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Mitochondrial Dysfunction Present
Early in Alzheimer's,
Before Memory Loss
Wednesday, February 29, 2012
ROCHESTER, Minn. — Mitochondria — subunits inside cells that
produce energy — have long been thought to play a role in
Alzheimer's disease. Now Mayo Clinic researchers using
genetic mouse models have discovered that mitochondria in
the brain are dysfunctional early in the disease. The
findings appear in the journal PLoS ONE.
The group looked at mitochondria in three mouse models, each
using a different gene shown to cause familial, or
early-onset, Alzheimer's disease. The specific mitochondria
changes corresponded with the mutation type and included
altered mitochondrial movement, structure, and energy
dynamics. The changes happened in the brain even before the
mice showed any symptoms such as memory loss. The group also
found that the mitochondrial changes contributed to the
later loss of mitochondrial function and the onset and
progression of Alzheimer's disease.
"One of the most significant findings of this study is our
discovery of the impact of mitochondrial dysfunction in
Alzheimer's disease," says Eugenia Trushina, Ph.D., Mayo
Clinic pharmacologist and senior investigator on the study.
"We are asking: Can we connect the degree of mitochondrial
dysfunction with the progression of symptoms in Alzheimer's
disease?"
Enlisting the expertise of Mayo researcher Petras Dzeja,
Ph.D., the team applied a relatively new method called
metabolomics, which measures the chemical fingerprints of
metabolic pathways in the cell — sugars, lipids,
nucleotides, amino acids and fatty acids, for example. It
assesses what is happening in the body at a given time and
at a fine level of detail, giving scientists insight into
the cellular processes that underlie a disease. In this
case, the metabolomic profiles showed changes in metabolites
related to mitochondrial function and energy metabolism,
further confirming that altered mitochondrial energetics is
at the root of the disease process.
The researchers hope that the panel of metabolomic
biomarkers they discovered can eventually be used for early
diagnosis, treatment, and monitoring of Alzheimer's
progression.
"We expect to validate metabolomic changes in humans with
Alzheimer's disease and to use these biomarkers to diagnose
the disease before symptoms appear — which is the ideal time
to start treatment," Dr. Trushina says.
The team looked at neurons of three different genetic animal
models of Alzheimer's disease. Researchers applied a
mitochondria-specific dye and observed their motion along
axons, a process called axonal trafficking. They showed that
even in embryonic neurons afflicted with Alzheimer's
disease, well before the mice show any memory loss,
mitochondrial axonal trafficking is inhibited. Using a panel
of techniques that included electron and light microscopy,
they determined that in the brains of mice with Alzheimer's
disease, mitochondria tended to lose their integrity,
ultimately leading to the loss of function. Importantly,
dysfunctional mitochondria were detected at the synapses of
neurons involved in maintaining memory.
"We are not looking at the consequences of Alzheimer's
disease, but at very early events and molecular mechanisms
that lead to the disease," Dr. Trushina says. The next step
is looking at the same mitochondrial biomarkers in humans,
she says. As the researchers begin to understand more about
the mitochondrial dynamics that are altered in Alzheimer's
disease, they hope to move on to designing drugs that can
restore the abnormal bioenergetics and mitochondrial
dynamics to treat the disease.
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J Alzheimers Dis. 2012;
Mitochondrial dysfunction and immune
activation are
detectable in early Alzheimer's disease
blood.
Abstract
Alzheimer's disease (AD), like other dementias, is
characterized by progressive neuronal loss and
neuroinflammation in the brain. The peripheral leukocyte
response occurring alongside these brain changes has not
been extensively studied, but might inform therapeutic
approaches and provide relevant disease biomarkers. Using
microarrays, we assessed blood gene expression alterations
occurring in people with AD and those with mild cognitive
changes at increased risk of developing AD.
Of the 2,908
differentially expressed probes identified between the three
groups (p < 0.01), a quarter were altered in blood from mild
cognitive impairment (MCI) and AD subjects, relative to
controls, suggesting a peripheral response to pathology may
occur very early. There was strong evidence for
mitochondrial dysfunction with decreased expression of many
of the respiratory complex I-V genes and subunits of the
core mitochondrial ribosome complex.
This mirrors changes
previously observed in AD brain. A number of genes encoding
cell adhesion molecules were increased, along with other
immune-related genes. These changes are consistent with
leukocyte activation and their increased the transition from
circulation into the brain. In addition to expression
changes, we also found increased numbers of basophils in
people with MCI and AD, and increased monocytes in people
with an AD diagnosis.
Taken together this study provides
both an insight into the functional response of circulating
leukocytes during neurodegeneration and also identifies
potential targets such as the respiratory chain for
designing and monitoring future therapeutic interventions
using blood.
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Prog Neuropsychopharmacol Biol Psychiatry.
2011 Mar 30;
Mitochondrial dysfunction and
Alzheimer's disease.
Abstract
To date, one of the most discussed hypotheses for
Alzheimer's disease (AD) etiology implicates mitochondrial
dysfunction and oxidative stress as one of the primary
events in the course of AD. In this review we focus on the
role of mitochondria and mitochondrial DNA (mtDNA) variation
in AD and discuss the rationale for the involvement of
mitochondrial abnormalities in AD pathology.
We summarize
the current data regarding the proteins involved in
mitochondrial function and pathology observed in AD, and
discuss the role of somatic mutations and mitochondrial haplogroups in AD development.
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J Alzheimers Dis. 2010;
Systemic mitochondrial dysfunction
and the etiology of
Alzheimer's disease and down syndrome
dementia.
Abstract
Increasing evidence is implicating mitochondrial dysfunction
as a central factor in the etiology of Alzheimer's disease
(AD). The most significant risk factor in AD is advanced age
and an important neuropathological correlate of AD is the
deposition of amyloid-beta peptide (Abeta40 and Abeta42) in
the brain. An AD-like dementia is also common in older
individuals with Down syndrome (DS), though with a much
earlier onset.
We have shown that somatic mitochondrial DNA
(mtDNA) control region (CR) mutations accumulate with age in
post-mitotic tissues including the brain and that the level
of mtDNA mutations is markedly elevated in the brains of AD
patients. The elevated mtDNA CR mutations in AD brains are
associated with a reduction in the mtDNA copy number and in
the mtDNA L-strand transcript levels. We now show that mtDNA
CR mutations increase with age in control brains; that they
are markedly elevated in the brains of AD and DS and
dementia (DSAD) patients; and that the increased mtDNA CR
mutation rate in DSAD brains is associated with reduced
mtDNA copy number and L-strand transcripts.
The increased mtDNA CR mutation rate is also seen in peripheral blood DNA
and in lymphoblastoid cell DNAs of AD and DSAD patients, and
distinctive somatic mtDNA mutations, often at high
heteroplasmy levels, are seen in AD and DSAD brain and blood
cells DNA. In aging, DS, and DSAD, the mtDNA mutation level
is positively correlated with beta-secretase activity and
mtDNA copy number is inversely correlated with insoluble
Abeta40 and Abeta42 levels.
Therefore, mtDNA alterations may
be responsible for both age-related dementia and the
associated neuropathological changes observed in AD and
DSAD.
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International Journal of Alzheimer's Disease
Volume 2010 (2010)
Alzheimer's Proteins, Oxidative
Stress, and Mitochondrial Dysfunction
Interplay in a
Neuronal Model of Alzheimer's Disease
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