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Visualizing Changes in Mitochondria in Alzheimer’s Disease

Alzheimer’s disease (AD) presently affects more than 5 million Americans with numbers expected to grow. The specific molecular mechanisms of AD are still under investigation thereby hindering the development of effective therapies. Progressive memory decline is associated with synaptic loss and neuronal cell death. Significant hypometabolic changes can be detected early in AD patients, which suggests that abnormal energy metabolism underlies disease etiology. Mitochondria are dynamic organelles that constantly move within the cell and undergo fission and fusion (collectively termed “mitochondrial dynamics”). Such changes are important for proper responses to cellular energy demands. Fidelity of mitochondrial dynamics is especially important for the proper functioning of neurons where mitochondria need to travel over long distances to provide energy for distant parts of axons. Excessive mitochondrial fragmentation was observed in brain tissue of transgenic animal models of AD and postmortem brain from AD patients. These data suggested modulation of mitochondrial dynamics could represent novel therapeutic strategies for AD treatment. However, the understanding of the molecular mechanisms and details involved in the changes in mitochondrial morphology are incomplete and are hindered by the lack of tools that could study these dynamic changes in intact brain tissue. In an elegant study, Zhang, Salisbury, Trushina et al. used three-dimensional electron microscopy (3D EM) to look for changes in mitochondria in the brain of patients and animal models of AD. Using well-accepted transgenic mouse models of AD (and non-transgenic littermates as controls) Zhang et al. noticed differences in mitochondrial morphology in the CA1 hippocampus using standard transmission electron microscopy and super-resolution immunofluorescence. In order to better visualize these morphological changes they used 3D EM that provided a “virtual” specimen thickness of 0.9 μ m to 3.6 μ m in 10 to 40 consecutive serial sections that were stacked, aligned, and reconstructed using 3D reconstruction software (Figure 1). They identified a previously unknown mitochondrial fission arrest phenotype that results in elongated interconnected organelles that they dubbed “mitochondria-on-a-string” (MOAS). Their data suggested that MOAS formation may occur at the final stages of the fission process and was not associated