Mitochondrial Dysfunction in Alzheimer's

10 Chronic Diseases linked to mitochondrial dysfunction

Listed below are the recent articles and published clinical studies documenting
the strong link between Mitochondrial Dysfunction and Alzheimer's.
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.

J Alzheimers Dis. 2012;
Mitochondrial dysfunction and immune activation are
detectable in early Alzheimer's disease blood.
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.

Prog Neuropsychopharmacol Biol Psychiatry.
2011 Mar 30;
Mitochondrial dysfunction and Alzheimer's disease.
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.

J Alzheimers Dis. 2010;
Systemic mitochondrial dysfunction and the etiology of
Alzheimer's disease and down syndrome dementia.
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.

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
In this paper, we discuss the interplay between beta-amyloid peptide, Tau fragments, oxidative stress, and mitochondria in the neuronal model of cerebellar granule neurons (CGNs) in which the molecular events reminiscent of AD are activated. The identification of the death route and the cause/effect relationships between the events leading to death could be helpful to manage the progression of apoptosis in neurodegeneration and to define antiapoptotic treatments acting on precocious steps of the death process.

Mitochondrial dysfunction is among the earliest events linked to AD and might play a causative role in disease onset and progression. Recent studies on CGNs have shown that adenine nucleotide translocator (ANT) impairment, due to interaction with toxic N-ter Tau fragment, contributes in a significant manner to bioenergetic failure and mitochondrial dysfunction.

These findings open a window for new therapeutic strategies aimed at preserving and/or improving mitochondrial function.