Andrew B. and Gretchen P. Jones
Professor and head of the Department of Neurology. "What we found was that when
ApoE is there, it amplifies the toxic function of tau, which means that if we
can reduce ApoE levels we may be able to stop the disease process."
To find out what effect ApoE variants have on
tauopathies, Holtzman and graduate student Yang Shi and their colleagues
conducted the study on genetically modified mice that carry a mutant form of
human tau that was to forming toxic tangles.
They utilized mice that lacked their own version
of the mouse ApoEgene or replaced it with one of the three variants of the
human ApoEgene. The three variants of the ApoEgene play different roles
Results of the Study
The mice were examined at the age 9 months, when
it was detected that the ones carrying human ApoE variants had widespread brain
Hippocampus and entorhinal cortex, important for
memory, were shrunken
Fluid-filled space of the brain had enlarged
where the dead cells had been. ApoE4 expressing mice exhibited the most severe
ApoE2 expressing mice exhibited the least severe
neurodegeneration the least. Mice that lacked ApoE entirely showed virtually no
Immune cells in the brains of mice with ApoE4
turned on a set of genes related to activation and inflammation much more
strongly than those from ApoE3 mice. Immune cells from mice lacking ApoE were
"ApoE4 seems to be causing more damage than the
other variants because it is instigating a much higher inflammatory response,
and it is likely the inflammation that is causing injury," Holtzman said. "But
all forms of ApoE - even ApoE2 - are harmful to some extent when tau is
aggregating and accumulating. The best thing seems to be in this setting to
have no ApoE at all in the brain."
To find out whether ApoE in people similarly
exacerbates neuronal damage triggered by tau, the researchers collaborated with
Bill Seeley, MD, from the University of California, San Francisco. Seeley
identified autopsy samples from 79 people who had died from tauopathies other
than Alzheimer's disease in the past 10 years. The researchers examined each
brain for signs of injury and noted the deceased's ApoE
found that, at the time of death, people with ApoE4
had more damage
than those that lacked ApoE4.
ApoE transports cholesterol around the body via
the bloodstream. Individuals who lack a functional ApoE
gene have very high cholesterol levels and, if
untreated, die young of cardiovascular disease. However, the lack of ApoE in
their brains creates no obvious problems.
"There are people walking around who have no ApoE
and they're fine cognitively," Holtzman said. "It doesn't appear to be required
for normal brain function."
This study suggests that decreasing ApoE
specifically in the brain could slow or block neurodegeneration, even if tau
tangles have already accumulated in the brain.
"Assuming that our findings are replicated by
others, I think that reducing ApoE in the brain in people who are in the
earliest stages of disease could prevent further neurodegeneration," Holtzman
Alzheimer's Disease (AD) Alzheimer's
is a neurodegenerative disease and the
most common form of dementia, accounting for 60 to 80 percent of dementia
cases. Dementia is a condition characterized by memory loss and other cognitive
abilities that are serious enough to interfere with daily life.
- Is not a normal part of aging
- Is a progressive disease, that worsens over time
- Affects one in 10 people over age 65
- Has no cure, but treatments for symptoms are
Causes for AD
- Early onset familial AD, that has an onset before
age 64 has a genetic cause. Mutations in one of three genes have
been implicated and it has an autosomal (not sex-linked) dominant
- The oldest hypothesis is the "cholinergic
hypothesis" that states that AD is caused by a deficiency in the
production of acetylcholine, a vital neurotransmitter.
- AD was identified as a protein misfolding disease,
when in 1991 the amyloid hypothesis postulated that accumulation of
abnormally folded extracellular amyloid beta (Aβ) deposits found in the
brains of AD patients are the fundamental cause of the disease.
- AD is also considered to be a part of a family of
diseases called tauopathies that are characterized by the presence of
abnormal aggregation of the tau protein.
processes are known to occur in the brains of people with Alzheimer's
ApoE proteins are a class of apolipoproteins
essential for the normal break down of triglyceride-rich lipoprotein
constituents. They are mainly produced by astrocytes in the central nervous
system, and are the principal cholesterol carriers to neurons via members of
the low density lipoprotein receptor gene family, ApoE receptors.
This protein is involved in Alzheimer's disease
and cardiovascular disease. The E4 variant was identified as the largest known
genetic risk factor for late-onset sporadic AD in a variety of ethnic groups
nearly a quarter century ago. Having the variant increases a person's chances
of developing the neurodegenerative disease by up to 12 times. When the
ApoE4 protein is present, clumps or plaques of a protein called amyloid beta (Ab) start getting
accumulated the brain
For decades, most researchers ignored the leading
genetic risk factor for Alzheimer's disease. Now, that is set to change.
The tau protein expressed in neurons is normally
regulated by phosphorylation and is bound to and acts to stabilize microtubules
in the cell cytoskeleton.
In neurodegenerative diseases like AD,
hyperphosphorylated tau accumulates as paired helical filaments that in turn
aggregate into masses known as neurofibrillary or gliofibrillary (in neurons or
glial cells) tangles and as dystrophic neurites associated with amyloid
plaques. When tangles get formed, the microtublues disintegrate destroying the
cell's cytoskeleton, which collapses the neuron's transport system. This may
initially result in malfunctions in biochemical communication between neurons
and later in the death of the cells.
Thus, inhibition of abnormal tau
hyperphosphorylation can offer a promising therapeutic target for AD and
Treatment for AD
While the current treatment methods for AD cannot
stop the progression of the disease, they prevent dementia symptoms from
getting worse and improve quality of life for the affected and their
There are two classes of drugs used for
- Cholinesterase inhibitors that prevent the enzyme
from breaking down a neurotransmitter in the brain called acetylcholine
(ACh). In normal individuals, cholinesterase prevents excess post-synaptic
and muscle activation by ACh by breaking it down.
- N-methyl D-aspartate (NMDA) receptor inhibitors
that prevent glutamate from attaching to the NMDA receptors and thus
inhibit their overstimulation by glutamate.
New targets and alternative therapeutic
strategies that can stop the progression of the disease have to be developed to
treat AD. As ApoE genotype determines AD risk, and ApoE has crucial roles in
cognition, targeting it might offer an attractive alternative target for AD
Drugs in development may change the physical
structure of the ApoE4 protein to behave more like the protective ApoE2
protein. The gene therapy approach attempts to insert ApoE2 genes into the
brains of people with APOE4 genes.
So far, investigational therapies for Alzheimer's
disease have focused on amyloid beta or tau, and none of them have changed the
trajectory of the disease. Targeting ApoE has not yet been tried, according to
- Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms, and therapy. Nature reviews Neurology. 2013;9(2):106-118.doi:10.1038/nrneurol.2012.263.
- Iqbal K, Liu F, Gong C-X, Grundke-Iqbal I. Tau in Alzheimer Disease and Related Tauopathies. Current Alzheimer research. 2010;7(8):656-664.
- Alzhiemer's Diseases - (https://en.wikipedia.org/wiki/Alzheimer%27s_disease)