Mitochondria Dysfunction Occurs Early in Alzheimer’s Disease Prior to Memory Loss, Amyloid Deposits

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Mitochondria are specialized subunits inside a cell that produce the cell’s energy and regulate its metabolism. Research suggests that mitochondria may play a central role in neuronal cell survival because they regulate both energy metabolism and cell death pathways. Using genetic mouse models of Alzheimer’s disease, researchers from Mayo Clinic have found that mitochondria in the brain are dysfunctional early in the disease. The findings were recently published in the open access journal PLoS ONE.

Using real time imaging, scientists examined mitochondria in live neurons from three different mouse models of Alzheimer’s disease. Each of the mouse models had a different gene mutation shown to cause familial, or early-onset, Alzheimer’s disease. To evaluate the the impact of a given mutation, mitochondrial motility, distribution, ultrastructure and function in neurons and brain tissue was examined early in mouse development until the age where mice began to display memory loss and amyloid deposits formed.

Researchers used a mitochondria-specific dye and monitored axonal trafficking (i.e. motion along axons or nerve fibers). The investigators found that mitochondrial axonal trafficking is inhibited in embryonic neurons afflicted with Alzheimer’s disease, well before mice showed any memory loss or amyloid plaque formation.
Indeed, inhibition of axonal trafficking was found to be a general defect that occurred in all three mouse models of Alzheimer’s disease and was not specific for mitochondria. Nevertheless, neurons with inhibited mitochondrial trafficking were found to be more susceptible to excitotoxic cell death, a pathological process wherein nerve cells are killed by excessive neurotransmitter stimulation.

In the brains of all three mouse models of Alzheimer’s disease, mitochondria tended to lose their integrity and subsequently stopped functioning. Importantly, dysfunctional mitochondria were detected at the synapses of neurons involved in maintaining memory, suggesting a direct linkage with Alzheimer’s disease.

The scientists also applied a method called metabolomics, which measures the chemical fingerprints of specific metabolic pathways in the cell such as sugars, lipids, nucleotides, amino acids and fatty acids. The approach takes a snapshot of what is happening in the body at a given time and at a hight level of detail, and provides insight into the cellular processes that underlie a disease. For this study, the metabolomic profiles showed changes in metabolites related to mitochondrial function and cellular energy metabolism, which further confirmed that altered mitochondrial energetics is fundamental to the disease process.

The researchers identified a panel of metabolomic biomarkers. According to Eugenia Trushina, Ph.D., Mayo Clinic pharmacologist and senior investigator on the study [2]:

We are not looking at the consequences of Alzheimer’s disease, but at very early events and molecular mechanisms that lead to the disease. 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.

The researchers conclude by stating that Alzheimer’s disease can be viewed as a mitochondrial movement disorder with evolving energetic deficit represented by the panel of metabolomic biomarkers and that mitochondrial dysfunction is an underlying event in Alzheimer’s disease progression.

References

1. Trushina et al. Defects in mitochondrial dynamics and metabolomic signatures of evolving energetic stress in mouse models of familial Alzheimer’s disease. PLoS One. 2012;7(2):e32737. Epub 2012 Feb 29.
   View abstract
2. Mitochondrial Dysfunction Present Early in Alzheimer’s, Before Memory Loss. Mayo Clinic News. 2012 Feb 29.